Fine mapping on chromosome 13q32-34 and brain expression analysis implicates MYO16

Fine mapping on chromosome 13q32-34 and brain expression analysis implicates MYO16
Fine mapping on chromosome 13q32-34 and brain expression analysis implicates
MYO16 in schizophrenia
Laura Rodriguez-Murillo1, Bin Xu1,2, J. Louw Roos3, Gonçalo R. Abecasis4, Joseph A.
Gogos2,5, Maria Karayiorgou1,*
Author affiliations:
1
Columbia University, Department of Psychiatry, 1051 Riverside Drive, New York, NY 10032;
2
Columbia University, Department of Physiology, 630 West 168 th Street, New York, NY 10032;
3
University of Pretoria, Department of Psychiatry and Weskoppies Hospital, Pretoria, RSA 0001;
4
University of Michigan, Department of Biostatistics, Center for Statistical Genetics, 1420 Washington
Heights, Ann Arbor, MI 48109-2029;
5
Columbia University, Department of Neuroscience, 630 West 168 th Street, New York, NY 10032
*
Corresponding author
Tel.: 212-568-4189
E-mail: [email protected]
Running title: MYO16 fine mapping and brain expression in schizophrenia
Key words: Schizophrenia, association, MYO16, linkage, CNVs, SNPs, expression
Abstract
We previously reported linkage of schizophrenia and schizoaffective disorder to 13q32-34 in
the European descent Afrikaner population from South Africa. The nature of genetic
variation underlying linkage peaks in psychiatric disorders remains largely unknown and
both rare and common variants may be contributing. Here, we examine the contribution of
common variants located under the 13q32-34 linkage region. We employ densely spaced
1
SNPs to fine map the linkage peak region using both a discovery sample of 415 families and
a meta-analysis incorporating two additional replication family samples. In a second phase
of the study, we use one family-based dataset with 237 families and independent casecontrol datasets for fine mapping of the common variant association signal using HapMap
SNPs. We report a significant association with a genetic variant (rs9583277) within the gene
encoding for the myosin heavy chain Myr 8 (MYO16), which has been implicated in
neuronal phosphoinositide 3-kinase (PI3K) signaling. Follow-up analysis of HapMap
variation within MYO16 in a second set of Afrikaner families and additional case-control
datasets of European descent highlighted a region across introns 2 to 6 as the most likely
region to harbor common MYO16 risk variants. Expression analysis revealed a significant
increase in the level of MYO16 expression in brains of schizophrenia patients. Our results
suggest that common variation within MYO16 may contribute to the genetic liability to
schizophrenia.
Introduction
Susceptibility to schizophrenia is determined by multiple genetic and possibly
environmental factors. Recent studies addressing the role of high-penetrant rare variants
(Walsh et al, 2008; Xu et al, 2012; Xu et al, 2011; Xu et al, 2008; Xu et al, 2009) or
common genetic variants with low effect (ISC, 2008; Lee et al, 2012; O'Donovan et al,
2008; Ripke S, 2011; Shi et al, 2009; Shi et al, 2011; Stefansson et al, 2009) suggest that
patient genomes contain risk alleles at a wide range of frequencies, some driving and
some merely modifying the disease risk and expression, which in concert may affect the
structure and function of neural circuits (ISC, 2008; O'Donovan et al, 2008; RodriguezMurillo et al, 2012; Shi et al, 2009; Stefansson et al, 2009; Xu et al, 2011; Xu et al,
2008; Xu et al, 2009).
In complex diseases, the genetic structure of linkage signals most likely involves one or
several rare alleles with strong effect on disease risk, or a combination of rare and
common alleles, in the same or different genes (Bowden et al, 2010). Also, linkage
analyses of inbred mice have shown that more than one gene can contribute to the same
linkage signal for a given QTL trait (Karst et al, 2011). Along the same lines, association
2
studies coupled with targeted re-sequencing have suggested that the same genes carrying
common risk variants can also show an excess of rare risk variants implicated in the
disease (Cirulli and Goldstein, 2010; Di Rienzo, 2006; Manolio et al, 2009; Trynka et al,
2011).
A 9-cM genome-wide linkage scan on families from the European descent Afrikaner
population from South Africa identified three linkage signals on chromosomes 1, 9 and
13 (Abecasis et al, 2004). Subsequently, we increased the genomic coverage to better
define the linkage regions, and performed a 2-cM genome-wide linkage scan on an
extended set of Afrikaner families. The results from this genome scan identified
chromosome 13q32-34 as the most robustly linked locus in this population. We also
addressed the contribution of rare CNVs to schizophrenia in this cohort and found that, at
the level of resolution of the linkage scan, none of the linkage signals observed in these
families may be caused by the presence of CNVs within these genomic intervals (Xu et
al, 2009).
Here, we present the results of our ongoing systematic effort to elucidate the genetic
structure of our 13q32-34 linkage peak obtained in our 2-cM genome scan, by analyzing
the contribution of local common variants via a multistage association study. In addition
to genuine contributions to the risk associated with a given linkage signal, even in cases
where the linkage signal is accounted for only by rare variants, common variants may in
some cases help pinpoint with more accuracy the location of rare risk variants (Dickson
et al, 2010; Lin et al, 2004; Sanna et al, 2011). First, we genotyped 1223 individuals
from 415 Afrikaner families for 723 SNPs localized within 13q32-34. Subsequently, the
most significant SNPs were followed-up in two independent family-based replication
samples of European origin. One SNP showed replicated association in one of the two
independent samples and remained significant after meta-analysis and correction for
multiple testing. This SNP is located within the MYO16 (myosin XVI) gene (Patel et al,
2001; Yokoyama et al, 2011). Second, we performed a comprehensive fine-scale
mapping of the genetic contribution of this gene with respect to common variation, by
genotyping an independent set of families from the Afrikaner population for 102 SNPs
within MYO16 and by imputing the rest of the HapMap SNPs within the gene boundaries.
