U.S. patent application number 17/714276 was filed with the patent office on 2022-09-22 for methods of diagnosing and treating tourette syndrome.
This patent application is currently assigned to THE CHILDREN'S HOSPITAL OF PHILADELPHIA. The applicant listed for this patent is THE CHILDREN'S HOSPITAL OF PHILADELPHIA. Invention is credited to Hakon Hakonarson, Charlly Kao.
Application Number | 20220296582 17/714276 |
Document ID | / |
Family ID | 1000006379707 |
Filed Date | 2022-09-22 |
United States Patent
Application |
20220296582 |
Kind Code |
A1 |
Hakonarson; Hakon ; et
al. |
September 22, 2022 |
METHODS OF DIAGNOSING AND TREATING TOURETTE SYNDROME
Abstract
Methods and uses for diagnosing and treating Tourette syndrome
are encompassed, wherein diagnosis and treatment may be based upon
an assessment of genetic alterations in metabotropic glutamate
receptor (mGluR) network genes and wherein treatment is with
nonspecific activators of mGluRs such as fasoracetam.
Inventors: |
Hakonarson; Hakon; (Malvern,
PA) ; Kao; Charlly; (Philadelphia, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
THE CHILDREN'S HOSPITAL OF PHILADELPHIA |
Philadelphia |
PA |
US |
|
|
Assignee: |
THE CHILDREN'S HOSPITAL OF
PHILADELPHIA
Philadelphia
PA
|
Family ID: |
1000006379707 |
Appl. No.: |
17/714276 |
Filed: |
April 6, 2022 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16809045 |
Mar 4, 2020 |
11298347 |
|
|
17714276 |
|
|
|
|
15258924 |
Sep 7, 2016 |
|
|
|
16809045 |
|
|
|
|
62215628 |
Sep 8, 2015 |
|
|
|
62215633 |
Sep 8, 2015 |
|
|
|
62215636 |
Sep 8, 2015 |
|
|
|
62215673 |
Sep 8, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12Q 2600/156 20130101;
C12Q 2600/158 20130101; C12Q 1/6883 20130101; A61K 45/06 20130101;
A61K 31/454 20130101 |
International
Class: |
A61K 31/454 20060101
A61K031/454; A61K 45/06 20060101 A61K045/06; C12Q 1/6883 20060101
C12Q001/6883 |
Claims
1. A method of treating Tourette syndrome (TS) in a subject, the
method comprising administering an effective amount of fasoracetam
to the subject, wherein the fasoracetam is administered at a dose
of 50-400 mg, and wherein the dose is administered once, twice, or
three times daily, thereby treating TS.
2. The method of claim 1, wherein the subject has at least one
genetic alteration in an mGluR network gene.
3.-4. (canceled)
5. The method of claim 1, wherein the genetic alteration is a copy
number variation (CNV) or single nucleotide variation (SNV).
6. The method of claim 5, wherein the genetic alteration is a
CNV.
7. The method of claim 6, wherein the CNV is a duplication or
deletion.
8. (canceled)
9. The method of claim 1, wherein fasoracetam is fasoracetam
monohydrate (NS-105 or NFC-1).
10. The method of claim 1, wherein fasoracetam is administered at a
dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or
400 mg.
11.-18. (canceled)
19. The method of claim 1, wherein the TS is one or more of:
persistent (chronic) motor tic disorder, persistent (chronic) vocal
tic disorder, or provisional tic disorder.
20. The method of claim 1, wherein the subject is a pediatric,
adolescent, or adult subject.
21.-23. (canceled)
24. The method of claim 1, wherein the fasoracetam is administered
in combination with another pharmaceutical or non-pharmaceutical
therapy.
25. The method of claim 24, wherein the non-pharmaceutical therapy
comprises brain stimulation selected from the group consisting of
vagus nerve stimulation, repetitive transcranial magnetic
stimulation, magnetic seizure therapy, and deep brain
stimulation.
26. The method of claim 24, wherein the fasoracetam is administered
in combination with an antipsychotic agent.
27. The method of claim 1, wherein tic symptoms are reduced in the
subject following at least 1, 2, 3, or 4 weeks of treatment with
fasoracetam.
28. The method of claim 27, wherein the tic symptoms comprise
frequency and/or degree of movement.
29. The method of claim 1, wherein symptoms of inattentiveness,
hyperactivity, and/or impulsiveness are reduced in the subject
following at least 1, 2, 3, or 4 weeks of treatment with
fasoracetam.
30. The method of claim 1, wherein the subject also has obsessive
compulsive disorder (OCD).
31. The method of claim 30, wherein symptoms of obsessive
compulsive disorder (OCD) are reduced in the subject following at
least 1, 2, 3, or 4 weeks of treatment with fasoracetam.
32.-50. (canceled)
51. The method of claim 1, wherein the subject has TS as well as
schizophrenia.
52. The method of claim 1, wherein the subject has TS as well as
ADHD.
53. (canceled)
54. The method of claim 1, wherein the subject does not have one or
more of ADHD, schizophrenia, conduct disorder, anxiety disorder,
autism, a mood disorder, phobia, OCD, or depression.
55. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 16/809,045, filed Mar. 4, 2020, which is a continuation of
U.S. patent application Ser. No. 15/258,924, filed Sep. 7, 2016,
which claims priority to the following four United States
Provisional Patent Applications, each filed on Sep. 8, 2015:
62/215,628; 62/215,633; 62/215,636; and 62/215,673. The entire
disclosure of each of the aforesaid applications is incorporated
herein by reference in its entirety.
FIELD
[0002] This application relates to the treatment of Tourette
syndrome with nonselective activators of metabotropic glutamate
receptors (mGluRs) and of diagnosis and treatment of Tourette
syndrome in subjects having genetic alterations, such as copy
number variations (CNVs), in one or more mGluR network genes.
BACKGROUND
[0003] Tourette syndrome (TS) is a neurologic disorder that is
characterized by tics, which are involuntary vocalizations or
repetitive, purposeless movements. It is estimated that up to
200,000 Americans have the most severe form of TS, and as many as
one in 100 Americans show milder and less complex TS symptoms that
may include chronic motor or vocal tics, see NIH Handbook on
Tourette Syndrome (2012). The prevalence of TS is estimated to be
0.3% in US children aged 6-17 years, although there are suggestions
that this may be an underestimation of its prevalence, see Cohen S,
et al. Neurosci Biobehav Rev. 37(6): 997-1007 (2013).
[0004] The onset of symptoms of TS is usually between 3 and 9 years
of age, with approximately 3-4 times more males affected than
females. For many patients, TS is a chronic, lifetime disease with
a peak of symptoms in the teen years. Simple tics in TS may include
eye blinking, head jerking, or repetitive grunting, while complex
tics involve several muscle groups and can include hopping,
twisting, or vocalization of words or phrases. Tics can be
disabling, such as those that involve hitting oneself, swearing, or
repeating the words or phrases of others. It is estimated that
10%-15% of patients with TS have a progressive or disabling disease
course that lasts into adulthood, see NIH Handbook on Tourette
Syndrome (2012).
[0005] In addition to tics, patients with TS often experience other
neurobehavioral symptoms such as hyperactivity and impulsivity
(such as attention deficit hyperactivity disorder [ADHD]),
difficulties with reading and schoolwork, obsessive-compulsive
thoughts, and repetitive behaviors. It has been estimated that 90%
of patients with TS suffer from comorbid neuropsychiatric
disorders, most commonly ADHD and obsessive-compulsive disorder
(OCD) (Cohen 2013).
[0006] Individuals affected by both TS and ADHD are at a much
greater risk for academic and social impairment.
[0007] Diagnosis of TS may be based on patient history and presence
of tics for a sustained period. In children and adolescents, the
Yale Global Tic Severity Scale may be used as a clinician rating of
tic severity, which evaluates the number, frequency, intensity,
complexity, and interference of motor and vocal tics, see Storch et
al., Psychol. Assessment. 17(4):486-491. Because of the high
incidence of OCD in patients with TS, the Children's Yale-Brown
Obsessive Compulsive Scale may be used to evaluate
obsessive-compulsive symptoms severity in children and adolescents
with TS, see Scahill et al, J Am. Acad. Child Adolesc. Psychiatry.
36(6):844-852 (1997).
[0008] There is currently no medication that is helpful to all
patients with TS. While neuroleptic drugs (i.e., antipsychotics)
have been effective for treatment of tics in some patients, these
medications are associated with significant side effects, and these
medications do not entirely eliminate tic symptoms. In addition,
treatment of neurobehavioral disorders associated with TS, such as
ADHD, may be complicated as some medications used to treat ADHD are
contraindicated in patients with TS (see Prescribing Information
for Ritalin) (2013). Therefore, new treatments are needed to treat
the spectrum of symptoms of TS, including tics and neurobehavioral
disorders.
SUMMARY
[0009] In accordance with the description, the inventors have
studied the genotypes of over 90 patients diagnosed with Tourette
syndrome (TS) and have found that these patients possess genetic
alterations in one or more metabotropic glutamate receptor (mGluR)
network genes at a significantly higher frequency than historical
control patients. The frequency of genetic alterations in mGluR
network genes was substantially higher in this TS population than
in control populations that did not have other neuropsychological
disorders.
[0010] Thus, provided herein are methods of treating TS in a
subject comprising administering an effective amount of a
nonselective activator of metabotropic glutamate receptors (mGluRs)
to a subject, thereby treating TS. In some embodiments the subject
has at least one genetic alteration in an mGluR network gene, such
as a copy number variation (CNV). In some embodiments, the subject
to be treated has been diagnosed with TS by any method known in the
art for diagnosing TS, including meeting the criteria in the
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
(DSM-V) for a diagnosis of Tourette's Syndrome. In some
embodiments, a diagnosis of TS is made when it is discovered that
the subject has at least one genetic alteration in an mGluR network
gene. In some embodiments, a diagnosis of TS is made when it is
discovered that the subject has at least one genetic alteration in
an mGluR network gene and when the subject has at least one symptom
of TS including, but not limited to, a motor tic, a vocal tic, a
motor and vocal tic.
[0011] Also provided herein are methods of treating TS comprising
administering an effective amount of a nonselective activator of
metabotropic glutamate receptors (mGluRs) to a subject that has at
least one genetic alteration in an mGluR network gene, such as a
CNV, thereby treating TS. In some embodiments, where the subject
has a CNV in an mGluR network gene, the CNV is a duplication or
deletion.
[0012] In some embodiments, the invention comprises a method a
subject having a motor and/or vocal tic comprising administering an
effective amount of a nonselective activator of metabotropic
glutamate receptors (mGluRs), thereby treating TS. In some
embodiments, the subject also has at least one genetic alteration
in an mGluR network gene.
[0013] Also provided are methods of treating TS in a subject
comprising obtaining results from a genetic screen that determines
whether a subject has a genetic alteration in an mGluR network
gene, and, if the results show that the subject has at least one
genetic alteration in an mGluR network gene, treating the subject
by administering an effective amount of a nonselective activator of
mGluRs.
[0014] In some embodiments of the above methods, the nonselective
activator of mGluRs is fasoracetam, such as fasoracetam monohydrate
(NS-105 or NFC-1). In some embodiments the fasoracetam is
administered at a dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg,
300 mg, 350 mg, or 400 mg, wherein the dose is administered once,
twice, or three times daily. In some embodiments, fasoracetam is
administered at a dose of 50-400 mg, 100-400 mg, or 200-400 mg, and
administered once, twice, or three times daily. In some
embodiments, the fasoracetam is administered at a dose of 200-400
mg, such as 200 mg, 300 mg, or 400 mg, and administered twice
daily.
[0015] In some embodiments the method comprises considering results
of a screen to determine whether the subject has a genetic
alteration such as a CNV in an mGluR network gene. In some
embodiments of the above methods, the subject has a CNV in at least
1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mGluR network genes. In some
embodiments a CNV in an mGluR network gene is determined by
obtaining a nucleic acid-comprising sample from the subject and
subjecting the sample to a screen that assesses CNVs in at least 5,
6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, or all of Tier 1 mGluR
network genes. In some embodiments a CNV in an mGluR network gene
is determined by obtaining a nucleic acid-comprising sample from
the subject and subjecting the sample to a screen that assesses
CNVs in at least 50, at least 100, at least 150, at least 175, or
all of Tier 2 mGluR network genes. In some embodiments a CNV in an
mGluR network gene is determined by obtaining a nucleic acid sample
from the subject and subjecting the sample to a screen that
assesses CNVs in at least 50, at least 100, at least 200, at least
300, at least 400, at least 500, or all of Tier 3 mGluR network
genes. In some embodiments the screen does not assess CNVs in one
or more of GRM1, GRM2, GRM3, GRM4, GRM5, GRM6, GRM7, or GRM8. In
certain embodiments the subject does not have a CNV in one or more
of GRM1, GRM2, GRM3, GRM4, GRM5, GRM6, GRM7, or GRM8.
[0016] In some embodiments of the above methods, the TS is one or
more of persistent (chronic) motor tic disorder, persistent
(chronic) vocal tic disorder, or provisional tic disorder. In some
embodiments, the methods reduce the frequency and/or severity of
tics in the subject. In some embodiments, the methods reduce other
behavioral symptoms such as inattentiveness, hyperactivity, and/or
impulsiveness. In some embodiments, the methods also comprise
assessing symptoms such as the frequency, type (e.g. verbal or
motor), and/or severity of tics in the subject, as well as
inattentiveness, hyperactivity, and/or impulsiveness during or
after administration, for example, to determine if one or more of
these symptoms has been reduced in the subject. In some methods,
such assessment may be performed based on the Yale-Brown Pediatric
Obsessive-Compulsive Scale and/or the Tourette's Clinical Rating
Scale. In some embodiments, the methods further comprise obtaining
a clinical global impression of severity or improvement for the
subject during or after administration. In some embodiments, the
methods may improve clinical global improvement (CGI) scores in the
subject.
[0017] In some embodiments the subject is a pediatric or adolescent
subject, such as between the ages of 5 and 17, 5 and 8, 8 and 17, 8
and 12, 12 to 18, 13 to 18, or 12 and 17. In other embodiments the
subject is an adult.
[0018] In some embodiments of the above methods, the nonselective
activator of mGluRs is administered in combination with another
pharmaceutical, such as an antipsychotic agent, or
non-pharmaceutical therapy. The non-pharmaceutical therapy may
comprise brain stimulation, such as vagus nerve stimulation,
repetitive transcranial magnetic stimulation, magnetic seizure
therapy, or deep brain stimulation.
[0019] In some embodiments, tic symptoms in the TS subject, such as
frequency of tics or degree of movement for movement-based tics or
the intensity of language-based tics, are reduced in the subject.
In some embodiments, symptoms of inattentiveness, hyperactivity,
and/or impulsiveness are reduced in the subject.
[0020] Also provided herein are methods for diagnosing TS in a
subject comprising isolating a nucleic-acid comprising sample from
a subject, analyzing the sample for the presence or absence of a
genetic alteration in at least one mGluR network genes, and
diagnosing TS if the subject has at least one genetic alteration in
a mGluR network gene. Also provided are methods for diagnosing TS
in a subject comprising isolating a nucleic-acid comprising sample
from a subject, isolating nucleic acid from the sample, analyzing
the nucleic acid for the presence or absence of a genetic
alteration in at least one mGluR network genes, and diagnosing TS
if the subject has at least one genetic alteration in a mGluR
network gene. Provided as well are methods for identifying a
subject as having TS comprising obtaining a sample from a patient,
optionally isolating nucleic acid from the sample, optionally
amplifying the nucleic acid, and analyzing the nucleic acid in the
sample for the presence or absence of a genetic alteration, such as
a CNV, in at least one mGluR network gene, wherein the subject is
identified as having TS if at least one genetic alteration, such as
a CNV, in an mGluR network gene is detected. Additionally, provided
are methods for diagnosing TS in a subject comprising analyzing
genetic information about one or more mGluR network genes,
comparing the subject's information to a control subject that does
not have TS, and diagnosing TS if the genetic information suggests
that the subject has at least one genetic alteration in an mGluR
network gene.
