GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of Mendelian Variants in Complex Disease
et al. (2011) GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of
Mendelian Variants in Complex Disease. PLoS ONE 6(11): e27134. doi:10.1371/journal.pone.0027134
GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of Mendelian Variants in Complex Disease
Yutao Liu 0
Jason Gibson 0
Joshua Wheeler 0
Lydia Coulter Kwee 0
Cecile M. Santiago-Turla 0
Stephen K. Akafo 0
Paul R. Lichter 0
Douglas E. Gaasterland 0
Sayoko E. Moroi 0
Pratap Challa 0
Leon W. 0
Christopher A. Girkin 0
Donald L. Budenz 0
Julia E. Richards 0
R. Rand Allingham 0
Michael A. 0
Reiner Albert Veitia, Institut Jacques Monod, France
0 1 Center for Human Genetics, Duke University Medical Center , Durham , North Carolina, United States of America, 2 Department of Medicine, Duke University Medical Center , Durham , North Carolina, United States of America, 3 Duke University Eye Center, Duke University Medical Center , Durham , North Carolina, United States of America, 4 Unit of Ophthalmology, Department of Surgery, University of Ghana Medical School , Korle Bu , Ghana , 5 Department of Ophthalmology and Visual Sciences, University of Michigan , Ann Arbor , Michigan, United States of America, 6 Department of Epidemiology, University of Michigan , Ann Arbor , Michigan, United States of America, 7 Eye Doctors of Washington, Chevy Chase, Maryland, United States of America, 8 Department of Ophthalmology, University of Alabama at Birmingham , Birmingham , Alabama, United States of America, 9 Department of Ophthalmology, Bascom Palmer Eye Institute , Miami, Florida , United States of America
DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI 21.1-12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6-16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG.
Funding: This work is supported by National Institutes of Health (NIH) grants R01EY013315 (MAH), R01EY019126 (MAH), R03EY014939 (RRA), R01EY015543 (RRA),
R01EY011671 (JER), R01EY09580 (JER), the Glaucoma Research Foundation (YL), National Glaucoma Research of American Health Assistance Foundation (YL),
Research to Prevent Blindness (JER) and The Glaucoma Foundation (YL). This study was also supported in part by Duke Universitys CTSA grant 1 UL1 RR024128-01
from NCRR/NIH, as well as the research infrastructure of the Duke Center for Human Genetics. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Glaucoma is the leading cause of irreversible blindness worldwide
. As a heterogeneous group of disorders, glaucoma is a pathologic
condition characterized by progressive loss of retinal ganglion cells
with corresponding loss of the visual field. Primary open-angle
glaucoma (POAG, OMIM #137760) is the most common form of
glaucoma . POAG is characterized by typical glaucomatous
changes of the optic nerve and vision loss in the absence of
secondary causes. Well recognized risk factors for the development
of POAG include elevated intraocular pressure (IOP), increasing
age, African ancestry, and family history of glaucoma [3,4].
Genetics plays an important role in the pathogenesis of POAG
[2,3,5]. Traditional linkage studies have identified many genomic
regions (GLC1 loci) for familial cases . Among these, mutations
in several genes, such as myocilin, optineurin, WDR36 (WD repeat
domain 36) and CYP1B1 (cytochrome P450 1B1), are causal or
associated with increased risk of developing POAG in multiple
populations [7,8,9,10,11]. Association studies have identified many
variants that may contribute to POAG [6,12]. Recently,
genomewide association studies have been used to identify genetic risk
factors for POAG or glaucoma-related ocular phenotypes
[13,14,15,16,17,18,19]. These genes and regions include caveolin
1 and 2 (CAV1/2), transmembrane and coiled-coil domains 1
(TMCO1), SIX homeobox 1 (SIX1), and cyclin-dependent kinase
inhibitor 2B (CDKN2B) [13,19,20].
Figure 1. Heterozygous DNA deletion in the GALC gene. A heterozygous DNA deletion in the galactosylceramidase (GALC) gene present in 2
of 71 POAG cases and absent in 478 controls. The deletion was identified through six probes common to both the Illumina HumanCNV370-Duo and
Human610-Quad BeadChips. The deletion indicated by the red-colored box includes five exons (exons 1115) and abolishes enzymatic activity.