3
These analyses identified a preponderance of common variants implicated in
schizophrenia within introns 2-6 of the gene MYO16. Furthermore, expression analysis of
the MYO16 gene in brain samples from patients and controls identified a significantly
elevated level of expression in patients with schizophrenia.
Methods and Materials
We used a family-based approach studying families with at least one affected individual
per family. Datasets are presented in Supplementary Table 1.
Afrikaner Cohorts: Affected families were recruited and diagnosed as part of our
ongoing, large-scale genetic study of schizophrenia in the European descent Afrikaner
population from South Africa, as previously described (Abecasis et al, 2004;
Karayiorgou et al, 2004; Xu et al, 2008; Xu et al, 2009). Affected subjects were
classified as either narrowly or broadly affected. The narrow diagnosis includes subjects
with schizophrenia or schizoaffective disorder-depressive type, as previously described
(Abecasis et al, 2004; Xu et al, 2009). The broad diagnosis includes all individuals
classified under the narrow definition, as well as individuals with schizoaffective
disorder-bipolar type (Xu et al, 2009).
Afrikaner set 1 (SAF1): This dataset includes the 143 families used for the linkage
scan, plus an additional 272 families. The entire set comprises 474 affected individuals
who meet the narrow diagnostic criteria or 741 who meet the broad diagnostic criteria.
Afrikaner set 2 (SAF2): This dataset includes 237 families, 85 of whom have
family history of schizophrenia in the previous two generations. 232 individuals in these
families meet the narrow diagnostic criteria, while 266 individuals meet the broad
diagnostic criteria.
Rutgers families: From the entire set of families collected under the NIMH Schizophrenia
Genetics Initiative, maintained by the Rutgers University Cell and DNA Repository, we
selected a subset of 301 families matched according to ethnicity. Our selected Caucasian,
4
Table I LAMP P-values and risk alleles for the discovery (SAF1) and replication (Rutgers and US) family samples. Na stands for
narrow schizophrenia and Bd for broad schizophrenia. Rutgers and US phenotype is broad schizophrenia. Meta-analysis was
performed with SAF1(Bd).
SAF1 (Na)
CHR
SNP
bp
GENES
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs1323666
rs716504
rs7994782
rs2940695
rs4325412
rs9583277
rs277828
rs9521372
rs4773155
rs9515201
rs1927343
rs3742193
rs4771711
rs1163830
rs1550192
108054116
108061624
108393891
108567155
108708242
109333749
109693885
110093044
110971066
111040798
111053959
111280002
111502659
112113080
112833723
FAM155A
FAM155A
FAM155A
MYO16
MYO16
COL4A2
COL4A2
COL4A2
FLJ10769
-
A1 A2
G
G
G
G
T
C
C
T
C
C
A
T
G
G
T
C
C
A
A
G
A
A
G
A
A
C
C
A
A
C
FREQ
P
A1
0.48 0.021
0.32 0.026
0.46 0.002
0.38 0.012
0.23 0.003
0.26 0.002
0.22 0.011
0.16 0.019
0.46 0.013
0.30 0.004
0.32 0.011
0.10 0.001
0.42 0.009
0.44 2.0 10-04
0.18 0.014
SAF1 (Bd)
TDT
OR
0.86
1.39
1.28
1.17
0.63
1.35
1.24
0.66
0.79
1.41
1.16
1.41
1.27
0.68
1.55
*TDT ORs are calculated with respect to the A1 allele
5
FREQ
P
A1
0.46
0.087
0.33
0.880
0.46
0.002
0.38
0.021
0.23
0.014
0.25
0.001
0.21
0.010
0.16
0.072
0.45
0.036
0.30
0.021
0.33
0.013
0.11
0.014
0.41
0.003
0.45 7.6 10-04
0.17
0.002
Rutgers
TDT
OR
0.89
1.33
1.20
1.08
0.77
1.40
1.21
0.79
0.84
1.31
1.17
1.31
1.26
0.65
1.44
FREQ
A1
0.43
0.35
0.46
0.42
0.20
0.36
0.26
0.13
0.39
0.32
0.37
0.11
0.44
0.46
0.19
P
0.550
0.360
0.890
0.620
0.045
0.002
0.460
0.440
0.590
0.240
0.160
0.270
0.054
0.250
0.150
US
TDT
OR
1.03
0.89
1.23
1.11
1.02
1.18
0.86
0.94
1.05
0.78
1.01
1.23
0.88
0.76
1.33
FREQ
A1
0.47
0.33
0.48
0.44
0.19
0.33
0.29
0.12
0.37
0.34
0.37
0.15
0.48
0.45
0.18
P
0.450
0.750
0.980
0.160
0.630
0.600
0.260
0.360
0.550
0.058
0.015
0.470
0.960
0.990
0.910
TDT
OR
0.80
1.03
0.97
0.78
1.18
0.88
0.74
1.37
1.04
0.84
0.87
0.75
0.95
0.97
1.03
META-P
0.245
0.786
0.036
0.244
0.790
-4
2.25 10
0.444
0.225
0.416
0.982
0.190
0.054
0.395
0.004
0.004
European ancestry, subset includes a total of 1241 individuals (631 affected with
schizophrenia).
US families: 210 trios (consisting of one affected individual and both biological
unaffected parents for a total of 630 individuals) were included in this sample of
Caucasian, European descent families recruited from the US. All probands met full
diagnostic criteria for schizophrenia or schizoaffective disorder. Description of this
dataset and the methods of subject selection and clinical evaluation have been previously
described in Sobin et al. (Sobin et al, 2001; Sobin et al, 2003).
GAIN dataset: This study is part of the Genetic Association Information Network
(GAIN) (ID phs000021.v2.p1). Details on inclusion criteria and participants are available
at dbGap (Suarez et al, 2006). In total, 1314 cases and 1368 controls of European descent
were included in the final set.