[0021] Provided herein also are methods of confirming a diagnosis
of TS in a subject comprising: obtaining a nucleic acid-comprising
sample from a subject diagnosed with TS by a method that does not
comprise detecting or analyzing genetic alterations in mGluR
network genes; optionally amplifying the nucleic acid in the
sample; and determining whether the subject has at least one
genetic alteration, such as a CNV, in an mGluR network gene, and
confirming a diagnosis of TS if the subject has at least one
genetic alteration in an mGluR network gene.
[0022] In any of the above methods, the analysis for the presence
or absence of at least one genetic alteration in an mGluR network
gene may comprise microarrays, whole genome sequencing, exome
sequencing, targeted sequencing, FISH, comparative genomic
hybridization, genome mapping, or other methods using
next-generation sequencing, Sanger sequencing, PCR, or TaqMan
technologies.
[0023] In some embodiments, the subject has CNVs in one, two, or
more mGluR network genes. In some embodiments, the methods comprise
detecting CNVs in mGluR network genes by subjecting the sample to a
screen that assesses CNVs in at least 2, 3, 4, 5, 6, 7, 8, 9, or 10
mGluR network genes. In some embodiments, CNVs in mGluR network
genes are determined by subjecting the sample to a screen that
assesses CNVs in at least 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50,
60, 70, or all of Tier 1 mGluR network genes. In some embodiments,
CNVs in mGluR network genes are determined by subjecting the sample
to a screen that assesses CNVs in at least 50, at least 100, at
least 150, at least 175, or all of Tier 2 mGluR network genes. In
some embodiments, CNVs in mGluR network genes are determined by
subjecting the sample to a screen that assesses CNVs in at least
50, at least 100, at least 200, at least 300, at least 400, at
least 500, or all of Tier 3 mGluR network genes.
[0024] In some embodiments of the above methods, the TS is one or
more of persistent (chronic) motor tic disorder, persistent
(chronic) vocal tic disorder, or provisional tic disorder. In some
embodiments, the subject is a pediatric or adolescent subject, such
as a subject between the ages of 5 and 17, 5 and 8, 8 and 17, 8 and
12, 12 to 18, 13 to 18, or 12 and 17. In other embodiments, the
subject is an adult subject.
[0025] In some embodiments, the screening method for determining
the presence or absence of at least one mGluR network gene genetic
alteration comprises microarrays, whole genome sequencing, exome
sequencing, targeted sequencing, FISH, comparative genomic
hybridization, genome mapping, or other methods using
next-generation sequencing, Sanger sequencing, PCR, or TaqMan
technologies.
[0026] In some embodiments, the subject is not assessed for genetic
alterations or CNVs in one or more of GRM1, GRM2, GRM3, GRM4, GRM5,
GRM6, GRM7, and GRM8. In some embodiments, the subject does not
have CNVs in one or more of GRM1, GRM2, GRM3, GRM4, GRM5, GRM6,
GRM7, and GRM8. In some embodiments, the subject does not have CNVs
in any of GRM1, GRM2, GRM3, GRM4, GRM5, GRM6, GRM7, and GRM8.
[0027] In any of the methods and embodiments described in the
preceding paragraphs of this Summary, the subject may have TS as
well as one or more comorbid conditions such as attention-deficit
hyperactivity disorder (ADHD), oppositional defiant disorder (ODD),
conduct disorder, anxiety disorder, autism, a mood disorder,
schizophrenia, obsessive compulsive disorder (OCD), difficulty
controlling anger, disruptive behavior symptoms, dermatillomania, a
developmental disorder, a co-morbid movement disorder, or
depression. In other cases, the subject does not have one or more
of ADHD, ODD, conduct disorder, anxiety disorder, phobia, autism, a
mood disorder, schizophrenia, or depression. In yet other cases,
the subject does not have any of ADHD, ODD, conduct disorder,
anxiety disorder, phobia, autism, a mood disorder, schizophrenia,
obsessive compulsive disorder (OCD), difficulty controlling anger,
disruptive behavior symptoms, dermatillomania, a developmental
disorder, a co-morbid movement disorder, or depression.
[0028] In one embodiment, a method for diagnosing an
mGluR-associated disorder is provided, wherein a subject is
diagnosed with an mGluR-associated disorder if at least one genetic
alteration in an mGluR network gene is detected.
[0029] Additional objects and advantages will be set forth in part
in the description which follows, and in part will be obvious from
the description, or may be learned by practice. The objects and
advantages will be realized and attained by means of the elements
and combinations particularly pointed out in the appended
claims.
[0030] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the claims.
[0031] The accompanying drawings, which are incorporated in and
constitute a part of this specification, illustrate one (several)
embodiment(s) and together with the description, serve to explain
the principles described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIGS. 1A-1D show the mGluR network genes included in the
Tier 1 gene set. These genes have 2 degrees of protein-protein
interaction with mGluR genes (GRM1-8) based on the Cytoscape Human
Interactome, which is software for integrating biomolecular
interaction networks with high-throughput data (as described in
Shannon P (2003) Genome Research 13:2498-2504). The Tier 1 gene set
includes 76 genes. The exact location for each gene in Tier 1 is
listed in both the Human Genome version 18 (hg18) and Human Genome
version 19 (hg19). In addition, the exact gene location plus 500
kilobase (i.e., the range from 500 kilobase before and 500 kilobase
after the gene of interest) is listed for hg19. The start single
nucleotide polymorphism (StartSNP) (i.e., the SNP located 500
kilobases before the gene of interest) and the EndSNP (i.e., the
SNP located 500 kilobases after the gene of interest) are also
listed. Genes of the mGluRs themselves are noted as "GRM." The
expanded regions (i.e., 500 kg up and down stream) frequently
harbor regulatory elements and if impacted by a CNV, can have the
same impact on the gene expression and function as a CNV residing
in the gene sequence itself.
[0033] FIGS. 2A-2J show the mGluR network genes included in the
Tier 2 gene set. These genes have 2 degrees of protein-protein
interaction with mGluR genes (GRM1-8) based on the Cytoscape Human
Interactome but exclude genes from Tier 1. The Tier 2 gene set
includes 197 genes. The exact location for each gene in Tier 2 is
listed in both the Human Genome version 18 (hg18) and Human Genome
version 19 (hg19). In addition, the exact gene location plus 500
kilobase (i.e., the range from 500 kilobase before and 500 kilobase
after the gene of interest) is listed for hg19. The start single
nucleotide polymorphism (StartSNP) (i.e., the SNP located 500
kilobases before the gene of interest) and the EndSNP (i.e., the
SNP located 500 kilobases after the gene of interest) in hg19 are
also listed.
[0034] FIGS. 3A-3AC show genes within the Tier 3 gene set. Genes
with reciprocal gene querying with 2 degrees of protein-protein
interaction with mGluR genes based on Cytoscape Human Interactome
are included. Genes contained within Tiers 1 and 2 are excluded
from Tier 3. The Tier 3 gene set includes 599 genes. The exact
location for each gene in Tier 3 is listed in both the Human Genome
version 18 (hg18) and Human Genome version 19 (hg19). In addition,
the exact gene location plus 500 kilobase (i.e., the range from 500
kilobase before and 500 kilobase after the gene of interest) is
listed for hg19. The StartSNP (i.e., the SNP located 500 kilobases
before the gene of interest) and the EndSNP (i.e., the SNP located
500 kilobases after the gene of interest) in hg19 are also
listed.
[0035] FIG. 4 shows the number of copy number variation (CNV) calls
containing an mGluR network gene within the samples from the 95 TS
patients who were fully genotyped. Note that some patients had more
than one CNV call that contained an mGluR network gene.
[0036] FIG. 5 shows the percentage of fully-genotyped patients with
TS who had a CNV within Tier 1, Tiers 1+2, or Tiers 1+2+3 mGluR
network gene sets.
DESCRIPTION OF THE EMBODIMENTS
I. Definitions
[0037] In addition to definitions included in this sub-section,
further definitions of terms are interspersed throughout the
text.
[0038] In this invention, "a" or "an" means "at least one" or "one
or more," etc., unless clearly indicated otherwise by context. The
term "or" means "and/or" unless stated otherwise. In the case of a
multiple-dependent claim, however, use of the term "or" refers back
to more than one preceding claim in the alternative only.
[0039] An "mGluR" or metabotropic glutamate receptor refers to one
of eight glutamate receptors expressed in neural tissue named
mGluR1, mGluR2, mGluR3, mGluR4, mGluR5, mGluR6, mGluR7, and mGluR8.
Their genes are abbreviated GRM1 to GRM8. The mGluR proteins are
G-protein-coupled receptors. They are typically placed into three
sub-groups, Group I receptors including mGluR1 and mGluR5 are
classed as slow excitatory receptors. Group II includes mGluR2 and
mGluR3. Group III includes mGluR4, mGluR6, mGluR7, and mGluR8.
Groups II and III are classed as slow inhibitory receptors. The
mGluRs are distinguished from the ionotropic GluRs or iGluRs, which
are ion channel-associated glutamate receptors and are classed as
fast excitatory receptors.
[0040] An "mGluR network gene," for purposes of this invention,
comprises not only the mGluR genes GRM1, GRM2, GRM3, GRM4, GRM5,
GRM6, GRM7, and GRM8, but also each of the other genes listed
herein in FIGS. 1-3 as well as the regions of DNA that regulate the
genes listed in FIGS. 1-3. In addition, "mGluR network proteins"
are the proteins encoded by the mGluR network genes.
[0041] The mGluR network genes are grouped into three subsets: Tier
1, Tier2, and Tier 3. (See FIGS. 1-3.) Tier 1 mGluR network genes,
shown in FIG. 1, comprise 76 genes, including some GRM genes
themselves as well as a number of other genes. The Tier 2 mGluR
network genes, shown in FIG. 2, comprise 197 genes, and exclude the
Tier 1 genes.
[0042] Tiers 1 and 2 together are included in the "primary mGluR
network." The "primary network" of mGluR genes also includes the
genes 4-Sep, LOC642393, and LOC653098, for a total of 276 genes.
There are presently technical difficulties in assessing the 4-Sep,
LOC642393, and LOC653098 genes. Thus, they are not included in the
genes of Tiers 1 and 2, although they are included in the primary
network of genes of the present invention. The genes of Tier 1 and
Tier 2 differ in that alterations in Tier 1 genes had been
documented in previous genotyping studies of subjects suffering
from mental disorders.
[0043] Tier 3 mGluR network genes, shown in FIG. 3, comprise 599
genes that are in the distal part of the mGluR network based on the
merged human interactome provided by the Cytoscape Software
(Shannon P et al. (2003) Genome Research 13:2498-2504), and exclude
the Tier 1 and Tier 2 genes. The Tier 3 genes are thus part of the
"distal mGluR network." In addition to the Tier 3 genes, the genes
LOC285147, LOC147004, and LOC93444 are included in the "distal
mGluR network," although they were not assessed in the present
study and are not included in Tier 3 due to technical difficulties
in assessing genetic alterations in these genes.
[0044] A "genetic alteration" as used herein means any alteration
in the DNA of a gene, or in the DNA regulating a gene. A genetic
alteration, for example, may result in a gene product that is
functionally changed as compared to a gene product produced from a
non-altered DNA. A functional change may be differing expression
levels (up-regulation or down-regulation) or loss or change in one
or more biological activities, for example. A genetic alteration
includes without limitation, copy number variations (CNVs), single
nucleotide variants (SNVs), also called single nucleotide
polymorphisms (SNPs) herein, frame shift mutations, or any other
base pair substitutions, insertions, and deletions or
duplications.
[0045] A "copy number variation" or "CNV" is a duplication or
deletion of a DNA segment encompassing a gene, genes, segment of a
gene, or DNA region regulating a gene, as compared to a reference
genome. In some embodiments, a CNV is determined based on variation
from a normal diploid state. In some embodiments, a CNV represents
a copy number change involving a DNA fragment that is 1 kilobase
(kb) or larger. CNVs described herein do not include those variants
that arise from the insertion/deletion of transposable elements
(e.g., 6-kb KpnI repeats). The term CNV therefore encompasses terms
such as large-scale copy number variants (LCVs; Iafrate et al.
2004), copy number polymorphisms (CNPs; Sebat et al. 2004), and
intermediate-sized variants (ISVs; Tuzun et al. 2005), but not
retrotransposon insertions.
[0046] A "CNV deletion" or "deletion CNV" or similar terms refer to
a CNV in which a gene, DNA segment regulating a gene, or gene
segment is deleted. A "CNV duplication" or "duplication CNV" or
similar terms refer to a CNV in which a gene, DNA segment
regulating a gene, or gene segment is present in at least two, and
possibly more than two, copies in comparison with the single copy
found in a normal reference genome.
[0047] A "sample" refers to a sample from a subject that may be
tested, for example, for presence of a CNV in one or more mGluR
network proteins, as described herein. The sample may comprise
cells, and it may comprise body fluids, such as blood, serum,
plasma, cerebral spinal fluid, urine, saliva, tears, pleural fluid,
and the like.
[0048] Tourette syndrome is described in the Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5 2013)
as a disorder characterized by the presence of both multiple motor
and one or more vocal tics with symptoms that have persisted for
more than one year. Tics are sudden, rapid, recurrent, nonrhythmic
motor movement or vocalization. Typically, symptoms appear before
age 18. The term "Tourette syndrome" as used herein includes each
of: "persistent (chronic) motor tic disorder," "persistent
(chronic) vocal tic disorder," "provisional tic disorder," and "tic
disorder." A Tourette syndrome patient may have both motor and
vocal tic symptoms that have been present for at least a year. A
patient with a "tic disorder," however, may have only motor or only
vocal tics. A patient with "persistent (chronic) motor tic
disorder" may have only motor tics. A patient with "persistent
(chronic) vocal tic disorder" may have only vocal tics. A patient
with "provisional tic disorder" may have symptoms for less than one
year.
[0049] Patients with TS may also have inattention, hyperactivity,
anxiety, mood, and sleep disturbances. Currently, TS may be
diagnosed using one or more rating scales, such as, Yale Global Tic
Severity Scale, as described in Storch 2005.
[0050] The terms "subject" and "patient" are used interchangeably
to refer to a human.
[0051] The terms "pediatric subject" or "pediatric patient" are
used interchangeably to refer to a human less than 18 years of age.
An "adult patient" or "adult subject" refers to a human 18 years of
age or older. An "adolescent patient" or "adolescent subject" is a
subject typically about 12 to 18, such as 12 to 17 or 13 to 18,
years old.
II. Methods of Diagnosing Tourette's Syndrome
[0052] In some embodiments, the invention comprises a method of
diagnosing TS in a subject comprising analyzing the genetic
information of the subject to determine whether the subject has a
genetic variation in at least one mGluR network gene, and
diagnosing the subject as having TS if a genetic variation is
found. In some embodiments, the subject has TS but does not have
ADHD, oppositional defiant disorder (ODD), conduct disorder,
anxiety disorder, phobia, autism, a mood disorder, schizophrenia,
obsessive compulsive disorder (OCD), difficulty controlling anger,
disruptive behavior symptoms, dermatillomania, another movement
disorder, a developmental disorder, or depression. In some
embodiments, the subject has TS and also one or more of ADHD,
conduct disorder, anxiety disorder, phobia, autism, a mood
disorder, schizophrenia, obsessive compulsive disorder (OCD),
difficulty controlling anger, disruptive behavior symptoms,
dermatillomania, another movement disorder, a developmental
disorder, and depression. In some embodiments, the subject has both
TS and ADHD.
[0053] "Developmental disorders" herein include, for example, those
classified under the International Classification of Diseases
9.sup.th Ed. (World Health Organization) under codes 299.80,
299.90, 315.2, 315.39, 315.4, 315.5, 315.8, and 315.9, and may
affect behaviors such as learning, coordination, and speech.
"Dermatillomania" is also called skin picking disorder or
excoriation, and is a disorder involving excessive picking at one's
own skin to the extent of causing damage, and includes picking at
normal skin as well as at real or imagined skin defects such as
moles, freckles, or acne.