In addition to DNA sequence variation, DNA copy number
variations (CNV) have been increasingly reported in human
genetic disorders such as autism, HIV/AIDS, and cancer .
However, the role of CNV in POAG has been unclear.
AbuAmero et al. found no evidence of CNVs associated with POAG
among 27 POAG cases and 12 controls using array comparative
genomic hybridization (array CGH) . However, in a larger
dataset, Davis et al. using SNP genotyping arrays  studied 400
POAG cases and 500 non-glaucoma controls and found eleven
rare CNVs that may be relevant to POAG. Fingert et al. recently
identified a large duplication of TBK1 (Tank-binding kinase 1) in
patients with normal tension glaucoma . Replications of these
studies in larger datasets will help to clarify the importance of these
CNVs in glaucoma risk.
In order to systematically examine the role of CNVs in POAG,
we performed a discovery project using a genome-wide SNP
genotyping array in a POAG case-control dataset. A set of
candidate CNVs was selected for validation using realtime PCR.
One specific CNV in the galactosylceramidase (GALC, OMIM
*606890) gene was further examined in an independent
casecontrol dataset. The heterozygous loss of the GALC gene was
confirmed using three-primer PCR assays and array CGH.
In the discovery phase of our study, we performed genome-wide
DNA copy number variant analysis in 92 POAG cases genotyped
on the Illumina HumanHap610 BeadChip. The CNV frequencies
in our POAG patients were compared to publicly available
controls genotyped on the Illumina HumanCNV370 BeadChip
(dbGAP study accession phs000126.v1.p1.c1). The analysis was
limited to the 363,185 markers shared between the two BeadChip
platforms. After applying quality control protocols described in the
methods section, 71 POAG samples and 478 dbGAP controls
(greater than 40 years old) were analyzed using PennCNV
software. Overall, 15,940 CNV calls were generated for a total
of 549 DNA samples, with an average of 29 CNV events per
sample. About one third of CNV calls overlapped with known
coding genes. We performed a case-control comparison with all
the identified CNVs. However, none of the CNVs reached
genome-wide significance (p value,561028). CNVs in five
genomic regions were selected for further follow-up based on
their potential functional annotation and relative frequency in
cases versus controls. These five candidate regions were RASA4
(RAS p21 protein activator 4), EYA1 (eyes absent 1 homolog 1),
CROCC (ciliary rootlet coiled-coil, rootlletin), ALDH1A2 (aldehyde
dehydrogenase 1 family, member A2), and GALC
In order to validate the CNV calls generated from the SNP
genotyping array, we used TaqMan-based realtime PCR on the 71
genotyped POAG cases using probes in these five selected regions.
Realtime PCR validated the presence of the GALC deletion, but
not the CNV calls in the regions of RASA4, EYA1, CROCC, or
ALDH1A2. In the discovery dataset, 2/71 (2.8%) POAG cases
were identified with heterozygous deletions in GALC while none
were found in 478 age-matched US Caucasian controls (Figure 1).
The difference in allele frequency between cases and controls was
statistically significant (p = 0.017, Fishers exact test). The GALC
deletion was further validated in the POAG cases using a human
chromosome 14-specific CGH array (Roche NimbleGen, Inc.,
Madison, WI) which demonstrated that it encompasses a 31 kb
genomic region (Figure 2).