MGS_nonGAIN dataset: This study is part of the Molecular Genetics of Schizophrenia
(MGS) genome wide association study (ID phs000167). Details on inclusion criteria and
participants are available at dbGap. 1405 cases and 1347 controls of European descent
were included in the final set.
PGC dataset: This dataset is part of the Schizophrenia Psychiatric Genome-wide
association study consortium (Ripke et al, 2011). We included the results from stage 1
mega-analysis published in Ripke et al (Ripke et al, 2011) that correspond to the MYO16
gene region overlapping SNPs genotyped or imputed in our SAF2 dataset. This dataset
included 9,394 schizophrenia cases.
Genotyping, quality control and imputation
SAF1: Family members were genotyped for 723 SNPs covering 14.65 Mb under the
13q32-34 linkage peak and within candidate genes (ZIC2, ZIC5, NALCN, FGF14, G72
and EFNB2) in the immediate vicinity of the linkage peak (Supplementary Table 2), on
the Illumina GoldenGate platform at the Center for Inherited Disease Research (CIDR).
Rutgers and US samples: Family members were genotyped for 22 SNPs on a Taq Man
Open Array Genotyping Platform (Applied Biosystems). These 22 SNPs were chosen
6
among the top associated SNPs resulting from the association analysis in stage 1 (SAF1)
or surrogates of those (i.e., in strong LD with at least one of the top associated SNPs).
SAF2: This set of families was genotyped as part of a wider genotyping project on a
Human Genome-Wide SNP Array 5.0 (Affymetrix), which contains 500,568 SNPs
(manuscript in preparation). Samples were processed as previously described (Xu et al,
2008). Average call rate on arrays used in this study was 99.43%. All microarray
experiments were performed in the Vanderbilt Microarray Shared Resource.
GAIN and MGS: Individual genotypes as well as phenotypic information were available
to download from the dbGap website. Only individuals of European descent were
included in the analysis.
For all datasets, quality control procedures per family, individual, and marker were
performed with PLINK (Purcell et al, 2007) and PedStats (see URLs). All datasets went
through quality control and we only selected samples with a call rate > 95%. We
eliminated from the analysis duplicated SNPs, monomorphic SNPs, and SNPs with
Hardy-Weinberg Exact Test P < 10-6. Only SNPs with minor allele frequency over 0.01
were included in the downstream analyses. We also checked for Mendelian inheritance
errors among families, and removed SNPs with more than 4 Mendelian errors in the total
sample. For the case-control datasets, we corrected for population stratification with the
program EIGENSTRAT, eliminating outliers from the downstream analyses.
Imputation of non-genotyped HapMap SNPs for SAF2, GAIN and MGS datasets was
performed with MACH (see URLs) using 100 Markov iterations with the two-step
procedure recommended in the manual. HapMap Phased Haplotypes (release 22) on CEU
subjects were used in the imputation. After imputation, only SNPs with a MACH R2 over
0.3 were further considered. This estimates the correlation between imputed and true
genotypes; a value less than 0.3 flags poorly imputed SNPs (Li et al, 2010). In addition,
Mendelian checks (for the family-based samples) and Hardy-Weinberg equilibrium tests
were performed to eliminate unreliable imputation calls in order to include imputed
7
genotypes in downstream analyses. Imputed SNPs were then analyzed as the genotyped
SNPs.
Statistical analyses
Family-based association testing for single SNPs was performed using LAMP (see
URLs) (Li et al, 2005, 2006). We adopted a free model for the analysis that does not
constrain the penetrances for the three genotypes. Haplotype-based associations were
assessed by means of the Transmission Disequilibrium Test (TDT) for haplotypes
implemented in PLINK. For the case-control datasets, a trend-test was performed to
evaluate the SNP association. We applied Bonferroni correction in all tests to obtain an α
corrected threshold. We calculated the number of independent tests in each case based on
LD patterns between SNP pairs. These procedures were performed in PLINK (see
URLs).
Meta-analysis of the results for the independent samples was performed with Metal (see
URLs). The algorithm checks for heterogeneity and performs meta-analysis under a fixed
effects model. All base pair positions are based on the current Human genome assembly
(hg19) (see URLs).
To identify duplicated individuals and family relationships between individuals across
datasets, we performed identity by descent (IBD) analysis of GAIN, MGS_nonGAIN and
Rutgers samples merged together using PLINK. Duplicated and related individuals across
datasets were removed from all but one of the datasets to avoid bias in the analysis.
Specifically, GAIN and MGS_nonGAIN included 10 duplicated individuals that were
removed from the larger MGS_nonGAIN dataset.
Expression analysis
Total RNA from frontal cortex was obtained from the Stanley Medical Research Institute
(SMRI) (Bethesda, Maryland) (see URLs). The SMRI Array Collection includes 35
individual subjects in each of three groups: control, schizophrenia and bipolar disorder
subjects (Torrey et al, 2000). qRT-PCR was performed with pre-designed TaqMan®
Gene Expression assay by ABI (Applied Biosystems; ABI assay number
8
#Hs01031284_m1) on a 7900HT Fast Real Time PCR system (Applied Biosystems).
Human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as the
endogenous control. Relative quantitation of expression comparing the three groups
(schizophrenia, bipolar disorder, and controls) was tested with generalized linear models
(GLM) and incorporating covariates into the model. Descriptive statistics, means
comparison and GLM were analyzed with R statistics software.