[0054] In other embodiments, the invention encompasses confirming a
diagnosis of TS in a subject. As used herein, "confirming a
diagnosis of TS" means diagnosing a subject who has already been
diagnosed with TS. In some embodiments, the method of confirming a
diagnosis of TS comprises analyzing the genetic information of a
subject that has been diagnosed as having TS by a method that does
not comprise analyzing mGluR network genes, to determine whether
the subject has a genetic variation in at least one mGluR network
gene, and confirming the diagnosis of TS if a genetic variation in
at least one mGluR network gene is found. In some embodiments, a
screen for the presence of mGluR network gene variations is one of
two or more tests or evaluations that are performed to confirm a
diagnosis in a subject. In some embodiments, the subject has TS but
does not have ADHD, ODD, conduct disorder, anxiety disorder,
phobia, autism, a mood disorder, or depression. In some
embodiments, the subject has TS and also one or more of ADHD, ODD,
conduct disorder, anxiety disorder, autism, a mood disorder,
phobia, and depression. In some embodiments the subject has both TS
and ADHD.
[0055] In other embodiments, the invention comprises confirming a
diagnosis of TS in a subject who does not have ADHD, ODD, conduct
disorder, anxiety disorder, autism, a mood disorder, phobia, or
depression, comprising analyzing the genetic information of a
subject that has been diagnosed as having TS by a method that does
not comprise analyzing mGluR network genes, to determine whether
the subject has a genetic variation in at least one mGluR network
gene, and confirming the diagnosis of TS if a genetic variation in
at least one mGluR network gene is found.
[0056] In one embodiment, TS is diagnosed and/or confirmed if at
least one CNV, SNV, frameshift mutation, or any other base pair
substitution, insertion, deletion or duplication in an mGluR
network gene is detected. In other embodiments, TS is diagnosed
and/or confirmed if at least one CNV, SNV, frameshift mutation, or
any other base pair substitution, insertion, or deletion in a Tier
1 mGluR network gene is detected. In another embodiment, TS is
diagnosed and/or confirmed if at least one CNV, SNV, frameshift
mutation, or any other base pair substitution, insertion, or
deletion in a Tier 2 mGluR network gene is detected. In still other
embodiments, TS is diagnosed and/or confirmed if at least one CNV,
SNV, frameshift mutation, or any other base pair substitution,
insertion, or deletion in a Tier 3 mGluR network gene is
detected.
[0057] A diagnosis or confirmation of diagnosis of TS may be based
or confirmed on finding a genetic alteration in a Tier 1, Tier 2,
and/or Tier 3 mGluR network gene. The genetic alteration may be a
CNV. The CNV may be a duplication or deletion of a region of DNA
that contains some or all of the DNA encoding and
controlling/regulating an mGluR network gene. In another
embodiment, the diagnosis or confirmation of diagnosis of TS is
made in a patient who does not have ADHD, ODD, conduct disorder,
anxiety disorder, autism, a mood disorder, phobia, or depression.
In some embodiments, the diagnosis or confirmation of diagnosis of
TS is made in a patient who has TS as well as one or more of ADHD,
ODD, conduct disorder, anxiety disorder, autism, a mood disorder,
autism, a mood disorder, phobia, and depression.
[0058] In some embodiments, the diagnosis or confirmation of
diagnosis of TS is based on a finding that the copy number of an
mGluR network gene deviates from the normal diploid state. In some
embodiments, the diagnosis or confirmation of diagnosis of TS is
based on a copy number of zero or one, which indicates a CNV
deletion. In some embodiments, the diagnosis or confirmation of
diagnosis of TS is based on a copy number of three or greater,
which indicates a CNV duplication. In another embodiment, the
diagnosis or confirmation of diagnosis of TS is made in a patient
who does not have ADHD, ODD, conduct disorder, anxiety disorder,
autism, a mood disorder, phobia, or depression by the presence of a
copy number of zero or one, by a copy number of three or greater,
or by any deviation from the diploid state.
[0059] In one embodiment, a more severe form of TS is diagnosed if
at least two CNVs in mGluR network genes are detected. In one
embodiment, a more severe form of TS in a patient who does not have
ADHD, ODD, conduct disorder, anxiety disorder, autism, a mood
disorder, phobia, or depression is diagnosed if at least two CNVs
in mGluR network genes are detected.
[0060] In one embodiment, a method of diagnosing and/or confirming
TS comprises: obtaining a nucleic acid-containing sample from a
subject, optionally amplifying the nucleic acid; optionally
labeling the nucleic acid sample; applying the nucleic acid to a
solid support that comprises one or more nucleic acids of mGluR
network genes, wherein the nucleic acids optionally comprise SNVs
of mGluR network genes; removing any unbound nucleic acid sample;
and detecting any nucleic acid that has bound to the nucleic acid
on the solid support, wherein the subject is diagnosed or confirmed
as having TS if bound nucleic acids are detected. In one embodiment
the method further comprises comparing any bound nucleic acids to a
standard or control and diagnosing or confirming TS if the analysis
finds that the test sample is different from the control or
standard. In another embodiment of this method, the patient with TS
does not have ADHD, ODD, conduct disorder, anxiety disorder,
autism, a mood disorder, autism, a mood disorder, phobia, or
depression. In another embodiment, the TS patient also has one or
more of ADHD, ODD, conduct disorder, anxiety disorder, autism, a
mood disorder, phobia, or depression.
[0061] In each diagnostic, confirming, and treatment method of the
invention, the disorder may be TS, persistent (chronic) vocal tic
disorder, persistent (chronic) motor tic disorder, or provisional
tic disorder. In each diagnostic, confirming, and treatment method
of the invention, the subject has TS but not any of ADHD, ODD,
conduct disorder, anxiety disorder, autism, a mood disorder,
phobia, or depression. In other diagnostic, confirming, and
treatment methods of the invention, the subject has TS and one or
more additional disorders such as ADHD, conduct disorder, anxiety
disorder, autism, a mood disorder, phobia, or depression. In some
methods, the subject has both TS and ADHD.
III. Methods and Uses for Treating Tourette's Syndrome
[0062] Encompassed herein are methods of treating TS in a subject
comprising administering an effective amount of a nonselective
mGluR activator. The term "treatment," as used herein, includes any
administration or application of a therapeutic for a disease or
disorder in a subject, and includes inhibiting the disease,
arresting its development, relieving the symptoms of the disease,
or preventing occurrence or reoccurrence of the disease or symptoms
of the disease.
[0063] The mGluR proteins are typically placed into three
sub-groups, group I receptors including mGluR1 and mGluR5 are
classed as slow excitatory receptors. Group II includes mGluR2 and
mGluR3. Group III includes mGluR4, mGluR6, mGluR7, and mGluR8.
Groups II and III are classed as slow inhibitory receptors.
[0064] The mGluRs are distinguished from the ionotropic GluRs or
iGluRs, which are ion channel-associated glutamate receptors and
are classed as fast excitatory receptors.
[0065] A "nonselective activator of mGluRs" refers to a molecule
that activates mGluRs from more than one of the group I, II, and
III categories. Thus, a nonselective activator of mGluRs may
provide for a general stimulation of the mGluR networks. This is in
contrast to specific mGluR activators that may only significantly
activate a single mGluR, such as mGluR5, for example. Nonselective
mGluR activators include, for example, nonselective mGluR
agonists.
[0066] In some embodiments, the nonselective mGluR activator is
fasoracetam. Fasoracetam is a nootropic (i.e., cognitive-enhancing)
drug that can stimulate both group I and group II/III mGluRs in in
vitro studies. (See Hirouchi M, et al. (2000) European Journal of
Pharmacology 387:9-17.) Fasoracetam may stimulate adenylate cyclase
activity through activation of group I mGluRs, while it may also
inhibit adenylate cyclase activity by stimulating group II and III
mGluRs. (Oka M, et al (1997) Brain Research 754:121-130.)
Fasoracetam has been observed to be highly bioavailable (79%-97%)
with a half-life of 5-6.5 hours in prior human studies (see Malykh
A G, et al. (2010) Drugs 70(3):287-312). Fasoracetam is a member of
the racetam family of chemicals that share a five-carbon
oxopyrrolidone ring.
[0067] The structure of fasoracetam is:
##STR00001##
[0068] The term "fasoracetam" as used herein encompasses
pharmaceutically acceptable hydrates and any solid state,
amorphous, or crystalline forms of the fasoracetam molecule. For
example, the term fasoracetam herein includes forms such as NFC-1:
fasoracetam monohydrate. In addition to NFC-1, fasoracetam is also
known as C-NS-105, NS105, and LAM-105.
[0069] NFC-1 has been previously studied in Phase I-III clinical
trials in dementia-related cognitive impairment but did not show
sufficient efficacy in dementia in Phase III trials. These trials
demonstrated that NFC-1 was generally safe and well tolerated for
those indications. Phase III data indicated that NFC-1 showed
beneficial effects on psychiatric symptoms in cerebral infarct
patients and adult dementia patients with cerebrovascular
diseases.
[0070] In each of the method of treatment embodiments, a
metabotropic glutamate receptor positive allosteric modulator, a
metabotropic glutamate receptor negative allosteric modulator, or a
tachykinin-3/neurokinin-3 receptor (TACR-3/NK3R) antagonist may be
administered alone or in combination with a nonselective activator
of mGluRs to a subject, for example, having an alteration in an
mGluR network gene. In some embodiments, the treatment agent
comprises ADX63365, ADX50938, ADX71149, AMN082, a
1-(hetero)aryl-3-amino-pyrrolidine derivative, LY341495, ADX48621,
GSK1144814, or SB223412.
[0071] Also encompassed herein are methods of treating TS
comprising administering fasoracetam to a subject that has a
genetic alteration in at least one mGluR network gene. In some
embodiments, this subject has TS but does not have ADHD, ODD,
conduct disorder, anxiety disorder, autism, a mood disorder,
phobia, schizophrenia, obsessive compulsive disorder (OCD),
difficulty controlling anger, disruptive behavior symptoms,
dermatillomania, another movement disorder, a developmental
disorder, or depression, while in other embodiments, the subject
has TS as well as at least one of ADHD, ODD, conduct disorder,
anxiety disorder, autism, a mood disorder, phobia, schizophrenia,
obsessive compulsive disorder (OCD), difficulty controlling anger,
disruptive behavior symptoms, dermatillomania, another movement
disorder, a developmental disorder, or depression. In some
embodiments, the subject has both TS and ADHD.
[0072] In some embodiments, the treatment methods comprise
identifying or diagnosing a subject as having a genetic alteration
in at least one mGluR network gene, and administering a
nonselective mGluR activator such as fasoracetam to the identified
or diagnosed subject. In some of the embodiments, the subject has
TS, but does not have ADHD, ODD, conduct disorder, anxiety
disorder, autism, a mood disorder, phobia, or depression. In other
embodiments, the subject has TS, as well as one or more
neuropsychological disorders such as ADHD, ODD, conduct disorder,
anxiety disorder, autism, a mood disorder, phobia, and
depression.
[0073] In each method of the treating embodiments of the invention,
the disorder may be TS, persistent (chronic) vocal tic disorder,
persistent (chronic) motor tic disorder, or provisional tic
disorder. In each method of treating, the nonselective mGluR
activator, such as fasoracetam, may lessen the frequency or the
degree of motion in the subject's tics, and/or it may improve
symptoms of inattention, hyperactivity, anxiety, mood, and sleep
disturbances that may be seen in patients with TS or a tic
disorder. For example, these symptoms may be lessened after 1 week
of treatment with the activator, such as after 2 weeks, after 3
weeks, or after 4 weeks of treatment.
[0074] In some embodiments, the subject has co-morbid symptoms of
anxiety and in some cases, the method reduces anxiety symptoms. In
some embodiments, the subject has OCD and in some cases, the method
reduces OCD symptoms. In some cases, the subject has co-morbid
symptoms of dermatillomania, such as excessive skin picking, and
the method reduces those symptoms. In some embodiments, the subject
has one or more co-morbid developmental disorders, and in some
cases, the method reduces the severity of symptoms related to the
developmental disorders.
[0075] In some embodiments, the subject may have one or more of the
following changes in symptoms after at least one, two, three, or
four weeks of treatment with the activator: (a) the subject has
symptoms of anger control and the anger control symptoms are
reduced; (b) the subject has symptoms of disruptive behavior and
the disruptive behavior symptoms are reduced; (c) the subject's
CGI-I is reduced by at least 1 or by at least 2; (d) the subject's
CGI-I score after one, two, three, or four weeks of treatment is 1
or 2; (e) the subject's CGI-S score after one, two, three, or four
weeks of treatment is 1; (f) the subject has ADHD and the subject's
ADHD Rating Scale score is reduced by at least 25%, such as at
least 30%, at least 35%, or at least 40%; (g) the subject has
symptoms of inattentiveness and the inattentiveness symptoms are
reduced; (h) the subject has symptoms of hyperactivity and the
hyperactivity symptoms are reduced; (i) the subject has symptoms of
impulsiveness and the impulsiveness symptoms are reduced; (j) the
subject has symptoms of ODD such as anger and irritability,
argumentation and defiance, and/or vindictiveness and the ODD
symptoms are reduced; (k) the subject has symptoms of conduct
disorder and the conduct disorder symptoms are reduced; (l) the
subject has symptoms of anxiety and the anxiety symptoms are
reduced; (m) the subject has symptoms of OCD, and the OCD symptoms
are reduced; (n) the subject has symptoms of autism, and the autism
symptoms are reduced; and (o) the subject has symptoms of a
movement disorder other than Tourette's and the movement disorder
symptoms are reduced.
[0076] In one embodiment, the nonselective mGluR activator, such as
fasoracetam, is administered to a subject that has TS and has been
confirmed as having at least one genetic alteration in an mGluR
network gene. The genetic alteration may be in a Tier 1 mGluR
network gene. The genetic alteration may be in a Tier 2 mGluR
network gene. The genetic alteration may be in a Tier 3 mGluR
network gene. The genetic alteration may be more than one genetic
alteration, and the more than one alteration may be in one of Tiers
1, 2, or 3, or in any combination of Tiers.
[0077] Some embodiments include a method of treating TS comprising
obtaining genetic information about a subject's mGluR network
genes, and administering a nonselective mGluR activator, such as
fasoracetam, if the subject has at least one genetic alteration,
such as a CNV, in an mGluR network gene. Other embodiments
encompass a method of treating TS comprising obtaining genetic
information about a subject's mGluR network genes, and
administering a nonselective mGluR activator, such as fasoracetam,
if the subject has least one genetic alteration, such as a CNV, in
a Tier 1 mGluR network gene.
[0078] Other embodiments include a method of treating TS comprising
obtaining genetic information about a subject's mGluR network
genes, and administering a nonselective mGluR activator, such as
fasoracetam, if the subject has at least one genetic alteration,
such as a CNV, in a Tier 2 mGluR network gene.
[0079] Still other embodiments encompass a method of treating TS
comprising obtaining genetic information about a subject's mGluR
network genes, and administering a nonselective mGluR activator,
such as fasoracetam, if the subject has at least one genetic
alteration, such as a CNV, in a Tier 3 mGluR network gene.
[0080] Subjects having more than one CNV in any one Tier, or in a
combination of any of the three Tiers, may be treated by
administering a nonselective mGluR activator, such as
fasoracetam.
[0081] In some embodiments, subjects having TS, but not having
ADHD, ODD, conduct disorder, anxiety disorder, autism, a mood
disorder, phobia, schizophrenia, difficulty controlling anger,
disruptive behavior, symptoms, obsessive compulsive disorder (OCD),
dermatillomania, a developmental disorder, another movement
disorder other than TS, or depression, may be treated. In other
method of treatment embodiments of the invention, the subject has
one or more neuropsychological disorders such as ADHD, ODD, conduct
disorder, anxiety disorder, autism, a mood disorder, phobia,
schizophrenia, difficulty controlling anger, disruptive behavior,
symptoms, obsessive compulsive disorder (OCD), dermatillomania, a
developmental disorder, another movement disorder other than TS,
and depression in addition to TS.