Association of the GALC CNV was replicated in a second
Caucasian POAG case/control dataset. This dataset consisted of
959 cases and 1104 examined normal controls genotyped with
realtime PCR that were augmented by an additional 748 publicly
available population controls (greater than 40 years old) genotyped
with the Affymetrix 6.0 array . In this analysis, 9/959 POAG
cases (0.94%) and 5/1852 controls (0.27%) carried the
heterozygous DNA loss in GALC (P = 0.021, Fishers exact test; OR = 3.5,
95%CI 1.112.0). After combining the discovery and replication
datasets the strength of association was increased (p = 0.002,
Fishers exact test, OR = 5.0, 95% CI 1.616.4). The CNV
deletion for GALC was found in 1.07% of POAG cases and 0.21%
of the controls in the combined Caucasian dataset. There were no
significant differences in age-at-diagnosis, maximum IOP, or
visual acuity in POAG cases with the GALC deletion compared
with POAG cases without the deletion. Realtime PCR-based
screening was applied to African American (400 cases/290
controls) and West African (Ghana) (190 cases/500 controls)
case-control datasets. No GALC CNV deletions were identified in
either dataset (Table 1). This suggests that GALC deletions are
either absent or extremely rare in individuals of West African
ancestry. This finding is supported Shaikh et al. who report that
GALC deletions were absent in 694 African American samples
To further define the observed deletion, we used a 3-primer
PCR assay (Figure 3) to examine our POAG cases and controls
[26,27,28]. Three samples carry a previously reported 31 kb
deletion (Human genome build 37, chromosome 14: 88,391,505
88,423,176) while the others have deletions with previously
unreported and variable endpoints in our POAG cases. The
heterogeneity of GALC CNV events was validated by array CGH
(Figure 4). The 31 kb GALC deletion has been reported to carry a
4 bp direct repeat (TATC) at the deletion junction .
We have identified CNV deletions of GALC that, when
heterozygous, increase risk of POAG by four-fold in Caucasian
Figure 2. Validation of GALC deletion with array CGH. The GALC deletion from Figure 1 was validated with high resolution chromosome 14
specific CGH array. This figure showed a 31 kb deletion in the GALC gene, indicated by the red line.
individuals. CNV deletions were not found in subjects of African
ancestry. The normal GALC mRNA encodes an 80 kDa precursor,
which is processed into 50 and 30 kDa subunits to form an
enzymatically active complex [26,29]. The 31 Kb GALC deletion
abolishes production of the 30 kDa subunit and results in the
production of a significantly shortened (15%) 50 kDa subunit .
GALC encodes the enzyme galactosylceramidase, which is required
for the degradation of specific galactolipids in the white matter of
the central and peripheral nervous system. These galactolipids
include galactosylceramide, galactosylsphingosine (psychosine),
lactosylceramide, and monogalactosyldiglyceride. GALC is critical
in the maintenance of the myelin sheath, which functions as the
protective covering around certain nerve cells to ensure the rapid
transmission of nerve impulses. Psychosine forms during the
production of myelin and is catabolized in part by GALC.
Normally, only small amounts of psychosine are present in the
brains of individuals with normal GALC enzymatic activity;
however complete loss of activity leads to accumulation of
psychosine and galactosylceramide, resulting in the development
of Krabbe disease, a form of globoid cell leukodystrophy. Krabbe
disease is a rare, autosomal recessive disorder of the central and
peripheral nervous system  that is characterized by increased
muscle tone, impaired motor control, seizures, hearing loss and
Among all the GALC mutations causing Krabbe disease, the
most common in Caucasian individuals (4045%) is the large
31kb deletion beginning in intron 10 and continuing past the end of
GALC [29,30]. This deletion has not been reported in African
American or African Krabbe disease patients. Based on the
incidence of Krabbe disease in the United States (1 in 100,000
births) [29,30], the estimated combined frequency of all
functionally-relevant GALC mutations is 0.003, implying a population
frequency of the 30-kb deletion of approximately 0.0013, very
similar to the frequency of 0.0011 we have detected in the present
study (5 deletions in 4660 chromosomes of 2330 controls). This
frequency match suggests that the controls included in our studies
are appropriate and representative of the overall Caucasian
Although optic neuropathy with associated loss of vision is one
of the most common clinical manifestations of Krabbe disease,
poor patient prognosis has limited studies of the molecular
mechanism of vision loss. In 1978, Brownstein et al. reported
optic atrophy in an infant Krabbe disease patient . Absence of
GALC activity and accumulation of its substrates,
galactosylcerRealtime PCR+SNP-based array
The CHOP dataset was obtained from the Copy Number Variation project at the Childrens Hospital of Philadephia (CHOP) ; Fishers exact p-value was based on
onetailed test, as we hypothesize that loss or decrease of GALC function results in POAG risk.