Results
SNP association in a discovery set of Afrikaner families, replication, and metaanalysis
To follow-up the 13q32-34 linkage signal obtained through our 2-cM coverage linkage
scan, we genotyped 723 SNPs from chromosome 13, on 1223 individuals from the 143
Afrikaner families included in the 2-cM linkage scan plus 272 additional families from
the same homogeneous population (SAF1). We performed family-based association tests
on these 415 families using LAMP (Li et al, 2005, 2006). 115 SNPs reached nominal
significance at this stage (Figure 1 and Supplementary Table 2). None of these SNPs
were within candidate genes (ZIC2, ZIC5, NALCN, FGF14, G72 and EFNB2) abutting
the linkage peak. 22 associated SNPs were followed-up in two independent samples of
European descent (Rutgers and US samples, see Methods). These 22 SNPs were selected
from the top associated SNPs, or surrogates of these, chosen based on the LD structure,
each one representing one independent LD block, and the availability of a genotyping
assay in a TaqMan Open Array Genotyping platform (Applied Biosystems). Family
members from the replication samples (Rutgers and US) were genotyped for these 22
SNPs (Table 1). Following quality control procedures, 7 SNPs were removed from the
analysis, two due to bad calls, four due to Mendelian errors (these were not concentrated
in specific families), and one due to deviations from Hardy-Weinberg equilibrium. The
remaining 15 SNPs were tested for association in the replication samples by using
LAMP. Table 1 shows the P-values and odd ratios for the association in the discovery
sample (SAF1) and in the replication samples (Rutgers and US). Subsequently, meta-
9
Figure 1: Genome-wide linkage and fine mapping. Bd, broad; LOD, logarithm of the odds; Na, narrow;
SNP, single-nucleotide polymorphism.
10
analysis was performed combining P-values obtained from the SAF1 and both replication
samples. Meta-analysis identified one SNP with combined P-values that survive
Bonferroni in correction for multiple testing (Table 1) (αcorrected = 0.0023). The top
associated SNP, rs9583277, has a meta-analysis P-value of 1.86x10-4 and 2.25x10-4 for
the combined sample SAF1-Rutgers-US families, for both narrow and broad definition of
schizophrenia, respectively. It is worth noting that the Bonferroni correction we employ
to declare significance reflect the number of independent tests (n) we performed (n = 22,
αcorrected = 0.05/22 = 0.0023) and therefore are not as stringent as thresholds employed in
GWAS that reflect corrections for ~1 million tests performed. The identified variant
(rs9583277) maps to 109,333,749 bp on chromosome 13q33.3, within the second intron
of the MYO16 gene. Our previous linkage analysis indicated dominant inheritance for the
risk locus at 13q32-34 (Xu et al, 2009). Consistent with this finding, we did not detect
any excess of homozygosity (an indication of recessive mode of inheritance) at
rs9583277, either when the entire SAF1 dataset was considered or upon stratified
analysis including only families linked to 13q32-34 (data not shown). Overall, our
analysis, employing densely spaced SNPs to fine map the prior 13q32-34 linkage peak
region on a discovery and two replication family samples (a total of 923 families),
highlighted a potential contribution of the MYO16 gene locus.
Fine mapping of the common variant association signal using MYO16 HapMap
SNPs
Having identified a significant association with a genetic variant (rs9583277) within the
MYO16 gene, we then performed a comprehensive fine scale mapping of the common
variant association signal in an independent set of families and cases. To this end, we
genotyped, or imputed when necessary, all HapMap SNPs within the MYO16 gene
boundaries, according to UCSC genome browser genome positions (hg19). First, we
examined a sample of 228 Afrikaner families with an average of 3.2 individuals per
family (SAF2). Following quality control procedures (see Methods), 102 genotyped and
470 imputed HapMap SNPs were available for analysis of the MYO16 gene locus with
respect to underlying common risk variants. It should be noted that there is no overlap
with MYO16 SNPs genotyped in SAF1 and that the SNP previously found associated in
11
Figure 2: Plot depicts the negative logarithm of the SNP association p values for the Afrikaner Set 2 data
set with narrow (SAF2(NARROW)) and broad (SAF2(BROAD)) schizophrenia diagnosis, as well as the
meta-analysis p-values for the combined sample SAF2(BROAD)/GAIN/MGS data sets (META(BROAD)).
The background graph represents the recombination rate throughout the region. GAIN, Genetic Association
Information Network; MGS, Molecular Genetics of Schizophrenia.
12
Table 2 LAMP P-values and maximum-likelihood estimates of Penetrance, Genotype Relative Risk (GRR), Population
Attributable Risk (PAR), and Odd Ratios (OR) for top associated SNPs in SAF2.
SNP
Narrow
rs9520990
rs9520991
rs932678
rs9514889
rs984298
rs9514918
rs7324758
rs7321660
Broad
rs9520990
rs9520991
rs932678
rs7321660
rs9521010
rs9521011
bp
P
A1 A2
109376993
109378071
109382119
109375338
109456170
109457217
109828818
109523912
3.9 10-5
3.9 10-5
3.9 10-5
1.2 10-4
5.1 10-4
5.1 10-4
8.6 10-4
9.4 10-4
C
G
A
A
G
C
T
T
109376993
109378071
109382119
109523912
109412639
109412704
1.9 10-4
1.9 10-4
1.9 10-4
7.6 10-4
9.5 10-4
9.5 10-4
C
G
A
T
G
A
FREQA1
Pen(1/1)
Pen(1/2)
T
A
C
G
A
G
C
C
0.685
0.685
0.685
0.668
0.792
0.792
0.821
0.628
0.014
0.014
0.014
0.013
0.008
0.008
0.012
0.010
0.007
0.007
0.007
0.007
0.013
0.013
0.006
0.012
0.005
0.005
0.005
0.006
0.018
0.018
0.005
0.006
T
A
C
C
A
G
0.687
0.687
0.687
0.641
0.505
0.505
0.013
0.013
0.013
0.009
0.011
0.011
0.008
0.008
0.008
0.012
0.012
0.012
0.006
0.006
0.006
0.007
0.006
0.006
*ORs are calculated with respect to the A1 allele.