IV. Methods for Determining the Presence or Absence of Genetic
Alterations
[0082] Any biological sample may be used to determine the presence
or absence of mGluR network gene alterations, including, but not
limited to, blood, urine, serum, gastric lavage, CNS fluid, any
type of cell (such as brain cells, white blood cells, mononuclear
cells) or body tissue. Any biological sample whereby DNA can be
extracted may be used to determine the presence or absence of mGluR
network gene alterations. Samples may be freshly collected, or
samples may have been previously collected for any use/purpose and
stored until the time of testing for genetic alterations. DNA that
was previously purified for a different purpose may also be
used.
[0083] Various methods for determining genetic alterations are
known, including the following:
[0084] A. Single Nucleotide Variant (SNV)/Single Nucleotide
Polymorphism (SNP) Genotyping
[0085] Determining whether a patient has a genetic alteration, such
as a CNV, in an mGluR network gene may be done by SNP/SNV
Genotyping. A "single nucleotide variant (SNV)," also called a
"single nucleotide polymorphism (SNP)" herein, refers to a change
in which a single base in the DNA differs from the usual base at
that position. Millions of SNVs have been cataloged in the human
genome. Some SNVs are normal variations in the genome, while others
are associated with disease. While specific SNVs may be associated
with disease states or susceptibility, high-density SNV genotyping
can also be undertaken, whereby sequencing information on SNVs is
used to determine the unique genetic makeup of an individual.
[0086] In SNV genotyping, SNVs can be determined by hybridizing
complementary DNA probes to the SNV site. A wide range of platforms
can be used with SNV genotyping tools to accommodate varying sample
throughputs, multiplexing capabilities, and chemistries. In
high-density SNV arrays, hundreds of thousands of probes are
arrayed on a small chip, such that many SNVs can be interrogated
simultaneously when target DNA is processed on the chip. By
determining the amount of hybridization of target DNA in a sample
to a probe (or redundant probes) on the array, specific SNV alleles
can be determined. Use of arrays for SNV genotyping allows the
large-scale interrogation of SNVs.
[0087] When analyzing CNVs, after SNVs have been analyzed, a
computer program can be used to manipulate the SNV data to arrive
at CNV data. PennCNV or a similar program, can then be used to
detect signal patterns across the genome and identify consecutive
genetic markers with copy number changes. (See Wang K, et al. (June
2008) Cold Spring Harb Protoc). PennCNV allows for
kilobase-resolution detection of CNVs. (See Wang K, et al.
(November 2007) Genome Res. 17(11):1665-74).
[0088] In CNV analysis, the SNV genotyping data is compared with
the behavior of normal diploid DNA. The software uses SNV
genotyping data to determine the signal intensity data and SNV
allelic ratio distribution and to then use these data to determine
when there is deviation from the normal diploid condition of DNA
that indicates a CNV. This is done in part by using the log R Ratio
(LRR), which is a normalized measure of the total signal intensity
for the two alleles of the SNV (Wang 2008). If the software detects
regions of contiguous SNVs with intensity (LRR) trending below 0,
this indicates a CNV deletion. If the software instead detects
regions of contiguous SNVs with intensity (LRR) trending above 0,
this indicates a CNV duplication. If no change in LRR is observed
compared to the behavior of diploid DNA, the sequence is in the
normal diploid state with no CNV present. The software also uses B
allele frequency (BAF), a normalized measure of the allelic
intensity ratio of two alleles that changes when alleles are lost
or gained as with a CNV deletion or duplication. For example, a CNV
deletion is indicated by both a decrease in LRR values and a lack
of heterozygotes in BAF values. In contrast, a CNV duplication is
indicated by both an increase in LRR values and a splitting of the
heterozygous genotype BAF clusters into two distinct clusters. The
software automates the calculation of LRR and BAF to detect CNV
deletions and duplications for whole-genome SNV data. The
simultaneous analysis of intensity and genotype data accurately
defines the normal diploid state and determines CNVs.
[0089] Array platforms such as those from Illumina, Affymetrix, and
Agilent may be used in SNV Genotyping. Custom arrays may also be
designed and used based on the data described herein.
[0090] B. Comparative Genomic Hybridization
[0091] Comparative genomic hybridization (CGH) is another method
that may be used to evaluate genetic alterations such as CNVs. CGH
is a molecular cytogenetic method for analyzing genetic alterations
such as CNVs in comparison to a reference sample using competitive
fluorescence in situ hybridization (FISH). DNA is isolated from a
patient and a reference source and independently labeled with
fluorescent molecules (i.e., fluorophores) after denaturation of
the DNA. Hybridization of the fluorophores to the resultant samples
are compared along the length of each chromosome to identify
chromosomal differences between the two sources. A mismatch of
colors indicates a gain or loss of material in the test sample in a
specific region, while a match of the colors indicates no
difference in genetic alterations such as copy number between the
test and reference samples at a particular region.
[0092] C. Comparative Genomic Hybridization
[0093] Whole genome sequencing, whole exome sequencing, or targeted
sequencing may also be used to analyze genetic alterations such as
CNVs. Whole genome sequencing (also known as full genome
sequencing, complete genome sequencing, or entire genome
sequencing) involves sequencing of the full genome of a species,
including genes that do or do not code for proteins. Whole exome
sequencing, in contrast, is sequencing of only the protein-coding
genes in the genome (approximately 1% of the genome). Targeted
sequencing involves sequencing of only selected parts of the
genome.
[0094] A wide range of techniques would be known to those skilled
in the art to perform whole genome, whole exome, or targeted
sequencing with DNA purified from a subject. Similar techniques
could be used for different types of sequencing.
[0095] Techniques used for whole genome sequencing include nanopore
technology, fluorophore technology, DNA nanoball technology, and
pyrosequencing (i.e., sequencing by synthesis). In particular,
next-generation sequencing (NGS) involves sequencing of millions of
small fragments of DNA in parallel followed by use of
bioinformatics analyses to piece together sequencing data from the
fragments.
[0096] As whole exome sequencing does not need to sequence as large
an amount of DNA as whole genome sequencing, a wider range of
techniques are may be used. Methods for whole exome sequencing
include polymerase chain reaction methods, NGS methods, molecular
inversion probes, hybrid capture using microarrays, in-solution
capture, and classical Sanger sequencing. Targeted sequencing
allows for providing sequence data for specific genes rather than
whole genomes and can use any of the techniques used for other
types of sequencing, including specialized microarrays containing
materials for sequencing genes of interest.
[0097] D. Other Methods for Determining Genetic Alterations
[0098] Proprietary methodologies, such as those from BioNano or
OpGen, using genome mapping technology can also be used to evaluate
genetic alterations such as CNVs.
[0099] Standard molecular biology methodologies such as
quantitative polymerase chain reaction (PCR), droplet PCR, and
TaqMan probes (i.e., hydrolysis probes designed to increase the
specificity of quantitative PCR) can be used to assess genetic
alterations such as CNVs. Fluorescent in situ hybridization (FISH)
probes may also be used to evaluate genetic alterations such as
CNVs. The analysis of genetic alterations such as CNVs present in
patients with TS is not limited by the precise methods whereby the
genetic alterations such as CNVs are determined.
V. Methods for Diagnosing TS Based on CNV Data
[0100] In some embodiments, the genetic alteration is a SNV or CNV.
The SNV(s) or CNV(s) associated with TS are found in an mGluR
network gene, such as a gene listed in Tier1, Tier2, or Tier3 as
shown in FIGS. 1-3 or a set or panel of such genes.
[0101] In some embodiments, gene sets of mGluR network genes are
used for analyzing samples from patients with or suspected of
having TS. In some embodiments, the presence of CNV duplications or
deletions within these gene sets or panels is determined. In some
embodiments, CNVs in the Tier 1 genes shown in FIG. 1 are
determined. In some embodiments a panel of at least 10, at least
20, at least 30, at least 40, at least 50, at least 60, at least
70, or all 76 of the Tier 1 genes is evaluated for the presence of
CNVs. Within any such panel of genes, individual, specific Tier 1
genes may be excluded from the analysis set. Any or all of GRM1-8
may be excluded from the panel, for example.
[0102] In some embodiments, the Tier 2 genes as shown in FIG. 2 are
analyzed for the presence of genetic alterations such as CNVs. Tier
2 genes are those that are tightly associated with mGluRs, but
which are not contained within Tier 1.
[0103] In some embodiments, the Tier 2 genes are evaluated together
with Tier 1 genes. In some embodiments, at least 100 Tier 2 genes
are evaluated, while in some embodiments, at least 150, or 197 of
the Tier 2 genes are evaluated. Individual, specific Tier 2 genes
may be excluded from the gene set for evaluation in some
embodiments.
[0104] In some embodiments, the 599 Tier 3 genes shown in FIG. 3
are evaluated for genetic alterations such as CNVs. In some
embodiments, the Tier 3 genes are evaluated together with Tier 1
and/or Tier 2 genes. In some embodiments, at least 100 Tier 3 genes
are evaluated, while in some embodiments, at least 150, 200, 250,
300, 350, 400, 450, or 599 of the Tier 3 genes are evaluated.
Individual, specific Tier 3 genes may be excluded from the gene set
for evaluation in some embodiments.
VI. Methods of Administration and Combination Therapy
[0105] In some embodiments, the agent that modulates mGluR
signaling is fasoracetam or fasoracetam monohydrate (also known as
C-NS-105, NFC1, NS105, or LAM-105).
[0106] A. Dosing
[0107] In some embodiments, fasoracetam may be administered as
fasoracetam monohydrate (NFC-1). In some embodiments, fasoracetam
may be administered by mouth (i.e., per os). In some embodiments,
fasoracetam may be administered as capsules. In some embodiments,
fasoracetam capsules may contain 50, 60, 70, 80, 90, 100, 110, 120,
125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185,
190, 195, or 200 mg of fasoracetam monohydrate. In some
embodiments, fasoracetam may be dosed once daily or twice daily. In
some embodiments, the daily dose of fasoracetam may be 50 mg
once-daily, 100 mg once-daily, 200 mg once-daily, 400 mg
once-daily, 50 mg twice-daily, 100 mg twice-daily, 200 mg
twice-daily, or 400 mg twice-daily. In some embodiments,
fasoracetam dosing may be adjusted using a series of dose
escalations. In some embodiments, pharmacokinetic data on drug
level or clinical response is used to determine changes in dosing.
In some embodiments, dose escalation of fasoracetam is not used. In
some embodiments, subjects are treated at a dose of fasoracetam
expected to be clinically efficacious without a dose-escalation
protocol.
[0108] B. Combination Therapies
[0109] In some embodiments, fasoracetam is used in combination with
other agents for the treatment of TS. The other agent used in
combination with fasoracetam may be an antipsychotic, including
haloperidol, chlorpromazine, amisulpride, aripiprazole, asenapine,
blonaserin, clozapine, iloperidone, lurasidone, melperone,
olanzapine, paliperidone, quetiapine, risperidone, sertindole,
sulpiride, ziprasidone, or zotepine.
[0110] In some embodiments, fasoracetam may be used in combination
with a non-pharmacologic treatment, such as psychotherapy or brain
stimulation therapies. In some embodiments, fasoracetam is used in
combination with brain stimulation, which may be vagus nerve
stimulation, repetitive transcranial magnetic stimulation, magnetic
seizure therapy, deep brain stimulation, or any other therapies
involving modulation of brain function by electricity, magnets, or
implants.
VII. Articles of Manufacture
[0111] In some embodiments, the invention comprises articles of
manufacture that may be used in the methods and treatments
described herein. In one embodiment, the manufacture is a solid
support or microarray for use in detecting genetic alterations in
some or all of the mGluR network genes listed in FIGS. 1-3 (i.e.,
Tiers 1-3). (See also Tables 1-3 herein providing start and stop
locations for different mGluR network-related SNPs. This
information may be useful in constructing a microarray.) In some
embodiments, genes contained in multiple Tiers are assessed within
the same solid support or microarray. In some embodiments, certain
mGluR network genes are excluded. In some embodiments, the GRM
genes are excluded.
[0112] Thus, for example, in some embodiments in which mGluR
network genes are assayed to determine if there is a genetic
alteration in one or more of the genes, such as a CNV, a solid
support or microarray, such as on a chip, is used that contains
appropriate probes for determining the presence of genetic
alterations in 10, 20, 30, 40, 50, 60, 70 or all of the Tier 1
genes. In certain embodiments, the detectable labels are
non-naturally occurring. In some embodiments, the solid support or
microarray may also include appropriate probes for determining the
presence of genetic alterations in at least 10, 20, 30, 50, 100,
150, or all of the Tier 2 genes. In some embodiments, it may
further include appropriate probes for determining the presence of
genetic alterations in at least 10, 20, 50, 100, 200, 300, 400, 500
or all of the Tier 3 genes. For example, such a solid support,
microarray, or chip may be used to determine the presence of
genetic alterations such as CNVs or SNVs in the Tier 1, Tier 1+2,
or Tier 1+2+3 mGluR gene networks as part of a method of treating
an ADHD or 22q deletion and/or duplication patient.
[0113] In some embodiments, the manufacture is a set of probes for
mGluR network genes of interest from Tiers 1, 2, and/or 3. In some
embodiments the probes are labelled. Similarly, sets of probes may
be manufactured for determining the presence of genetic alterations
in 10, 20, 30, 40, 50, 60, 70 or all of the Tier 1 genes. In some
embodiments, probes may be manufactured for determining the
presence of genetic alterations in at least 10, 20, 30, 50, 100,
150, or all of the Tier 2 genes. In some embodiments, probes may
further include those for determining the presence of genetic
alterations in at least 10, 20, 50, 100, 200, 300, 400, 500 or all
of the Tier 3 genes. These various probe sets may be used in
methods of determining the presence of genetic alterations, such as
CNVs and SNVs in the Tier 1, Tier 1+2, or Tier 1+2+3 mGluR gene
networks as part of a method of treating an ADHD or 22q deletion
and/or duplication patient.
EXAMPLES
Example 1. Enrichment of CNV Calls Containing mGluR Network Genes
in Samples from Patients with TS
[0114] Previously, a large-scale genome association study for
copy-number variations enriched in patients with ADHD was
performed, as described in Elia et al., Nature Genetics, 44(1):
78-84 (2012)). Elia's study included about 2,493 patients with ADHD
and about 9,222 controls, all of whom were of European ancestry and
were between the ages of 6 to 18 years of age. This study noted
that the rate of CNVs that contained an mGluR network gene was 1.2%
in the control group, and that this rate increased to 11.3% in ADHD
patients.
[0115] The study revealed that rare, recurring CNVs impacting
specific mGluR network genes (i.e. GRM1, GRM5, GRM7, and GRM8)
encoding for metabotropic glutamate receptors (mGluRs) were found
in ADHD patients at significantly higher frequencies compared to
healthy controls. The large effect sizes (with odds-ratios of
>15) suggest that these mutations likely are highly penetrant
for their effects on ADHD. Single cases with GRM2 and GRM6
deletions were also observed that were not found in controls. When
genes in the signaling pathway of mGluR network genes were
assessed, significant enrichment of CNVs was found to reside within
this network in ADHD cases compared to controls.
[0116] We have identified a total of 279 mGluR primary network
genes based on the merged human interactome provided by the
Cytoscape Software. A network analysis of the mGluR pathway found
that in a population of approximately 1,000 cases and 4,000
controls from subjects of European ancestry, genes involved with
mGluR signaling or their interactors are significantly enriched for
CNVs in cases (P=4.38.times.10-10), collectively impacting
.about.20% of the ADHD cases, corrected for control occurrence.
These data suggest that mGluR network genes may serve as critical
hubs that coordinate highly-connected modules of interacting genes,
many of which may harbor CNVs and are enriched for synaptic and
neuronal biological functions. Thus, several rare, recurrent CNVs
were identified that are overrepresented in multiple independent
ADHD cohorts that impact genes involved in glutamatergic
neurotransmission.
[0117] TS frequently coexists in children with ADHD. Specifically,
about two thirds of pediatric TS patients also have ADHD. In
addition, as much as 10% of ADHD patients may have tics. Thus, we
examined if mGluR gene alterations would also be enriched in
children with TS.