Figure 3. Three-Primer PCR assay for GALC deletion. (A) Schematic diagram of a portion of the GALC gene showing the region around the
known GALC deletion. Both primers Del_P1 and Del_P3 are located outside of the deletion while primer Del_P2 is inside the deletion and close to the
left breakpoint. (B) DNA samples with heterozygous deletion produced two DNA bands (329 bp and 615 bp in size) while DNA samples without
GALC deletion generated one DNA band of 615 bp in size. The white arrow indicates the DNA sample with heterozygous deletion.
ebroside and psychosine, in the optic nerve caused optic nerve
fiber and ganglion cell layer degeneration . The carriers of
GALC mutations are known to have reduced enzymatic activity
[29,30], and we hypothesize that this reduced activity is the
mechanism by which GALC deletions increase risk of POAG.
Measurements of GALC enzymatic activity could be used to
screen patients for risk of POAG. Currently it is estimated that
there are hundreds of thousands of individuals who carry GALC
deletions in the United States [29,30]. The findings reported here
show that these carriers are at increased risk for glaucoma. In
addition, the variability of GALC activity in the general
population is broad. These estimates suggest that a substantial
fraction of the population is expected to have as little as 2030% of
the normal GALC enzymatic activity levels [29,30]. It will be
important to examine POAG-related phenotypes in the parents or
grandparents of Krabbe disease patients, especially those GALC
deletion carriers. This examination will provide direct evidence to
the functional involvement of GALC in the pathogenesis of
glaucoma. This work is currently underway.
McCarroll et al. and Redon et al. have reported two CEPH
individuals (NA12716 and NA11840) with a heterozygous 24 kb
deletion in the GALC gene using the Affymetrix 6.0 array [32,33].
Supplementary data from two genome-wide expression studies
using HapMap samples [34,35], indicates that the GALC gene
Figure 4. Heterogeneity of GALC deletions in different DNA samples. Two heterozygous GALC deletions with different end-points were
identified by array CGH, indicated by the red line. The lower diagram shows the previously reported 31 kb GALC deletion while the upper diagram
shows a smaller deletion of approximately 15 kb.
expression in these two CEPH individuals is the lowest in their
respective families (pedigrees 1358 and 1349). Further, the GALC
activity for these individuals is in the lowest 20th percentile
compared to 90 other Caucasian subjects. These data suggest that
GALC enzymatic activity may constitute a potential biomarker as
well as therapeutic target for POAG.
In conclusion, this is the first study to report the role of
heterozygous GALC deletions as a significant risk factor for POAG.
We hypothesize that increased POAG risk is mediated through
reduced gene expression and enzymatic activity that in turn leads
to functional deficits in retinal ganglion cells. Further studies are
warranted on the role of GALC in optic nerve function, the impact
of GALC mutations in pathogenesis of glaucoma, and
galactosylceramidase activity as a biomarker and a potential therapeutic
target for POAG.
Materials and Methods
This study was reviewed and approved by the Institutional
Review Board of Duke University Medical Center (Durham, NC)
and adhered to the tenets of the Declaration of Helsinki. Written
informed consent was obtained from all study participants.
Study Sample and Phenotype Description
Subjects with POAG were unrelated and met the following
inclusion criteria  : 1) glaucomatous optic neuropathy in both
eyes; 2) visual field loss consistent with optic nerve damage in at
least one eye. Glaucomatous optic neuropathy was defined as a
cup-to-disc ratio greater than 0.7 or focal loss of the nerve fiber
layer resulting in a notch in the neuroretinal rim, associated with a
glaucomatous visual field defect. Visual fields were performed
using standard automated perimetry or frequency doubling test
(FDT) . IOP was not used as an inclusion criterion. The
exclusion criteria for POAG subjects included the diagnosis or
history of a secondary form of glaucoma or history of ocular
trauma. Medical records for all POAG cases and control subjects
were reviewed by professionally trained glaucoma subspecialists
(RRA, SEM). The examined control subjects were unrelated and
met the following criteria: 1) no self-report of a first-degree relative
with glaucoma; 2) IOP less than 21 mmHg in both eyes without
treatment; 3) no evidence of glaucomatous optic neuropathy in
either eye; 4) normal visual field in both eyes.