13
PAR
TDT-OR*
1.37
1.37
1.37
1.17
0.72
0.72
1.38
2.00
0.47
0.47
0.47
0.37
0.81
0.81
0.55
0.45
1.82
1.82
1.82
1.69
0.72
0.72
1.11
2.10
1.42
1.42
1.42
1.84
1.86
1.86
0.44
0.44
0.44
0.34
0.38
0.38
1.69
1.69
1.69
1.40
1.41
1.41
Pen(2/2) GRR(1/2)
the SAF1 sample (rs9583277) was not genotyped in the SAF2 sample since it is not a
HapMap SNP, nor is it present in the common genotyping platforms. Therefore, this
stage is not intended to be a replication of the previous findings, but a deeper
characterization of the common variation within MYO16 in the context of schizophrenia.
Even though several SNPs genotyped at this stage are located in the general vicinity of
rs9583277 within the MYO16 gene, rs9583277 is in a region of low LD.
Figure 2 shows LAMP P-values for the association of MYO16 SNPs for both narrow and
broad definitions of schizophrenia, along with the recombination frequency across the
region. Table 2 shows the top associated SNPs within this dataset. Notably, 4 SNPs
showed significant association with narrow definition schizophrenia after correction for
multiple testing (αcorrected = 2.17x10-4, based on a Bonferroni correction after estimating
the number of independent tests to 230, taking into account the LD pattern among SNP
pairs). Three of these four SNPs also showed association with the disease under its
broader definition. All these four SNPs were located within intron 3 of the MYO16 gene,
within an LD block that expands from intron 2 to intron 6.
We also investigated if there was any specific configuration of alleles or haplotypes
conferring susceptibility to schizophrenia for either narrow or broad definition. Only
directly genotyped SNPs were used to test association on haplotypes. Haplotype-based
association in Afrikaner families was assayed with the TDT. First, we estimated
haplotype blocks based on the LD structure by means of the default procedure
implemented in Haploview. Subsequently, each haplotype within each block was tested
for association with the hap-tdt option implemented in PLINK. In this fashion, we tested
74 haplotypes, each comprising of 2 to 10 SNPs. Table 3 shows the top associated
haplotypes for either schizophrenia definition. Two distinct two-SNP haplotypes show
under-transmission and significant association with schizophrenia (αcorrected = 6.76x10-4,
74 independent tests). It is worth noting that, of the two haplotypes with significant Pvalues, the CG haplotype including SNPs rs558322 and rs4976845 is associated with the
narrow definition; and the GA haplotype including rs4578513 and rs10492418 is
associated with the broad definition. Notably, these two haplotypes reside within distinct
haplotype blocks, suggesting that the observed association signals are independent of
14
Table 3 Haplotypic association
Start (bp)
End (bp)
Kb Haplotype
Freq
T
U
P
SNPs
8.48 10-4 rs4578513|rs10492418
109379006 109380726 1.721
GA
0.313
55 96
Narrow 109819961 109824928 4.968
CG
0.192
30 64 4.53 10-4*
109379006 109380726 1.721
GA
0.313
65 110 6.69 10-4 rs4578513|rs10492418
Broad 109819961 109824928 4.968
α Bonferroni corrected = 0.00068
CG
0.192
43 71
T: Transmitted
U: Untransmitted
15
0.0087
rs558322|rs4976845
rs558322|rs4976845
each other. Of note, there are other examples where independent haplotypes are
associated with distinct forms of a disease (Cruz et al, 2008). In our study, the two
independent haplotypes might be acting as modifiers of the clinical presentation or reflect
two distinct patient subpopulations.
We extended our follow-up studies to two additional, independent, case-control datasets,
which are part of genome-wide genotyping projects (GAIN and MGS). To this end, we
extracted SNP genotypes located within the MYO16 gene boundaries and also imputed
non-genotyped HapMap SNPs from this region in order to facilitate comparison with the
SNPs in our SAF2 dataset. The SNPs extracted from GAIN and MGS datasets matched
the SNPs in SAF2, and so the LD patterns were equivalent. Therefore, we employed the
same significance threshold for the SAF2 as well as the GAIN and MGS datasets.
Following quality control procedures, 572 single SNP P-values from the three datasets
SAF2, GAIN and MGS (a total of 3,307 cases) were meta-analyzed. The lowest
combined P-value after meta-analysis was 1.1x10-3 for the combined sample SAF2
(broad status of SCZ)-GAIN-MGS for SNP rs4772996 (Table 4). Although this SNP
does not survive the correction for multiple testing when considering 230 independent
tests (corrected α level, 0.05/230 = 2.17x10-4), it is important to note that direction of
association is consistent across all three datasets for the top associated SNPs. Moreover,
all top associated SNPs following meta-analysis are located within intron 4 of the gene,
in complete LD with the top associated SNPs in the SAF2 dataset (D’ = 1), strongly
suggesting that the association signal obtained upon meta-analysis points to the same
associated region within the MYO16 gene. The fact that these SNPs do not reach
significance after correction for multiple testing likely reflects the presence of
heterogeneity across datasets (Table 4). Sample heterogeneity also likely explains change
of ranking among top SNPs. Specifically, although the top associated SNPs in the SAF2
dataset continue to show nominally significant association in the meta-analysis they are
not present among the top-ranking SNPs (Table 4). However, top-ranking SNPs from
either dataset are in high LD with each other and likely represent the same association
signal.
16
Table 4 P-values for the individual replication samples and P-values following meta-analysis (Meta-P).