[0118] Samples for the present study were selected based on ICP-9
codes for diagnoses of children and adolescents from electronic
health records that were treated at the Children's Hospital of
Philadelphia (CHOP). All 95 subjects had been evaluated by a
pediatric psychiatrist who had entered a diagnosis of TS. All
subjects had recurrent tics of sufficient duration to meet
diagnostic criteria for Tourette syndrome. Certain patients in the
study had a diagnosis of both schizophrenia and TS.
[0119] Single nucleotide variant (SNV)/single nucleotide
polymorphism (SNP) genotype data were used to determine CNVs. SNV
genotyping provides a genetic fingerprint of an individual using a
large number of SNV markers to provide high-density SNV genotyping
data (see Wang K, et al. (November 2007) Genome Res.
17(11):1665-74). HumanHap550 Genotyping BeadChip.TM. (Illumina) or
Human610-Quad v1.0 BeadChip.TM. (Illumina) were used in this study.
For both chips, the same 520 SNVs were analyzed; therefore, data
from these two chips are interchangeable. Standard manufacturer
protocols were used for all genotyping assays. Illumina readers
were used for all experiments.
[0120] SNV genotyping data from each fully genotyped patient sample
were analyzed with the PennCNV software to determine the signal
intensity data and SNV allelic ratio distribution. These data were
then used to determine CNVs via simultaneous analysis of intensity
and genotype data (as previously described in Wang 2008). Using
this analysis, data indicating a region of loss of contiguous SNVs
lead to a call of a CNV deletion. Data indicating a region of gain
of contiguous SNVs lead to a call of a CNV duplication. A single
individual may have multiple CNV deletions/duplications or may not
have any CNVs.
[0121] As discussed previously, three tiers of mGluR network genes
were developed. FIGS. 1-3 show the genes that are included in the
three gene sets--Tier 1 (76 genes) in FIG. 1, Tier 2 (197 genes) in
FIG. 2, and Tier 3 (599 genes) in FIG. 3. Note that these gene sets
were non-inclusive, so a single gene was only contained in a single
Tier.
[0122] FIG. 4 shows data on the number of CNV calls in each mGluR
gene Tier for the TS patients. CNVs are either duplications or
deletions. The data indicate that a relatively high number of CNV
calls were seen for each gene set of mGluR network genes in the
samples from patients with TS.
[0123] The percentage of patients who had a CNV call (either
duplication or deletion) in each gene set of mGluR network genes is
shown in FIG. 5. Among 95 genotyped children with TS, 20
(.about.21%) had mutations in the Tier 1 genes that were found to
be most significant in ADHD and we have labelled as Tier 1 (all are
genes in the mGluR primary network). A total of 28 children had
mutations within the full mGluR primary network genes assessed
(Tiers 1+2) or .about.29%. About 52% of the children had mutations
in either the primary or secondary (Tiers 1+2+3) mGluR networks,
suggesting that up to 50% of patients with TS might have this
pathway disrupted and may be responsive to therapy that reverses
the consequences of these mutations.
[0124] These data also indicate that a substantially higher
percentage of patients with TS had a CNV call within each of the
mGluR network gene sets compared with the previously reported
frequency of CNV calls in a control population. The control
frequency of patients with CNVs in mGluR network genes was
previously estimated to be 1.2% (see Elia), supporting the
specificity of the enrichment of mGluR network genes within CNVs in
patients with TS.
[0125] As indicated in FIGS. 4-5, there was a significant
enrichment of mGluR network gene alterations in the patients with
TS. Therefore, diagnostics and treatments focused on modulation of
mGluR gene networks may be of particular use in patients with
TS.
Example 2. Analysis of mGluR Network Genes Contained within CNVs
from Samples of Patients with TS
[0126] We next analyzed genotyping data from the 95 fully genotyped
patients with TS to identify the genes associated with the
CNVs.
[0127] Table 1 shows data of representative CNVs from patients with
TS wherein a Tier 1 mGluR network gene was located within, or in
the vicinity of, a CNV in the patient's sample. CNVs can lead to
structural changes that affect the transcription of genes located
outside of, but in the vicinity of, the CNV. As such, mGluR network
genes within one of the Tiers that were located within 500,000 base
pairs of a CNV were included in the analysis. When an mGluR network
gene is contained within the listed CNV, this is noted with a
"distance from gene" value of 0. When an mGluR network gene is
contained in close proximity to a CNV but not within it, this is
presented with a "distance from gene" value of greater than 0.
[0128] Table 1 lists the chromosome wherein the CNV was located,
with its start and stop location in relation to the Human Genome
version 19 (hg19). The number of SNVs (SNPs) located within the CNV
is noted as "Num SNP," and the length of the CNV is noted in base
pairs. The StartSNP and EndSNP of the CNV are also provided.
[0129] The "State, CN" column indicates the copy number resulting
from the CNV. As normal human DNA (i.e. with no CNV) should be
diploid and would have a "State, CN" of 2. CNVs with a "State, CN"
of 0 or 1 indicate a copy number deletion. In contrast, CNVs with a
"State, CN" of three or greater indicate a copy number
duplication.
[0130] The confidence value indicates the relative confidence that
the call of the CNV is correct. All CNVs included in this analysis
had a positive confidence value, indicating a high likelihood that
the CNV call is correct. A value of 15 or greater was seen for most
CNVs and is considered extremely high confidence in the CNV call
based on qPCR and Taqman genotyping validation.
[0131] In Table 1, the "mGluR gene" column lists the specific mGluR
network gene within Tier 1 contained within the listed CNV. Table 1
is sorted to show all of the CNVs that included a given Tier 1
mGluR network gene. Some Tier 1 genes may be represented in
multiple CNVs from different patients in the study, leading to
multiple rows for those particular mGluR network genes. Some Tier 1
genes may not have been represented in a CNV from this particular
patient population.
[0132] Table 2 shows data from specific CNVs that contained a Tier
1 or Tier 2 mGluR network gene. The organization of Table 2 follows
that of Table 1. The "mGluR gene" column lists the specific mGluR
network gene within Tier 1 or Tier 2 contained within the listed
CNV. Table 2 is sorted to show all of the CNVs that included a
given Tier 1 or Tier 2 mGluR network gene. Some Tier 1 or Tier 2
genes may be represented in multiple CNVs from different patients
in the study, leading to multiple rows for those particular genes.
Some Tier 1 or Tier 2 genes may not have been represented in a CNV
from this particular patient population.
[0133] Table 3 shows data from specific CNVs that contained a Tier
1, 2, or 3 mGluR network gene. The organization of Table 3 follows
that of Tables 1 and 2. The "mGluR gene" column lists the specific
mGluR network gene within Tier 1, Tier 2, or Tier 3 contained
within the listed CNV. Table 3 is sorted to show all the CNVs that
included a given Tier 1, 2, or 3 mGluR network gene. Some Tier 1,
2, or 3 genes may be represented in multiple CNVs from different
patients in the study, leading to multiple rows for those
particular mGluR network genes. Some Tier 1, 2, or 3 genes may not
have been represented in a CNV from this particular patient
population.
[0134] Together, the data in Tables 1-3 indicate that a wide
variety of mGluR network genes contained within each Tier are
present in CNVs from patients with TS. If a larger patient cohort
with TS was genotyped, all the genes in Tier 1, Tier 2, and Tier 3
would show enrichment for CNVs in patients with TS.
Example 3. Treatment with Fasoracetam Monohydrate (NFC-1) of ADHD
Patients with CNVs in mGluR Network Genes and Impact on Tic
Symptoms
[0135] An open-label Phase Ib clinical trial was conducted to
investigate the safety, pharmacokinetics and efficacy of NFC-1
(fasoracetam monohydrate) in adolescent subjects between the ages
of 12 and 17 previously diagnosed with ADHD who also had at least
one genetic alteration in an mGluR network gene.
[0136] The study included 30 ADHD subjects who were between ages 12
and 17, of any ancestry or race, of weight within the 5th to 95th
percentile for their age, and otherwise judged to be in good
medical health. Subjects were genotyped and included in the trial
if they possess at least one genetic alteration in the form of at
least one copy number variation (deletion or duplication) in a
mGluR network gene that potentially disrupts the function of the
gene. Seventeen of the 30 subjects have a CNV in a tier 1 mGluR
network gene, while 7 subjects have a CNV in a tier 2 gene and 6 in
a tier 3 gene. At enrollment, several trial subjects showed
evidence of co-morbid phenotypes, including two subjects having
recurrent tics.
[0137] Exclusion criteria comprised subjects suffering from a
clinically significant illness, either mental or physical, that, in
the investigator's opinion, might confound the results of the study
or that might prevent them from completing the study, subjects that
are pregnant or nursing, subjects that test positive for illicit
drugs of that have a history of drug abuse, subjects that consume
alcoholic beverages, or subjects for which the investigator is
otherwise concerned regarding their compliance or suitability.
[0138] NFC-1 capsules of either 50 mg or 200 mg comprising
fasoracetam monohydrate as active ingredient and placebo capsules
comprising microcellulose were used for the study. The design of
the trial was a phone screening (1 day), enrollment phase (1 to 2
days), a wash-out phase for subjects currently on ADHD medications
(1-14 days), pharmacokinetic (PK) assessment (2 days), followed by
a dose-escalation phase (35 days) and a follow-up phone visit
approximately four weeks after the last dose, for a maximum of 127
days. All ADHD medications were discontinued during the wash-out
phase prior to the study. The wash-out period for stimulants was
2-3 days and that for atomoxetine or noradrenergic agonists was
10-12 days. No new ADHD medications were started during the
study.
[0139] A dose-escalation phase of the trial ran over a 5-week
period, after the initial wash-out period and the PK and initial
safety assessments. During week 1, all subjects were administered
placebo capsules twice daily. After one week of placebo treatment,
patients were started on 50 mg bid NFC-1 for 1 week. If safety and
responsiveness data from prior dose level of fasoracetam indicated
it was appropriate, subjects were then escalated to the next higher
dose (100, 200, or 400 mg). Subjects who showed tolerance to the 50
mg bid dose as well as response to the drug were to be maintained
at that level for the remaining 3 weeks of the trial.
[0140] Subjects who showed tolerance but lack of response or
partial response to the 50 mg bid dose were to be moved up to the
next higher dose of 100 mg during the following week. Subjects who
showed tolerance at 100 mg but lack of response or partial response
were to be moved up to the 200 mg dose the following week while
those who showed both tolerance and response at 100 mg were to be
kept at 100 mg bid for the remainder of the trial. Similarly,
subjects moved up to the 200 mg dose who showed both tolerance and
response were to be kept at 200 mg for the final week of the trial
while those showing tolerance but lack of response or partial
response were moved to a 400 mg dose for the final week. Of the 30
trial subjects, 3 received a maximum dose of 100 mg, 9 received a
maximum dose of 200 mg, and the remaining 18 received a maximum
dose of 400 mg.
[0141] While this study was not specifically directed at measuring
tics or TS, the two individuals with history of recurrent tics did
not demonstrate tics during the therapy with NFC-1.
Example 4. Treatment with Fasoracetam Monohydrate (NFC-1) of ADHD
Patients with CNVs in mGluR Network Genes and Impact on Obsessive
Compulsive Symptoms
[0142] Among the 30 ADHD subjects tested in the open-label Phase Ib
clinical trial described in Example 2, eight had symptoms of
obsessive compulsive-disorder (OCD). One of the subjects with tics
also had symptoms of OCD. In all eight subjects, OCD symptoms
improved during therapy with NFC-1.
[0143] One subject with OCD also had a history of ear scratching
(i.e., dermatillomania), leading to a bleeding ulcer. The bleeding
ulcer healed during therapy with NFC-1, indicating that the
subject's dermatillomania symptoms had reduced during NFC-1
therapy.
Example 5. Study of Phenotypes Associated with mGluR Network
CNVs
[0144] A total of 1,000 ADHD patients aged 6-17 years were enrolled
in a trial to consider phenotypes that may be associated with CNVs
in Tier 1 or 2 mGluR network genes. Study sites collected saliva
for a DNA sample. Each DNA sample was then subjected to DNA
extraction, genetic sequencing, and biobanking of DNA.
[0145] Genetic sequencing results together with medical history
were used to evaluate genotype (based on genetic sequencing) and
phenotype (based on interviews conducted by a clinician with the
subject's parent(s)/guardian(s)). Subjects had ADHD as defined by
the Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition (DSM-V).
[0146] A single clinician posed a series of questions related to
potential behavioral or health phenotypes to the parent(s) or legal
guardian(s) of the subjects. For each individual phenotype, the
parent/guardian was asked: "Is this a current concern" and a Yes or
No answer was collected. The clinician determined the frequency of
Yes and No responses to generate phenotype data.
[0147] The study found that prevalence of anger control as a
current concern for parents was 58.9% in ADHD subjects with a Tier
1 or 2 mGluR network gene CNV but only 47.4% in ADHD subjects
without such an mGluR network gene CNV. This difference was
statistically significant (odds ratio of 1.59, P=0.003). This odds
ratio of greater than 1 implies a higher prevalence of current
anger control concerns in parents in ADHD subjects who had a Tier 1
or 2 mGluR network gene CNV versus those without such a CNV.
[0148] The prevalence of disruptive behavior as a current concern
for parents was 57.1% in ADHD subjects with a Tier 1 or 2 mGluR
network gene CNV and 43.9% in ADHD subjects without such an mGluR
network gene CNV. This difference was also statistically
significant (odds ratio of 1.70, P<0.001), indicating a higher
prevalence of current disruptive behavior concerns in parents in
ADHD subjects who also had an mGluR network gene mutation versus
those without a mutation.
Example 6: Copy Number Variation in mGluR Network Genes in ADHD
Subjects with Co-Morbid Disorders
[0149] Samples from 2707 known ADHD pediatric subjects (mean age of
about 10-10.5 years) were genotyped on 550/610 Illumina chips to
determine if they have one or more CNVs in Tier 1 or Tier 2 genes.
The 2707 subjects included 759 females and 1778 males of African
American or white ethnicity (1063 and 1483, respectively). 430 of
the 2707 subjects (16.9%) had at least one CNV in an mGluR Tier 1
or Tier 2 gene.
[0150] The 2707 subjects' records were also checked to determine if
they had co-morbid diagnoses according to the World Health
Organization International Classification of Diseases 9th Edition
(ICD-9). Of the 2707 subjects, 1902 (about 70) had comorbidities
while 805 did not. Of those 1902 subjects with comorbidities, about
30 had more than one comorbidity, and about 20% had two or more,
while smaller percentages had larger numbers of comorbidities.
[0151] The most prevalent comorbidities, each occurring in more
than 100 of the subjects, are listed in Table 4. The table lists
the comorbidities by ICD-9 code and provides the number of cases
among the 2707 subjects (column titled "N") and name for each
co-morbid condition or disorder.
TABLE-US-00001 TABLE 4 ICD-9 Code N Name N_299.00 342 Autistic
disorder, current or active state N_299.80 267 Other specified
pervasive developmental disorders, current or active state N_299.90
179 Unspecified pervasive developmental disorder, current or active
state N_300.00 407 Anxiety state unspecified N_311 244 Depressive
disorder not elsewhere classified N_312.9 568 Unspecified
disturbance of conduct N_313.81 313 Oppositional defiant disorder
(ODD) N_314.9 120 Unspecified hyperkinetic syndrome of childhood
N_315.2 320 Other specific developmental learning difficulties
N_315.31 189 Expressive language disorder N_315.32 157 Mixed
receptive-expressive language disorder N_315.39 327 Other
developmental speech disorder N_315.4 116 Developmental
coordination disorder N_315.5 160 Mixed development disorder
N_315.8 398 Other specified delays in development N_315.9 479
Unspecified delay in development N_319 110 Unspecified intellectual
disabilities
[0152] The comorbidies in Table 4 tend to cluster into a few
different groups: disorders related to anxiety, depression, or
mood; prevalent developmental disorders; less prevalent
developmental disorders; and autism and related disorders.