We have used a twostage study design: discovery and
replication phases. The Caucasian POAG cases in the discovery
phase were recruited at Duke University Eye Center. The
Caucasian controls in the discovery phase were controls from a
previous Parkinsons GWAS study (dbGAP study accession
phs000126.v1.p1.c1). This study only uses those controls at least
40 years of age, with a total of 478 individuals. These controls are
negative for neurologic disease and do not have a family history of
any neurodegenerative disease. They are Caucasian and
nonHispanic subjects. They were enrolled at either Boston University
or Indiana University and deposited into the NINDS Repository.
The Caucasian POAG cases in the replication phase were enrolled
at several sites: Duke University Eye Center, the University of
Michigan Kellogg Eye Center, or Eye Doctors of Washington at
Chevy Chase, MD. The examined control individuals in the
replication phase were enrolled at either Duke University Eye
Center or the University of Michigan Kellogg Eye Center. In the
replication phase, we also included 748 US Caucasian controls
from a previous Bipolar dbGAP GWAS study (phs000017.v2.p1)
with an age cut-off at 40 years old. These controls will serve as
non-examined population controls. These controls were
genotyped using Affymetrix 6.0 array containing 1,800,000 probes for
CNV analysis. All the African American POAG cases and controls
were enrolled at Duke University Eye Center. The Ghanaian
POAG cases and controls were collected in Ghana (West Africa).
Extraction of genomic DNA by standard techniques (Gentra,
Minneapolis, MN) was carried out for 1130 Caucasian POAG
cases, 1350 Caucasian controls, 400 African American POAG
cases, 300 African American controls, 190 Ghanaian POAG cases
and 500 Ghanaian controls. Ninety-two POAG cases were
subjected to genome-wide SNP genotyping with the Infinium II
Human610-Quad BeadChip (Illumina, San Diego, CA, USA) at
the Molecular Genetics Core of the Center for Human Genetics at
Duke University. High quality genomic DNA (500 ng) was used to
genotype each sample according to the manufacturers guidelines
. BeadStudio software (Illumina) was used to analyze DNA
genotype and intensity. For 943 controls we obtained the genotype
and intensity files from dbGAP (study accession phs000126.v1.p1).
These samples were genotyped using Illumina
HumanCNV370Duo BeadChip. For CNV analysis, samples were required to have
the following criteria: First, only samples with call rates .98%
were included. Second, only samples with the standard deviation
of normalized intensity (Log R Ratio, LRR) #0.35 were included.
Third, only samples where the correlation of LRR to wave model
ranged between 20.2 and 0.4 were included. Finally, only samples
with the initial CNV call count #40 were included in the analysis.
A total of 71 POAG cases and 478 controls met all inclusion
measures in the final CNV analysis. For those 748 GAIN controls
genotyped with Affymetrix 6.0 array, we applied a similar quality
control procedure: 1) standard deviation of LRR #0.35; 2) a
minimum of 5 probes per CNV due to a much higher density of
probes (a total of 1.8 million probes per sample); 3) #100 CNV
calls per sample; 4) drift of B allele frequency (BAF) #0.01; and 5)
wave factor #0.05.
To call CNVs, we used the PennCNV algorithm , which
combines multiple sources of information, including LRR and
BAF at each SNP marker. We required a minimum of 3
consecutive probes for a CNV call. Since POAG cases and
controls were genotyped with different types of Illumina
Beadchips, only SNPs and probes shared in common between
these two Beadchips (approximately 370,000) were utilized to
generate CNV calls. The differences in CNV frequency between
POAG cases and controls were evaluated using Fishers exact test.
A list of specific CNVs was selected for further validation using
realtime PCR in a large POAG case/control dataset.
CNV Validation and Screening by Realtime PCR
To validate the CNVs determined by PennCNV, we selected
five candidate CNVs identified in the initial genome-wide screen.