SNP
rs4772996
rs878536
rs1019863
rs1022801
rs12862455
rs17482465
rs9634572
rs1118797
rs732974
rs12857877
Allele 1
BP
(reference)
109429712
A
109431493
T
109438967
A
109439661
A
109433076
T
109422400
T
109426194
A
109433982
T
109415758
A
109424041
A
P SAF2 (Na)
0.034
0.034
0.008
0.008
0.034
0.013
0.063
0.034
0.051
0.170
P SAF2 (Bd)
0.097
0.097
0.016
0.016
0.097
0.084
0.103
0.097
0.004
0.026
17
P GAIN
0.013
0.013
0.003
0.003
0.015
0.007
0.040
0.023
0.021
0.017
P MGS
0.125
0.125
0.673
0.673
0.135
0.209
0.061
0.139
0.781
0.103
META-P
1.16x10-3
1.16x10-3
1.18x10-3
1.18x10-3
1.36x10-3
1.45x10-3
1.47x10-3
1.67x10-3
1.78x10-3
1.60x10-3
Direction of
the
association
+++
--+++
+++
----+++
+++
--+++
We further compared the results obtained in our SAF2 dataset with recently
available results from the Schizophrenia Psychiatric Genome-Wide Association Study
(GWAS) Consortium (Ripke et al, 2011) The PGC study is a meta-analysis that combines
various datasets, including GAIN and MGS. Therefore, meta-analysis of our dataset and
the PGC dataset is not intended as a replication, but as a test of our hypothesis using a
more extensive set of data. We extracted results for SNPs mapping within MYO16 and
performed a meta-analysis following the same procedure as with the SAF2-GAIN-MGS
datasets. We meta-analyzed 248 SNPs overlapping across datasets, for a total of 22,640
individuals. The top associated SNP following meta-analysis is rs9284246
(Supplementary Table 3) located within intron 2 of the MYO16 gene (109,327,788 bp).
This finding further points to the region across introns 2 to 6 as the most likely region to
harbor common variants implicated in schizophrenia.
Expression analysis
In seeking convergent supporting evidence we also tested the expression levels of the
MYO16 gene in brains of patients with schizophrenia. Our analysis of the SMRI Array
Collection using qRT-PCR showed that mean levels of expression of MYO16 were
significantly higher in the frontal cortex of schizophrenia patients as compared to controls
[F(1, 66) = 4.2; P = 0.044]. The significance holds when we incorporate either sex and
age at death [F(3,64) = 3.008; P = 0.037] or brain pH and post-mortem interval [F(3,64)
= 2.778; P = 0.048] as covariates in our analysis. The comparison of the bipolar group to
controls did not result in a significant difference, although mean levels of expression
were slightly higher in the bipolar group (see Supplementary Figure 1 for a scatter plot of
expression levels). Furthermore, 6 out of 11 expression studies that have profiled the
SMRI Array Collection samples using array technology reported increased levels of
MYO16 expression in schizophrenia patients versus controls.
We also tested 28 SNPs genotyped in the Stanley Array Collection, located at both ends
of our significant SNPs, but none of these SNPs showed association with MYO16
expression levels (P > 0.05). It should be noted that SNP rs9583277, as well as most of
the significant SNPs in SAF2, were not included in this set since they had not been
genotyped in the Stanley Array Collection.
18
Discussion
This study employed seven patient cohorts and a dense array of SNPs to fine map the
prior linkage region at the 13q32-34 locus. We provide evidence suggesting that variants
within MYO16 contribute to the genetic liability to schizophrenia conferred by the 13q3234 locus. The MYO16 gene stretches along 611,856 bps on chromosome 13q33. It
consists of 35 exons and has several isoforms. All associated SNPs from SAF1, SAF2
and meta-analysis, and one haplotype from SAF2 are located within introns 2 to 6 of the
gene. Considering that there was no significant excess of total genotyped SNPs in this
region, this finding indicates that the signal related to common risk variation from this
gene is likely localized in this region of the gene. It should be noted that incorporating the
initial findings in the meta-analyses is necessary due to the small effect sizes of common
variants and the need to increase the power of our association study, albeit the potential
for introducing biases (Zeggini and Ioannidis, 2009). The effect of the associated SNPs
on the function of the MYO16 gene remains unknown. It should be noted, however, that
one of the most significant SNPs in the SAF2 dataset (rs9301323, P-value = 1.7x10-3),
which is in strong LD with the top associated SNP in the same dataset (rs9520990), is
located within a splice site region in intron 6 (see URLs), and could affect the pattern of
splicing of the MYO16 gene. This position is conserved in the mouse. The Human
Splicing Finder (HSF) program (Desmet et al, 2009) indicates that the minor allele (G) of
rs9301323 disrupts a predicted branch point sequence in intron 6.
Myosin XVI appeared very recently during the evolution of mammals and is unique in
both its structure and function (Thompson and Langford, 2002). Earlier evidence
suggested that MYO16 is important for neuronal migration and brain development (Patel
et al, 2001). More recently, MYO16 has been implicated in neuronal phosphoinositide 3kinase (PI3K) signaling (Yokoyama et al, 2011), an extensively studied pathway
involved in neuronal function and morphogenesis as well as in a number of neurological
and psychiatric disorders, including schizophrenia and autism (Waite and Eickholt,
2010). MYO16 is a member of the Neuronal tyrosine-phosphorylated Adaptor for the PI
3-kinase (NYAP) family of phosphoproteins, which is comprised of NYAP1, NYAP2,
19
and Myo16/NYAP3. The NYAPs are expressed predominantly in developing neurons
and upon stimulation with Contactin5, they are tyrosine phosphorylated by Fyn.
Phosphorylated NYAPs interact with PI3K p85 and activate PI3K, Akt, and Rac1. In
addition, NYAPs interact with the WAVE1 complex, thus serving as a bridge for a PI3KWAVE1 interaction, which mediates PI 3-kinase-dependent remodeling of the actin
cytoskeleton. Importantly, disruption of the NYAP genes in mice affects brain size and
neurite elongation (Yokoyama et al, 2011). Notably, meta-analysis of the SAF2, GAIN
and MGS datasets (a total of 2,956 cases) showed a gene-wise significant association (Pvalue of 1.8x10-5) with a SNP located within the third intron of the NYAP2 gene
(rs1897227) suggesting that variation within this gene family may be modulating the risk
of schizophrenia.