[0153] The genotype data and the comorbidity data were then
combined to determine how many of the subjects with CNVs in Tier 1
or 2 mGluR network genes also had comorbidities. It was found that
316 of the subjects with such a CNV also had at least one
comorbidity (about 18% of the CNV-positive subjects or about 12% of
the total subjects) while 114 of the subjects without a Tier 1 or 2
mGluR network gene CNV had at least one comorbidity (about 15% of
the CNV-negative subjects or about 4% of the total subjects). This
difference showed a P value of 0.118. Thus, comorbidities tended to
be more common in CNV-positive than in CNV-negative subjects
overall. When only subjects identifying as white ethnicity are
considered, there was a highly significant correlation between
mGluR CNVs and ADHD comorbidities. Specifically, 218 of 1483
subjects had at least one CNV in a Tier 1 or 2 mGluR network gene,
and, of those 218 subjects, 169 also had a comorbidity whereas 49
did not. That difference showed a P value of 0.004.
[0154] The foregoing written specification is considered to be
sufficient to enable one skilled in the art to practice the
embodiments. The foregoing description and Examples detail certain
embodiments and describes the best mode contemplated by the
inventors. It will be appreciated, however, that no matter how
detailed the foregoing may appear in text, the embodiment may be
practiced in many ways and should be construed in accordance with
the appended claims and any equivalents thereof.
[0155] As used herein, the term about refers to a numeric value,
including, for example, whole numbers, fractions, and percentages,
whether or not explicitly indicated. The term about generally
refers to a range of numerical values (e.g., +/-5-10% of the
recited range) that one of ordinary skill in the art would consider
equivalent to the recited value (e.g., having the same function or
result). When terms such as at least and about precede a list of
numerical values or ranges, the terms modify all of the values or
ranges provided in the list. In some instances, the term about may
include numerical values that are rounded to the nearest
significant figure.
TABLE-US-00002 TABLE 1 Distance State, From mGluR Chr:
Start-Stop(hg19) NumSNP Length CN StartSNP EndSNP Confidence Gene
Gene chr2: 38328178-128536280 15926 90,208,103 1 rs232542 rs7608627
30.628 0 ACTR2 chr16: 16348605-90291153 14331 73,942,549 4
rs2856546 rs12325137 10.397 0 ALDOA chr21: 14601415-48084989 8249
33,483,575 3 rs2775537 rs2839378 6900.018 0 APP chr21:
14901920-48084989 8239 33,183,070 3 rs12626247 rs2839378 11089.459
0 APP chr14: 96684770-96688669 4 3,900 1 rs4905466 rs4905469 14.379
0 BDKRB2 chr8: 60997355-61008986 10 11,632 1 rs1464327 rs2611360
12.59 92437 CA8 chr8: 60654261-60775727 18 121,467 1 rs1949102
rs7822560 11.681 325696 CA8 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 CIC chr3: 2189641-2223722
19 34,082 1 rs2729015 rs7613165 52.462 0 CNTN4 chr3: 234726-6328081
2293 6,093,356 3 rs7632811 rs1595039 106.207 0 CNTN4 chr17:
43657921-43728376 4 70,456 1 rs9898857 rs417968 10.243 0 CRHR1
chr2: 38328178-128536280 15926 90,208,103 1 rs232542 rs7608627
30.628 0 CTNNA2 chr7: 153331061-153608121 32 277,061 3 rs4595033
rs12673076 37.54 0 DPP6 chr19: 22609759-55294329 -4174 32,684,571 3
rs7251413 rs2569676 20.948 0 FPR1 chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 GNAO1 chr16:
56362725-56384720 13 21,996 1 rs2241952 rs3790113 20.256 0 GNAO1
chr9: 1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864
36.66 0 GNAQ chr21: 14601415-48084989 8249 33,483,575 3 rs2775537
rs2839378 6900.018 0 GRIK1 chr21: 14901920-48084989 8239 33,183,070
3 rs12626247 rs2839378 11089.459 0 GRIK1 chr6: 69900102-165298477
19424 95,398,376 1 rs779484 rs1511063 38.802 0 GRM1 chr6:
69900102-165298477 19424 95,398,376 1 rs779484 rs1511063 38.802 0
GRM1 chr7: 85774549-86281198 56 506,650 3 rs41440 rs1024516 24.091
0 GRM3 chr11: 88696662-88744425 11 47,764 3 rs477399 rs7932640
10.213 0 GRM5 chr11: 88696662-88744425 11 47,764 3 rs477399
rs7932640 10.213 0 GRM5 chr3: 7405044-7411730 3 6,687 1 rs13091584
rs7647001 16.073 0 GRM7 chr3: 7405044-7411730 3 6,687 1 rs13091584
rs7647001 16.073 0 GRM7 chr7: 125999649-126219766 52 220,118 1
rs714237 rs2299470 25.109 0 GRM8 chr7: 125999649-126219766 52
220,118 1 rs714237 rs2299470 25.109 0 GRM8 chr9: 1399761-136852891
25442 135,453,131 1 rs12341621 rs2789864 36.66 0 GSN chr5:
78629346-78765405 28 136,060 1 rs9293769 rs7710089 19.586 0 HOMER1
chr5: 78661854-78673236 5 11,383 1 rs7732902 rs12187625 11.269 0
HOMER1 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 LARP7 chr21: 14601415-48084989 8249 33,483,575 3
rs2775537 rs2839378 6900.018 0 MX1 chr21: 14901920-48084989 8239
33,183,070 3 rs12626247 rs2839378 11089.459 0 MX1 chr2:
152065396-152499580 79 434,185 3 rs289871 rs4664494 89.838 0 NMI
chr21: 14601415-48084989 8249 33,483,575 3 rs2775537 rs2839378
6900.018 0 PCBP3 chr21: 14901920-48084989 8239 33,183,070 3
rs12626247 rs2839378 11089.459 0 PCBP3 chr19: 22609759-55294329
-4174 32,684,571 3 rs7251413 rs2569676 20.948 0 PPP2R1A chr11:
198510-244552 23 46,043 1 rs3802985 rs2272566 13.271 0 PSMD13 chr2:
152065396-152499580 79 434,185 3 rs289871 rs4664494 89.838 0 RIF1
chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676
20.948 0 RUVBL2 chr19: 22609759-55294329 -4174 32,684,571 3
rs7251413 rs2569676 20.948 0 RYR1 chr6: 1171596-29895228 43
28,723,633 0 rs3128994 rs9259831 43.568 0 SERPINB9 chr6:
2585208-31281876 -2 28,696,669 1 rs1634746 rs1634747 31.615 0
SERPINB9 chr21: 14601415-48084989 8249 33,483,575 3 rs2775537
rs2839378 6900.018 0 SETD4 chr21: 14901920-48084989 8239 33,183,070
3 rs12626247 rs2839378 11089.459 0 SETD4 chr19: 22609759-55294329
-4174 32,684,571 3 rs7251413 rs2569676 20.948 0 SHANK1 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
SLC7A10 chr3: 171220708-171220919 3 212 1 cnvi0011707 cnvi0011705
9.195 42511 TNIK
TABLE-US-00003 TABLE 2 Distance State, From mGluR Chr:
Start-Stop(hg19) NumSNP Length CN StartSNP EndSNP Confidence Gene
Gene chr6: 69900102-165298477 19424 95,398,376 1 rs779484 rs1511063
38.802 0 ACAT2 chr2: 38328178-128536280 15926 90,208,103 1 rs232542
rs7608627 30.628 0 ACTR2 chr2: 38328178-128536280 15926 90,208,103
1 rs232542 rs7608627 30.628 0 ADD2 chr10: 33340331-123920784 17036
90,580,454 1 rs10430560 rs1885516 36.263 0 ADRA2A chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
ALDOA chr9: 1399761-136852891 25442 135,453,131 1 rs12341621
rs2789864 36.66 0 ANXA2 chr21: 14601415-48084989 8249 33,483,575 3
rs2775537 rs2839378 6900.018 0 APP chr21: 14901920-48084989 8239
33,183,070 3 rs12626247 rs2839378 11089.459 0 APP chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
APTX chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 ARHGAP24 chr14: 96684770-96688669 4 3,900 1
rs4905466 rs4905469 14.379 0 BDKRB2 chr8: 60997355-61008986 10
11,632 1 rs1464327 rs2611360 12.59 92437 CA8 chr8:
60654261-60775727 18 121,467 1 rs1949102 rs7822560 11.681 325696
CA8 chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 CALB2 chr2: 38328178-128536280 15926 90,208,103
1 rs232542 rs7608627 30.628 0 CALM2 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 CALM3 chr7:
44376785-44388619 4 11,835 1 rs12535537 rs10257749 12.04 11555
CAMK2B chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 CIC chr6: 69900102-165298477 19424 95,398,376 1
rs779484 rs1511063 38.802 0 CNR1 chr17: 43657921-43728376 4 70,456
1 rs9898857 rs417968 10.243 0 CRHR1 chr12: 84152210-113464649 5560
29,312,440 1 rs10862748 rs16942470 28.181 0 DCN chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
FPR1 chr15: 73186518-94501564 4223 21,315,047 1 rs1947219 rs4344687
34.841 0 FURIN chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 FYN chr6: 31289284-56929863 15402 25,640,580 3
rs9265170 cnvi0015437 25.647 0 GLP1R chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 GNAO1 chr16:
56362725-56384720 13 21,996 1 rs2241952 rs3790113 20.256 0 GNAO1
chr9: 1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864
36.66 0 GNAQ chr10: 33340331-123920784 17036 90,580,454 1
rs10430560 rs1885516 36.263 0 GOT1 chr21: 14601415-48084989 8249
33,483,575 3 rs2775537 rs2839378 6900.018 0 GRIK1 chr21:
14901920-48084989 8239 33,183,070 3 rs12626247 rs2839378 11089.459
0 GRIK1 chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 GRM1 chr7: 85774549-86281198 56 506,650 3
rs41440 rs1024516 24.091 0 GRM3 chr6: 31289284-56929863 15402
25,640,580 3 rs9265170 cnvi0015437 25.647 0 GRM4 chr11:
88696662-88744425 11 47,764 3 rs477399 rs7932640 10.213 0 GRM5
chr3: 7405044-7411730 3 6,687 1 rs13091584 rs7647001 16.073 0 GRM7
chr7: 125999649-126219766 52 220,118 1 rs714237 rs2299470 25.109 0
GRM8 chr9: 1399761-136852891 25442 135,453,131 1 rs12341621
rs2789864 36.66 0 GSN chr5: 78661854-78673236 5 11,383 1 rs7732902
rs12187625 11.269 0 HOMER1 chr5: 78629346-78765405 28 136,060 1
rs9293769 rs7710089 19.586 0 HOMER1 chr6: 31289284-56929863 15402
25,640,580 3 rs9265170 cnvi0015437 25.647 0 HSP90AB1 chr3:
234726-6328081 2293 6,093,356 3 rs7632811 rs1595039 106.207 0 ITPR1
chr6: 69900102-165298477 19424 95,398,376 1 rs779484 rs1511063
38.802 0 LAMA4 chr4: 28602089-187390861 26883 158,788,773 1
rs16880825 rs1376534 32.409 0 LRP2BP chr6: 31289284-56929863 15402
25,640,580 3 rs9265170 cnvi0015437 25.647 0 LTA chr6:
31281438-31878433 -8677 596,996 1 cnvi0006173 rs519417 56.15 0 LTA
chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676
20.948 0 MARK4 chr18: 58316345-58573151 29 256,807 1 rs9964060
rs7233420 16.278 276344 MC4R chr18: 58267843-58310343 9 42,501 3
rs7240781 rs1346831 19.841 227842 MC4R chr18: 58117122-58120972 5
3,851 1 rs9967057 rs2000778 14.81 77121 MC4R chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0
MRPL14 chr10: 33340331-123920784 17036 90,580,454 1 rs10430560
rs1885516 36.263 0 MRPS16 chr21: 14601415-48084989 8249 33,483,575
3 rs2775537 rs2839378 6900.018 0 MX1 chr21: 14901920-48084989 8239
33,183,070 3 rs12626247 rs2839378 11089.459 0 MX1 chr8:
84037048-138506934 11020 54,469,887 1 rs13265895 rs1849692 72.228 0
MYC chr6: 69900102-165298477 19424 95,398,376 1 rs779484 rs1511063
38.802 0 MYO6 chr9: 1399761-136852891 25442 135,453,131 1
rs12341621 rs2789864 36.66 0 NANS chr2: 152065396-152499580 79
434,185 3 rs289871 rs4664494 89.838 0 NMI chr4: 28602089-187390861
26883 158,788,773 1 rs16880825 rs1376534 32.409 0 NPY2R chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
PAFAH1B3 chr2: 38328178-128536280 15926 90,208,103 1 rs232542
rs7608627 30.628 0 PCBP1 chr21: 14601415-48084989 8249 33,483,575 3
rs2775537 rs2839378 6900.018 0 PCBP3 chr21: 14901920-48084989 8239
33,183,070 3 rs12626247 rs2839378 11089.459 0 PCBP3 chr5:
140225908-140233387 8 7,480 1 rs7730895 rs10054866 22.285 0 PCDHA4
chr5: 140227999-140232346 3 4,348 0 rs4151689 rs17119246 10.222 0
PCDHA4 chr5: 140227999-140232346 3 4,348 1 rs4151689 rs17119246
14.695 0 PCDHA4 chr5: 140225908-140233387 8 7,480 1 rs7730895
rs10054866 18.25 0 PCDHA4 chr6: 69900102-165298477 19424 95,398,376
1 rs779484 rs1511063 38.802 0 PCMT1 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 PDCD5 chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
PHKB chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 PHKG2 chr6: 31289284-56929863 15402 25,640,580
3 rs9265170 cnvi0015437 25.647 0 PLA2G7 chr16: 16348605-90291153
14331 73,942,549 4 rs2856546 rs12325137 10.397 0 PLCG2 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
PPP2R1A chr17: 64287309-64288738 4 1,430 1 cnvi0008597 cnvi0008599
18.218 10188 PRKCA chr17: 64287309-64288738 4 1,430 1 cnvi0008597
cnvi0008599 15.126 10188 PRKCA chr10: 33340331-123920784 17036
90,580,454 1 rs10430560 rs1885516 36.263 0 PRLHR chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
PRMT1 chr9: 1399761-136852891 25442 135,453,131 1 rs12341621
rs2789864 36.66 0 PSAT1 chr9: 81429567-81443855 7 14,289 3
rs12345239 rs6559415 5.259 484558 PSAT1 chr11: 198510-244552 23
46,043 1 rs3802985 rs2272566 13.271 0 PSMD13 chr14:
22513116-32242747 1997 9,729,632 1 rs4982546 rs17098165 31.673 0
PSME1 chr1: 188802542-196412070 1346 7,609,529 1 rs10158341
rs12075206 61.486 0 RGS2 chr2: 152065396-152499580 79 434,185 3
rs289871 rs4664494 89.838 0 RIF1 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 RUVBL2 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
RYR1 chr2: 38328178-128536280 15926 90,208,103 1 rs232542 rs7608627
30.628 0 SCTR chr6: 1171596-29895228 43 28,723,633 0 rs3128994
rs9259831 43.568 0 SERPINB9 chr6: 2585208-31281876 -2 28,696,669 1
rs1634746 rs1634747 31.615 0 SERPINB9 chr9: 1399761-136852891 25442
135,453,131 1 rs12341621 rs2789864 36.66 0 SET chr21:
14601415-48084989 8249 33,483,575 3 rs2775537 rs2839378 6900.018 0