We used TaqManH Copy Number Assays from ABI (Applied
Biosystems Inc, Carlsbad, CA, USA) on the ABI PrismH 7900HT
Sequence Detection System for validation and further screening in
additional POAG cases and controls. A VIC-labeled Copy
Number Assay for RNase P was selected to be an endogenous
control as it performed in the same reaction with gene-specific
assays. Only one probe was selected for each CNV region. Each
sample was assayed with four replicates by using 10 ng DNA in
each reaction in 384-well format. The CNV calls were generated
with SDS software and CopyCallerTM from ABI (Applied
Biosystems Inc, Carlsbad, CA, USA). A known CEPH sample
was used as a reference for a copy number of 2. This CEPH
sample was already examined by SNP microarray to contain two
copies of candidate CNV regions. In order to make CNV calls in
CopyCallerTM software, a confidence score of greater than 0.95
was required with four replicates.
The CNV assay for EYA1 gene used Hs03668790 to target
intron 7. The assay for the CROCC gene used Hs01817683 to
target the boundary of exon 3 and intron 3. The assay for
ALDH1A2 gene used Hs02281830 to target the boundary of intron
7 and exon 8. The assay for RASA4 was custom-designed to target
the genomic region between exon 1 and exon 3. The specific CNV
assay for the GALC gene used Hs00121467 to target exon 13. The
assay for GALC was run with all Caucasian, African American, and
Ghana case-control samples as well as a multiplex familial POAG
Three-primer PCR assay for GALC Deletion
We utilized a three-primer PCR assay that was developed
previously  to examine a known deletion in the GALC gene.
The primer sequences were Del_P1:
59-AAGGAGCTAACATTTCAGGC39; and Del_P3: 59- AAGGAGCTAACATTTCAGGC-39.
Primers Del_P1 and Del_P3 were outside of the genomic deletion,
while primer Del_P2 was inside of the deleted region and close to
Del_P1 (Figure 3). Individuals with a homozygous deletion
generate a 329 bp fragment with PCR primers Del_P1 and
Del_P3 while subjects without deletion produce a 615 bp fragment
with PCR primers Del_P1 and Del_P2. Individuals with a
heterozygous deletion generate two PCR fragments of 329 and
615 bp in size. This three-primer PCR reaction was used to
examine all POAG cases and controls.
Validation with Array CGH
Selected DNA samples were examined with
experiments for CNV changes in GALC. A
chromosome 14 specific CGH array was used according to the
standard protocols provided by the manufacturer
(Roche-NimbleGen, Inc, Madison, WI, USA) . For each sample, 1 mg high
quality undegraded DNA was included with human reference
DNA from HapMap. The human chromosome 14-specific CGH
array provides measurements from 385,000 unique genomic loci
on chromosome 14. The experimental sample was labeled with
Cy3 and reference sample was with Cy5. The arrays were scanned
on an Axon 4100A scanner (Molecular Devices, Sunnyvale, CA,
USA). TIFF images were analyzed using NimbleScan 2.5 software
to obtain fluorescent intensity and the copy number was further
determined using the segMNT algorithm with a 106 averaging
window and minimum difference in log ratio of 0.2. A minimum
of 10 consecutive probes was required to make CNV calls. The
copy number variation result was visualized using SignalMap 1.8
from Roche NimbleGen.
We are grateful to the study participants, without whom this work would
not have been possible. We thank two previous genome-wide association
studies in dbGAP: Whole Genome Association Study of Bipolar Disorder
(phs000017.v2.p1) and CIDR: Genome Wide Association Study in
Familial Parkinson Disease (PD) (phs000126.v1.p1).
Conceived and designed the experiments: YL RRA JER PRL MAH.
Performed the experiments: YL JG JW MAH RRA. Analyzed the data: YL
RRA LCK CMST JG MAH. Contributed reagents/materials/analysis
tools: YL JW RRA LCK CMST SKA CAG DLB JER SEM PRL DEG PC LWH MAH. Wrote the paper: YL RRA JG JER PRL CAG DEG DLB SEM PC LWH MAH.
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