Additional supporting evidence was provided by expression analysis in brain
samples (frontal cortex), which revealed a significant increase in the levels of MYO16
expression in schizophrenia patients compared to controls. Finally, convergent supporting
evidence could be found in the existing literature. First, according to the SCAN database
(see URLs) the top associated MYO16 SNP rs9583277 is a potential trans-acting eQTL
(expression quantitative trait locus) for MAP3K13 (mitogen-activated protein kinase 13)
gene on chromosome 3q27 (P = 8x10-5). Given a potential convergence of MAP3K13 and
PI3K pathways (Ambacher et al, 2012), regulation in trans of MAP3K13 may be
mediated by altered MYO16 activity. Interestingly, MAP3K13 can phosphorylate
MAP2K7 (mitogen activated kinase protein 7), which has been recently implicated in
schizophrenia (Winchester et al, 2012). In addition, the 7 top associated SNPs identified
by our meta-analysis of the SAF2-GAIN-MGS datasets (Table 4) are reported by the
SCAN database to have a trans-acting effect on the expression of PAG1 (phosphoprotein
associated with glycosphingolipid microdomains 1) on chromosome 8q21.23 (P = 2x106
), a gene implicated in brain maturation (Lindquist et al, 2011). Notably, we have
previously reported a non-synonymous de novo mutation within PAG1 in a schizophrenia
proband (Xu et al, 2012; Xu et al, 2011). Finally, a recent study (Nakayama et al, 2002),
reported a physical interaction between the gene products of MYO16 and NRXN1, a
synaptic neuronal adhesion molecule that connects presynaptic and postsynaptic neurons
and has an important role in cognitive process (Sudhof, 2008). Rare and recurrent
20
deletions disrupting NRXN1 have been reported in patients with schizophrenia and
neurodevelopmental disorders. Furthermore, MYO16 has been identified as a candidate
risk gene in a genome-wide association study of autism where suggestive association
signals were reported in two independent discovery cohorts (Wang et al, 2009), as well as
in GWAS of alcohol response (Joslyn et al, 2010) and smoking cessation (Rose et al,
2010).
While our results suggest that common variation within MYO16 may contribute to
the genetic liability to schizophrenia we cannot exclude the possibility that common
variants within MYO16 act in combination with or as surrogates of rare alleles with
strong effect in the same or different genes to generate the observed linkage signal in the
13q32-34 locus. We started addressing this question using inherited exonic variant data
extracted from our recent whole exome sequencing study in 146 Afrikaner and 85 US
parent-proband trios afflicted with schizophrenia or schizoaffective disorder (Xu et al,
2012). Trios used in the present study and the Xu et al. (2012) study overlap by ~50%
(~72% if we considered just the South African sample). None of the MYO16 variants
located in exons 2-6 (Supplementary Table 4) are in LD with associated SNPs, show
differential enrichment in cases versus controls or show strong allele transmission
distortion in affected families. Also, no homozygous or compound heterozygous carriers
were identified. Although further analysis in expanded samples and in linked families is
required, these results suggest that the association observed with common variants of the
MYO16 gene is unlikely to be due to rare exonic variants.
Our results establish MYO16 as a novel candidate gene for schizophrenia.
Interpretation of our findings awaits replication in independent datasets.
21
Funding: This work was supported in part by National Institute of Mental Health
(NIMH) grant MH061399 (to M.K.) and the Lieber Center for Schizophrenia Research at
Columbia University. L.R.M. was partially supported by a Gray Matters Fellowship and
B.X. was partially supported by a NARSAD Young Investigator Award.
Financial Disclosures Statement: The authors have no biomedical financial interests or
potential conflicts of interest to declare.
Acknowledgments
We thank all the families who participated in this research. For our Afrikaner cohorts, we
thank H. Pretorius and nursing sisters R. van Wyk, C. Botha and H. van den Berg for
their assistance with subject recruitment, family history assessments and diagnostic
evaluations. We thank Yan Sun for technical assistance with all DNA sample
preparations. We also thank the Center for Inherited Disease Research (CIDR), and in
particular J. Roberts and KF Doheny, for custom genotyping services under NIH contract
number N01-HG-65403. We thank the Rutgers University Cell and DNA Repository for
samples and also the Stanley Medical Research Institute for brain samples. The Rutgers
samples were collected in three projects that participated in the NIMH Schizophrenia
Genetics Initiative. From 1991 to 1997, the Principal Investigators and Co-Investigators
were as follows: (i) Harvard University: MT Tsuang, S Faraone and J Pepple; (ii)
Washington University: CR Cloninger, T Reich and D Svrakic; and (iii) Columbia
University: C Kaufmann, D Malaspina and JH Friedman.
For the GAIN and MGS_nonGAIN datasets, funding was provided through U01s
MH79469 and MH79470. Assistance with data cleaning was provided by the National
Center for Biotechnology Information. The GAIN and MGS datasets used for the
analyses included in this manuscript were obtained from the database of Genotype and
Phenotype (dbGaP) found at dbGaP (see URLs) through dbGaP accession numbers
phs000021.v2.p1 (GAIN) and phs000167.v1.p1 (nonGAIN). Samples and associated
phenotype data for the MGS GWAS study were collected under the following grants:
NIMH Schizophrenia Genetics Initiative U01s: MH46276 (CR Cloninger), MH46289 (C
Kaufmann), and MH46318 (MT Tsuang); and MGS Part 1 (MGS1) and Part 2 (MGS2)
22
R01s: MH67257 (NG Buccola), MH59588 (BJ Mowry), MH59571 (PV Gejman),
MH59565 (Robert Freedman), MH59587 (F Amin), MH60870 (WF Byerley), MH59566
(DW Black), MH59586 (JM Silverman), MH61675 (DF Levinson), and MH60879 (CR
Cloninger). Further details of collection sites, individuals, and institutions may be found
in data supplement Table 1 of Sanders et al. (2008; PMID: 18198266) and at the study
dbGaP pages.