SETD4 chr21: 14901920-48084989 8239 33,183,070 3 rs12626247
rs2839378 11089.459 0 SETD4 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 SHANK1 chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
SIAH1 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 SNCA chr9: 1399761-136852891 25442 135,453,131 1
rs12341621 rs2789864 36.66 0 SYK chr6: 69900102-165298477 19424
95,398,376 1 rs779484 rs1511063 38.802 0 TCP1 chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0
TEAD3 chr10: 33340331-123920784 17036 90,580,454 1 rs10430560
rs1885516 36.263 0 TFAM chr15: 27740007-30366247 464 2,626,241 1
rs6497213 rs10152753 44.251 0 TJP1 chr4: 28602089-187390861 26883
158,788,773 1 rs16880825 rs1376534 32.409 0 TLR10 chr3:
171220708-171220919 3 212 1 cnvi0011707 cnvi0011705 9.195 42511
TNIK chr6: 19044000-31286381 -6774 12,242,382 0 rs6922929 rs9265057
32.224 0 TUBB chr6: 2585208-31281876 -2 28,696,669 1 rs1634746
rs1634747 31.615 0 TUBB chr9: 1399761-136852891 25442 135,453,131 1
rs12341621 rs2789864 36.66 0 TXN chr4: 28602089-187390861 26883
158,788,773 1 rs16880825 rs1376534 32.409 0 UCHL1 chr2:
38328178-128536280 15926 90,208,103 1 rs232542 rs7608627 30.628 0
ZAP70
TABLE-US-00004 TABLE 3 Distance State, From mGluR Chr:
Start-Stop(hg19) NumSNP Length CN StartSNP EndSNP Confidence Gene
Gene chr6: 69900102-165298477 19424 95,398,376 1 rs779484 rs1511063
38.802 0 ACAT2 chr2: 38328178-128536280 15926 90,208,103 1 rs232542
rs7608627 30.628 0 ACTR2 chr8: 84037048-138506934 11020 54,469,887
1 rs13265895 rs1849692 72.228 0 ADCY8 chr2: 38328178-128536280
15926 90,208,103 1 rs232542 rs7608627 30.628 0 ADD2 chr10:
33340331-123920784 17036 90,580,454 1 rs10430560 rs1885516 36.263 0
ADD3 chr10: 33340331-123920784 17036 90,580,454 1 rs10430560
rs1885516 36.263 0 ADRA2A chr6: 69900102-165298477 19424 95,398,376
1 rs779484 rs1511063 38.802 0 AKAP12 chr15: 73186518-94501564 4223
21,315,047 1 rs1947219 rs4344687 34.841 0 AKAP13 chr14:
105163532-105268228 14 104,697 3 rs7140154 rs4983387 15.629 0 AKT1
chr14: 105126354-105277209 20 150,856 3 rs4074077 rs4983559 14.395
0 AKT1 chr14: 105154105-105268228 15 114,124 1 rs3809456 rs4983387
16.554 0 AKT1 chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 ALDOA chr4: 28602089-187390861 26883
158,788,773 1 rs16880825 rs1376534 32.409 0 ANK2 chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
ANXA2 chr10: 33340331-123920784 17036 90,580,454 1 rs10430560
rs1885516 36.263 0 ANXA7 chr21: 14601415-48084989 8249 33,483,575 3
rs2775537 rs2839378 6900.018 0 APP chr21: 14901920-48084989 8239
33,183,070 3 rs12626247 rs2839378 11089.459 0 APP chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
APTX chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 ARHGAP24 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 ARHGEF1 chr10:
33340331-123920784 17036 90,580,454 1 rs10430560 rs1885516 36.263 0
ARL3 chr3: 234726-6328081 2293 6,093,356 3 rs7632811 rs1595039
106.207 0 ARL8B chr12: 84152210-113464649 5560 29,312,440 1
rs10862748 rs16942470 28.181 0 ATP2B1 chr6: 1171596-29895228 43
28,723,633 0 rs3128994 rs9259831 43.568 0 ATXN1 chr6:
2585208-31281876 -2 28,696,669 1 rs1634746 rs1634747 31.615 0 ATXN1
chr12: 63538458-63630987 15 92,530 1 rs10747983 rs1456040 22.29 0
AVPR1A chr9: 1399761-136852891 25442 135,453,131 1 rs12341621
rs2789864 36.66 0 B4GALT1 chr4: 28602089-187390861 26883
158,788,773 1 rs16880825 rs1376534 32.409 0 BANK1 chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
BCAR1 chr14: 96684770-96688669 4 3,900 1 rs4905466 rs4905469 14.379
0 BDKRB2 chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 BRD7 chr4: 28602089-187390861 26883 158,788,773
1 rs16880825 rs1376534 32.409 0 C4orf17 chr9: 1399761-136852891
25442 135,453,131 1 rs12341621 rs2789864 36.66 0 C9orf25 chr8:
60997355-61008986 10 11,632 1 rs1464327 rs2611360 12.59 92437 CA8
chr8: 60654261-60775727 18 121,467 1 rs1949102 rs7822560 11.681
325696 CA8 chr12: 2245636-2252924 7 7,289 1 rs12579529 rs4765899
11.807 0 CACNA1C chr12: 2245636-2252924 7 7,289 0 rs12579529
rs4765899 41.646 0 CACNA1C chr12: 2245636-2252924 7 7,289 1
rs12579529 rs4765899 19.469 0 CACNA1C chr16: 16348605-90291153
14331 73,942,549 4 rs2856546 rs12325137 10.397 0 CALB2 chr2:
38328178-128536280 15926 90,208,103 1 rs232542 rs7608627 30.628 0
CALM2 chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 CALM3 chr7: 44376785-44388619 4 11,835 1
rs12535537 rs10257749 12.04 11555 CAMK2B chr10: 33340331-123920784
17036 90,580,454 1 rs10430560 rs1885516 36.263 0 CAMK2G chr4:
28602089-187390861 26883 158,788,773 1 rs16880825 rs1376534 32.409
0 CASP3 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 CASP6 chr10: 33340331-123920784 17036 90,580,454
1 rs10430560 rs1885516 36.263 0 CASP7 chr7: 115525876-115956129 68
430,254 1 rs6948855 rs12667497 28.379 0 CAV1 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
CCNE1 chr10: 33340331-123920784 17036 90,580,454 1 rs10430560
rs1885516 36.263 0 CHAT chr10: 33340331-123920784 17036 90,580,454
1 rs10430560 rs1885516 36.263 0 CHUK chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 CIC chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
CMIP chr6: 69900102-165298477 19424 95,398,376 1 rs779484 rs1511063
38.802 0 CNR1 chr3: 118926656-121160369 362 2,233,714 1 rs4591498
rs4676677 42.841 0 COX17 chr4: 28602089-187390861 26883 158,788,773
1 rs16880825 rs1376534 32.409 0 CPE chr12: 84152210-113464649 5560
29,312,440 1 rs10862748 rs16942470 28.181 0 CRADD chr10:
33340331-123920784 17036 90,580,454 1 rs10430560 rs1885516 36.263 0
CREM chr17: 43657921-43728376 4 70,456 1 rs9898857 rs417968 10.243
0 CRHR1 chr2: 38328178-128536280 15926 90,208,103 1 rs232542
rs7608627 30.628 0 CRIPT chr16: 16348605-90291153 14331 73,942,549
4 rs2856546 rs12325137 10.397 0 CSNK2A2 chr6: 31289284-56929863
15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0 CSNK2B chr6:
31281438-31878433 -8677 596,996 1 cnvi0006173 rs519417 56.15 0
CSNK2B chr12: 84152210-113464649 5560 29,312,440 1 rs10862748
rs16942470 28.181 0 DCN chr10: 33340331-123920784 17036 90,580,454
1 rs10430560 rs1885516 36.263 0 DDIT4 chr9: 1399761-136852891 25442
135,453,131 1 rs12341621 rs2789864 36.66 0 DIRAS2 chr17:
7088923-7385454 57 296,532 3 rs11650232 rs3760422 2.875 0 DLG4
chr9: 1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864
36.66 0 DNM1 chr6: 31289284-56929863 15402 25,640,580 3 rs9265170
cnvi0015437 25.647 0 DST chr1: 1227897-1273116 14 45,220 3
rs3737721 rs307371 16.779 0 DVL1 chr1: 1163804-1314172 -103 150,369
3 rs7515488 rs2477777 25.97 0 DVL1 chr1: 1191870-1314172 -109
122,303 3 rs3818646 rs2477777 21.258 0 DVL1 chr1: 1239339-1307872
-123 68,534 3 rs11260584 rs2477774 18.526 0 DVL1 chr17:
7088923-7385454 57 296,532 3 rs11650232 rs3760422 2.875 0 DVL2
chr8: 144656187-144687092 17 30,906 3 rs12546272 rs896962 17.039 0
EEF1D chr13: 100580353-112257226 3428 11,676,874 1 rs10851110
rs1341154 52.726 0 EFNB2 chr6: 69900102-165298477 19424 95,398,376
1 rs779484 rs1511063 38.802 0 EPB41L2 chr6: 69900102-165298477
19424 95,398,376 1 rs779484 rs1511063 38.802 0 ESR1 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
ETHE1 chr10: 33340331-123920784 17036 90,580,454 1 rs10430560
rs1885516 36.263 0 FAS chr19: 22609759-55294329 -4174 32,684,571 3
rs7251413 rs2569676 20.948 0 FFAR1 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 FFAR2 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
FPR1 chr12: 69925695-70075933 47 150,239 1 rs518634 rs775474 15.726
0 FRS2 chr2: 38328178-128536280 15926 90,208,103 1 rs232542
rs7608627 30.628 0 FSHR chr2: 49533498-49537795 4 4,298 1 rs2350017
rs1991387 15.685 151832 FSHR chr15: 73186518-94501564 4223
21,315,047 1 rs1947219 rs4344687 34.841 0 FURIN chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
FXN chr6: 69900102-165298477 19424 95,398,376 1 rs779484 rs1511063
38.802 0 FYN chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 GABRR1 chr6: 69900102-165298477 19424 95,398,376
1 rs779484 rs1511063 38.802 0 GABRR2 chr4: 28602089-187390861 26883
158,788,773 1 rs16880825 rs1376534 32.409 0 GC chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
GFI1B chr2: 38328178-128536280 15926 90,208,103 1 rs232542
rs7608627 30.628 0 GFPT1 chr12: 84152210-113464649 5560 29,312,440
1 rs10862748 rs16942470 28.181 0 GIT2 chr6: 69900102-165298477
19424 95,398,376 1 rs779484 rs1511063 38.802 0 GJA1 chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0
GLP1R chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 GNAO1 chr16: 56362725-56384720 13 21,996 1
rs2241952 rs3790113 20.256 0 GNAO1 chr9: 1399761-136852891 25442
135,453,131 1 rs12341621 rs2789864 36.66 0 GNAQ chr10:
33340331-123920784 17036 90,580,454 1 rs10430560 rs1885516 36.263 0
GOT1 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 GPM6A chr4: 28602089-187390861 26883 158,788,773
1 rs16880825 rs1376534 32.409 0 GRIA2 chr21: 14601415-48084989 8249
33,483,575 3 rs2775537 rs2839378 6900.018 0 GRIK1 chr21:
14901920-48084989 8239 33,183,070 3 rs12626247 rs2839378 11089.459
0 GRIK1 chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 GRM1 chr7: 85774549-86281198 56 506,650 3
rs41440 rs1024516 24.091 0 GRM3 chr6: 31289284-56929863 15402
25,640,580 3 rs9265170 cnvi0015437 25.647 0 GRM4 chr11:
88696662-88744425 11 47,764 3 rs477399 rs7932640 10.213 0 GRM5
chr3: 7405044-7411730 3 6,687 1 rs13091584 rs7647001 16.073 0 GRM7
chr7: 125999649-126219766 52 220,118 1 rs714237 rs2299470 25.109 0
GRM8 chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 GSK3A chr3: 118926656-121160369 362 2,233,714 1
rs4591498 rs4676677 42.841 0 GSK3B chr9: 1399761-136852891 25442
135,453,131 1 rs12341621 rs2789864 36.66 0 GSN chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
HABP4 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 HAND2 chr6: 19044000-31286381 -6774 12,242,382 0
rs6922929 rs9265057 32.224 0 HLA-A chr6: 2585208-31281876 -2
28,696,669 1 rs1634746 rs1634747 31.615 0 HLA-A chr6:
19044000-31286381 -6774 12,242,382 0 rs6922929 rs9265057 32.224 0
HLA-C chr6: 2585208-31281876 -2 28,696,669 1 rs1634746 rs1634747
31.615 0 HLA-C chr6: 31289284-56929863 15402 25,640,580 3 rs9265170
cnvi0015437 25.647 0 HLA-DQA2 chr21: 14601415-48084989 8249
33,483,575 3 rs2775537 rs2839378 6900.018 0 HMGN1 chr21:
14901920-48084989 8239 33,183,070 3 rs12626247 rs2839378 11089.459
0 HMGN1 chr5: 162867195-162958461 20 91,267 1 rs2069347 rs7722476
13.271 0 HMMR chr5: 78661854-78673236 5 11,383 1 rs7732902
rs12187625 11.269 0 HOMER1 chr5: 78629346-78765405 28 136,060 1
rs9293769 rs7710089 19.586 0 HOMER1 chr15: 73186518-94501564 4223
21,315,047 1 rs1947219 rs4344687 34.841 0 HOMER2 chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0
HSP90AB1 chr6: 31289284-56929863 15402 25,640,580 3 rs9265170
cnvi0015437 25.647 0 HSPA1A chr6: 31281438-31878433 -8677 596,996 1
cnvi0006173 rs519417 56.15 0 HSPA1A chr6: 31289284-56929863 15402
25,640,580 3 rs9265170 cnvi0015437 25.647 0 HSPA1B chr6:
31281438-31878433 -8677 596,996 1 cnvi0006173 rs519417 56.15 0
HSPA1B chr7: 75337644-77143217 201 1,805,574 1 rs10954377 rs6976567
29.447 0 HSPB1 chr16: 16348605-90291153 14331 73,942,549 4
rs2856546 rs12325137 10.397 0 IL4R chr3: 234726-6328081 2293
6,093,356 3 rs7632811 rs1595039 106.207 0 IL5RA chr15:
73186518-94501564 4223 21,315,047 1 rs1947219 rs4344687 34.841 0
IQGAP1 chr21: 14601415-48084989 8249 33,483,575 3 rs2775537
rs2839378 6900.018 0 ITGB2 chr21: 14901920-48084989 8239 33,183,070
3 rs12626247 rs2839378 11089.459 0 ITGB2 chr3: 234726-6328081 2293
6,093,356 3 rs7632811 rs1595039 106.207 0 ITPR1 chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647
0
ITPR3 chr21: 14601415-48084989 8249 33,483,575 3 rs2775537
rs2839378 6900.018 0 KCNE1 chr21: 35726698-35904697 53 178,000 3
rs4817646 rs7280739 93.548 0 KCNE1 chr21: 14901920-48084989 8239
33,183,070 3 rs12626247 rs2839378 11089.459 0 KCNE1 chr17:
68408395-68506682 20 98,288 1 rs12601221 rs7218368 15.131 232212
KCNJ2 chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 KCNN4 chr20: 62038277-62053754 7 15,478 3
rs1801475 rs3893041 7.196 0 KCNQ2 chr20: 62045709-62053754 4 8,046
3 rs2281570 rs3893041 7.185 0 KCNQ2 chr8: 84037048-138506934 11020
54,469,887 1 rs13265895 rs1849692 72.228 0 KCNQ3 chr6:
69900102-165298477 19424 95,398,376 1 rs779484 rs1511063 38.802 0
KCNQ5 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 KDR chr5: 132036252-132114847 11 78,596 1
rs1468216 rs30514 12.981 0 KIF3A chr4: 28602089-187390861 26883
158,788,773 1 rs16880825 rs1376534 32.409 0 KIT chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
KLK10 chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 LAMA4 chr6: 69900102-165298477 19424 95,398,376
1 rs779484 rs1511063 38.802 0 LOC154092 chr4: 28602089-187390861
26883 158,788,773 1 rs16880825 rs1376534 32.409 0 LRP2BP chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0
LTA chr6: 31281438-31878433 -8677 596,996 1 cnvi0006173 rs519417
56.15 0 LTA chr14: 22513116-32242747 1997 9,729,632 1 rs4982546
rs17098165 31.673 0 LTB4R chr6: 31289284-56929863 15402 25,640,580
3 rs9265170 cnvi0015437 25.647 0 MAD2L1BP chr19: 22609759-55294329
-4174 32,684,571 3 rs7251413 rs2569676 20.948 0 MAP3K10 chr6:
69900102-165298477 19424 95,398,376 1 rs779484 rs1511063 38.802 0
MAP3K7 chr6: 31289284-56929863 15402 25,640,580 3 rs9265170
cnvi0015437 25.647 0 MAPK14 chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 MAPK3 chr6:
69900102-165298477 19424 95,398,376 1 rs779484 rs1511063 38.802 0
MARCKS chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 MARK4 chr18: 58316345-58573151 29 256,807 1
rs9964060 rs7233420 16.278 276344 MC4R chr18: 58267843-58310343 9
42,501 3 rs7240781 rs1346831 19.841 227842 MC4R chr18:
58117122-58120972 5 3,851 1 rs9967057 rs2000778 14.81 77121 MC4R
chr9: 1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864
36.66 0 MLLT3 chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 MPHOSPH6 chr6: 31289284-56929863 15402
25,640,580 3 rs9265170 cnvi0015437 25.647 0 MRPL14 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
MRPS12 chr10: 33340331-123920784 17036 90,580,454 1 rs10430560
rs1885516 36.263 0 MRPS16 chr21: 14601415-48084989 8249 33,483,575
3 rs2775537 rs2839378 6900.018 0 MRPS6 chr21: 14901920-48084989
8239 33,183,070 3 rs12626247 rs2839378 11089.459 0 MRPS6 chr21:
14601415-48084989 8249 33,483,575 3 rs2775537 rs2839378 6900.018 0
MX1 chr21: 14901920-48084989 8239 33,183,070 3 rs12626247 rs2839378
11089.459 0 MX1 chr8: 84037048-138506934 11020 54,469,887 1
rs13265895 rs1849692 72.228 0 MYC chr6: 69900102-165298477 19424
95,398,376 1 rs779484 rs1511063 38.802 0 MYO6 chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
NANS chr8: 84037048-138506934 11020 54,469,887 1 rs13265895
rs1849692 72.228 0 NCALD chr10: 33340331-123920784 17036 90,580,454
1 rs10430560 rs1885516 36.263 0 NFKB2 chr19: 22609759-55294329
-4174 32,684,571 3 rs7251413 rs2569676 20.948 0 NFKBIB chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0
NFKBIE chr2: 152065396-152499580 79 434,185 3 rs289871 rs4664494
89.838 0 NMI chr2: 38328178-128536280 15926 90,208,103 1 rs232542
rs7608627 30.628 0 NPHP1 chr4: 28602089-187390861 26883 158,788,773
1 rs16880825 rs1376534 32.409 0 NPY2R chr19: 22609759-55294329
-4174 32,684,571 3 rs7251413 rs2569676 20.948 0 NUCB1 chr6:
69900102-165298477 19424 95,398,376 1 rs779484 rs1511063 38.802 0
OPRM1 chr6: 154379152-154393884 5 14,733 1 rs3823010 rs3778153
18.342 0 OPRM1 chr19: 22609759-55294329 -4174 32,684,571 3
rs7251413 rs2569676 20.948 0 PAFAH1B3 chr5: 101558083-102529401 120
971,319 1 rs4323206 rs26819 39.848 0 PAM chr16: 16348605-90291153
14331 73,942,549 4 rs2856546 rs12325137 10.397 0 PARD6A chr2:
38328178-128536280 15926 90,208,103 1 rs232542 rs7608627 30.628 0
PCBP1 chr21: 14601415-48084989 8249 33,483,575 3 rs2775537
rs2839378 6900.018 0 PCBP3 chr21: 14901920-48084989 8239 33,183,070
3 rs12626247 rs2839378 11089.459 0 PCBP3 chr5: 140225908-140233387
8 7,480 1 rs7730895 rs10054866 22.285 0 PCDHA4 chr5:
140227999-140232346 3 4,348 0 rs4151689 rs17119246 10.222 0 PCDHA4
chr5: 140227999-140232346 3 4,348 1 rs4151689 rs17119246 14.695 0
PCDHA4 chr5: 140225908-140233387 8 7,480 1 rs7730895 rs10054866
18.25 0 PCDHA4 chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 PCMT1 chr21: 14601415-48084989 8249 33,483,575 3
rs2775537 rs2839378 6900.018 0 PCNT chr21: 47836122-47856106 5
19,985 1 rs2839245 rs2236616 11.082 0 PCNT chr21: 14901920-48084989
8239 33,183,070 3 rs12626247 rs2839378 11089.459 0 PCNT chr21:
14601415-48084989 8249 33,483,575 3 rs2775537 rs2839378 6900.018 0
PCP4 chr21: 14901920-48084989 8239 33,183,070 3 rs12626247
rs2839378 11089.459 0 PCP4 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 PDCD5 chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
PDCL chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 PHKB chr16: 16348605-90291153 14331 73,942,549
4 rs2856546 rs12325137 10.397 0 PHKG2 chr6: 31289284-56929863 15402
25,640,580 3 rs9265170 cnvi0015437 25.647 0 PLA2G7 chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
PLCG2 chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 PLEKHA4 chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 PLK1 chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
POLR2C chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 PPEF2 chr19: 22609759-55294329 -4174 32,684,571
3 rs7251413 rs2569676 20.948 0 PPP1R14A chr19: 22609759-55294329
-4174 32,684,571 3 rs7251413 rs2569676 20.948 0 PPP2R1A chr4:
28602089-187390861 26883 158,788,773 1 rs16880825 rs1376534 32.409
0 PPP3CA chr10: 46961667-47748912 104 787,246 3 rs506372 rs3013867
193.838 0 PPYR1 chr10: 33340331-123920784 17036 90,580,454 1
rs10430560 rs1885516 36.263 0 PPYR1 chr10: 46961667-47748912 104
787,246 3 rs506372 rs3013867 112.468 0 PPYR1 chr10:
46961667-47149117 12 187,451 3 rs506372 rs4979753 13.078 0 PPYR1
chr10: 46961667-47703613 102 741,947 3 rs506372 rs4128664 75.136 0
PPYR1 chr17: 64287309-64288738 4 1,430 1 cnvi0008597 cnvi0008599
18.218 10188 PRKCA chr17: 64287309-64288738 4 1,430 1 cnvi0008597
cnvi0008599 15.126 10188 PRKCA chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 PRKCG chr10:
33340331-123920784 17036 90,580,454 1 rs10430560 rs1885516 36.263 0
PRKG1 chr10: 53388223-53399900 4 11,678 1 rs7915186 rs4486574
14.875 0 PRKG1 chr10: 33340331-123920784 17036 90,580,454 1
rs10430560 rs1885516 36.263 0 PRLHR chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 PRMT1 chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
PSAT1 chr9: 81429567-81443855 7 14,289 3 rs12345239 rs6559415 5.259
484558 PSAT1 chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 PSG9 chr11: 198510-244552 23 46,043 1 rs3802985
rs2272566 13.271 0 PSMD13 chr14: 22513116-32242747 1997 9,729,632 1
rs4982546 rs17098165 31.673 0 PSME1 chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 PTGIR chr12:
84152210-113464649 5560 29,312,440 1 rs10862748 rs16942470 28.181 0
PTPN11 chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 RABAC1 chr2: 38328178-128536280 15926 90,208,103
1 rs232542 rs7608627 30.628 0 RALB chr14: 22513116-32242747 1997
9,729,632 1 rs4982546 rs17098165 31.673 0 RBM23 chr2:
38328178-128536280 15926 90,208,103 1 rs232542 rs7608627 30.628 0
REL chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676
20.948 0 RELB chr10: 33340331-123920784 17036 90,580,454 1
rs10430560 rs1885516 36.263 0 RGS10 chr1: 188802542-196412070 1346
7,609,529 1 rs10158341 rs12075206 61.486 0 RGS13 chr1:
191836316-191875752 12 39,437 1 rs2211195 rs9427811 47.094 251840
RGS18 chr1: 188802542-196412070 1346 7,609,529 1 rs10158341
rs12075206 61.486 0 RGS18 chr1: 191836316-191875752 12 39,437 1
rs2211195 rs9427811 47.13 251840 RGS18 chr1: 188802542-196412070
1346 7,609,529 1 rs10158341 rs12075206 61.486 0 RGS2 chr4:
28602089-187390861 26883 158,788,773 1 rs16880825 rs1376534 32.409
0 RHOH chr11: 198510-244552 23 46,043 1 rs3802985 rs2272566 13.271
0 RIC8A chr12: 84152210-113464649 5560 29,312,440 1 rs10862748
rs16942470 28.181 0 RIC8B chr2: 152065396-152499580 79 434,185 3
rs289871 rs4664494 89.838 0 RIF1 chr6: 1171596-29895228 43
28,723,633 0 rs3128994 rs9259831 43.568 0 RIPK1 chr6:
2585208-31281876 -2 28,696,669 1 rs1634746 rs1634747 31.615 0 RIPK1
chr8: 84037048-138506934 11020 54,469,887 1 rs13265895 rs1849692
72.228 0 RIPK2 chr9: 1399761-136852891 25442 135,453,131 1
rs12341621 rs2789864 36.66 0 RPL12 chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 RRAD chr2:
38328178-128536280 15926 90,208,103 1 rs232542 rs7608627 30.628 0
RTN4 chr19: 22609759-55294329 -4174 32,684,571 3 rs7251413
rs2569676 20.948 0 RUVBL2 chr19: 22609759-55294329 -4174 32,684,571
3 rs7251413 rs2569676 20.948 0 RYR1 chr2: 38328178-128536280 15926
90,208,103 1 rs232542 rs7608627 30.628 0 SCTR chr8:
84037048-138506934 11020 54,469,887 1 rs13265895 rs1849692 72.228 0
SDC2 chr6: 1171596-29895228 43 28,723,633 0 rs3128994 rs9259831
43.568 0 SERPINB9 chr6: 2585208-31281876 -2 28,696,669 1 rs1634746
rs1634747 31.615 0 SERPINB9 chr9: 1399761-136852891 25442
135,453,131 1 rs12341621 rs2789864 36.66 0 SET chr21:
14601415-48084989 8249 33,483,575 3 rs2775537 rs2839378 6900.018 0
SETD4 chr21: 14901920-48084989 8239 33,183,070 3 rs12626247
rs2839378 11089.459 0 SETD4 chr12: 84152210-113464649 5560
29,312,440 1 rs10862748 rs16942470 28.181 0 SH2B3 chr19:
22609759-55294329 -4174 32,684,571 3 rs7251413 rs2569676 20.948 0
SHANK1 chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 SIAH1 chr19: 22609759-55294329 -4174 32,684,571
3 rs7251413 rs2569676 20.948 0 SIRT2 chr9: 1399761-136852891 25442
135,453,131 1 rs12341621 rs2789864 36.66 0 SLC1A1 chr16:
16348605-90291153 14331 73,942,549 4 rs2856546 rs12325137 10.397 0
SMPD3 chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 SNAP91 chr4: 28602089-187390861 26883
158,788,773 1 rs16880825 rs1376534 32.409 0 SNCA
chr6: 19044000-31286381 -6774 12,242,382 0 rs6922929 rs9265057
32.224 0 SOX4 chr6: 1171596-29895228 43 28,723,633 0 rs3128994
rs9259831 43.568 0 SOX4 chr6: 21599766-21623715 6 23,950 1
rs9295513 rs1744855 10.637 917 SOX4 chr6: 2585208-31281876 -2
28,696,669 1 rs1634746 rs1634747 31.615 0 SOX4 chr8:
84037048-138506934 11020 54,469,887 1 rs13265895 rs1849692 72.228 0
SPAG1 chr16: 16348605-90291153 14331 73,942,549 4 rs2856546
rs12325137 10.397 0 SPG7 chr4: 28602089-187390861 26883 158,788,773
1 rs16880825 rs1376534 32.409 0 SPP1 chr2: 38328178-128536280 15926
90,208,103 1 rs232542 rs7608627 30.628 0 SPTBN1 chr13:
34141695-34143447 3 1,753 1 cnvi0006685 rs9285097 14.343 0 STARD13
chr13: 34141695-34143447 3 1,753 1 cnvi0006685 rs9285097 13.354 0
STARD13 chr13: 34141695-34143447 3 1,753 0 cnvi0006685 rs9285097
14.964 0 STARD13 chr19: 22609759-55294329 -4174 32,684,571 3
rs7251413 rs2569676 20.948 0 STRN4 chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 STX4 chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
STXBP1 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 SULT1E1 chr6: 69900102-165298477 19424
95,398,376 1 rs779484 rs1511063 38.802 0 SUMO4 chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
SYK chr12: 79441371-79473659 7 32,289 3 rs17273032 rs11838060
15.101 0 SYT1 chr2: 160064395-160668661 110 604,267 1 rs6737837
rs1549579 37.853 0 TANC1 chr2: 161901301-162018643 25 117,343 1
rs4664395 rs1267059 21.357 0 TANK chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 TAOK2 chr19:
1114119-1876566 213 762,448 3 rs3746162 rs10414308 25.766 0 TCF3
chr6: 69900102-165298477 19424 95,398,376 1 rs779484 rs1511063
38.802 0 TCP1 chr6: 31289284-56929863 15402 25,640,580 3 rs9265170
cnvi0015437 25.647 0 TEAD3 chr10: 33340331-123920784 17036
90,580,454 1 rs10430560 rs1885516 36.263 0 TFAM chr2:
38328178-128536280 15926 90,208,103 1 rs232542 rs7608627 30.628 0
TGFA chr21: 14601415-48084989 8249 33,483,575 3 rs2775537 rs2839378
6900.018 0 TIAM1 chr21: 14901920-48084989 8239 33,183,070 3
rs12626247 rs2839378 11089.459 0 TIAM1 chr15: 27740007-30366247 464
2,626,241 1 rs6497213 rs10152753 44.251 0 TJP1 chr4:
28602089-187390861 26883 158,788,773 1 rs16880825 rs1376534 32.409
0 TLR10 chr3: 171220708-171220919 3 212 1 cnvi0011707 cnvi0011705
9.195 42511 TNIK chr4: 2768630-2772530 3 3,901 1 rs6600766
rs7695151 12.121 10527 TNIP2 chr16: 16348605-90291153 14331
73,942,549 4 rs2856546 rs12325137 10.397 0 TRADD chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
TRAF1 chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 TRIM2 chr4: 28602089-187390861 26883 158,788,773
1 rs16880825 rs1376534 32.409 0 TRPC3 chr12: 84152210-113464649
5560 29,312,440 1 rs10862748 rs16942470 28.181 0 TRPV4 chr6:
31289284-56929863 15402 25,640,580 3 rs9265170 cnvi0015437 25.647 0
TTBK1 chr6: 69900102-165298477 19424 95,398,376 1 rs779484
rs1511063 38.802 0 UK chr6: 19044000-31286381 -6774 12,242,382 0
rs6922929 rs9265057 32.224 0 TUBB chr6: 2585208-31281876 -2
28,696,669 1 rs1634746 rs1634747 31.615 0 TUBB chr9:
1399761-136852891 25442 135,453,131 1 rs12341621 rs2789864 36.66 0
TXN chr4: 28602089-187390861 26883 158,788,773 1 rs16880825
rs1376534 32.409 0 UCHL1 chr10: 33340331-123920784 17036 90,580,454
1 rs10430560 rs1885516 36.263 0 VCL chr19: 22609759-55294329 -4174
32,684,571 3 rs7251413 rs2569676 20.948 0 WDR62 chr7:
75337644-77143217 201 1,805,574 1 rs10954377 rs6976567 29.447 0
YWHAG chr8: 84037048-138506934 11020 54,469,887 1 rs13265895
rs1849692 72.228 0 YWHAZ chr2: 38328178-128536280 15926 90,208,103
1 rs232542 rs7608627 30.628 0 ZAP70
* * * * *