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URLs:
dbGaP: http://www.ncbi.nlm.nih.gov/projects/gap
Plink: http://pngu.mgh.harvard.edu/~purcell/plink/
PedStats: http://www.sph.umich.edu/csg/abecasis/PedStats/
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UCSC genome browser: http://genome.ucsc.edu/
Stanley Medical Research Institute: http://stanleyresearch.org
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28
SUPPLEMENTARY INFORMATION
Supplementary figure 1 legend. Scatter plot by sample of MYO16 relative expression levels in schizophrenia (SCZ), controls
(Control) and bipolar (BP) subjects.
29
Supplementary Table 1
SAF1
Rutgers
US
SAF2
GAIN
MGS
# SNPs
# Individuals
# Families
# Affecteds
723
1661
415
741 (474
narrow)
22
630
207
207
(155 narrow)
Genome-Wide
784
237
266
(232 narrow)
Genome-Wide
2659
Case/control
1217
Genome-Wide
2752
Case/control
1405
Family history
Yes
22
1241
301
631
(587
narrow)
Yes
No
Yes
?
?
Unless otherwise specified, # affecteds refer to the broad definition of schizophrenia
30
Supplementary Table 2
CHR
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
SNP
rs12860901
rs1163830
rs1576166
rs11619453
rs10492684
rs3742193
rs7324447
rs9583277
rs7994782
rs10492482
rs7991436
rs440500
rs942648
rs9525253
rs4325412
rs1278760
rs9515201
rs7334530
rs2033539
rs1359480
rs9555589
rs7989816
rs7400121
rs7991409
rs2281973
rs4771711
rs1928454
POSITION
113901892
110911081
108986242
109564351
112561683
110078003
113908097
108131750
107191892
108862601
109824441
110098800
110749312
113871032
107506243
112579676
109838799
113816040
112511089
107413961
108783638
113118794
113557366
109161160
109928675
110300660
113831971
SAF1 Narrow
1.60E-04
2.00E-04
4.10E-04
0.0012
0.0012
0.0013
0.0013
0.0016
0.0018
0.0018
0.0019
0.0019
0.002
0.0027
0.0029
0.0034
0.0035
0.0044
0.0058
0.0059
0.0059
0.0068
0.0068
0.0075
0.0075
0.0085
0.0089
SAF1 Broad
0.0082
7.60E-04
3.30E-04
0.0017
0.0016
0.0144
0.0037
0.0012
0.0024
0.052
0.0027
0.0033
0.18
0.084
0.0144
0.0021
0.021
0.003
0.126
0.038
0.8
0.025
0.24
0.019
0.0107
0.0032
0.0121
alleles
C/T
A/G
C/T
A/C
C/G
C/T
A/G
A/C
A/G
A/G
A/G
C/T
C/T
A/G
G/T
C/T
A/C
A/G
C/T
A/C
C/G
C/T
C/T
C/T
A/G
A/G
A/G
gene
RASA3
NA
NA
NA
ATP11A
FLJ10769
RASA3
MYO16
FAM155A
NA
COL4A2
CARS2
ARHGEF7
RASA3
NA
ATP11A
COL4A2
RASA3
ATP11A
NA
NA
NA
GAS6
NA
COL4A2
NA
RASA3
31
feature
intron[NM_007368.2]
NA
NA
NA
intron[NM_032189.3]
intron[NM_018210.2]
intron[NM_007368.2]
intron[NM_015011.1]
NA
intron[NM_001846.2]
intron[NM_024537.1]
intron[NM_003899.3]
intron[NM_007368.2]
NA
intron[NM_032189.3]
intron[NM_001846.2]
intron[NM_007368.2]
intron[NM_032189.3]
NA
NA
NA
intron[NM_000820.1]
NA
intron[NM_001846.2]
NA
intron[NM_007368.2]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs9520422
rs1927343
rs277828
rs1018601
rs1019863
rs2940695
rs7993373
rs7319311
rs942336
rs4773155
rs1328837
rs1550192
rs2391824
rs496313
rs723067
rs1414318
rs1830756
rs2038706
rs2391753
rs7330849
rs1539070
rs4512966
rs277848
rs9521372
rs7400029
rs9555682
rs767210
rs1923735
rs1323666
rs1033869
106832542
109851960
108491886
107008201
108236968
107365156
111742897
109828579
111681733
109769067
108677100
111881724
109759283
108615052
110917523
109244941
106878224
108630288
108902236
109034647
104922458
109880059
108547255
108891045
113611527
109739978
110268039
111632186
106852117
108700278
0.0106
0.0109
0.011
0.0112
0.0113
0.0117
0.0118
0.0123
0.0124
0.0129
0.0134
0.0136
0.0137
0.0141
0.0143
0.015
0.016
0.016
0.017
0.017
0.018
0.018
0.019
0.019
0.019
0.02
0.02
0.02
0.021
0.021
0.17
0.0133
0.0102
0.0118
0.023
0.021
*
0.024
0.039
0.036
0.33
0.0024
0.017
0.049
0.017
0.125
0.058
0.22
0.0112
0.15
0.0066
0.036
0.39
0.072
0.031
0.38
0.018
0.035
0.087
0.021
C/T
A/C
A/C
C/T
A/T
A/G
A/G
A/G
C/T
A/C
C/T
C/T
A/G
A/G
A/G
C/T
A/C
C/T
C/T
C/T
C/G
C/T
A/G
G/T
A/G
A/G
C/T
G/T
C/G
G/T
FAM155A
COL4A2
MYO16
FAM155A
MYO16
NA
NA
COL4A2
NA
COL4A2
NA
NA
COL4A2
MYO16
NA
LOC728767
FAM155A
MYO16
NA
NA
DAOA
COL4A2
MYO16
NA
FAM70B
COL4A1
LOC100129390
NA
FAM155A
NA
32
intron[NM_001846.2]
intron[NM_015011.1]
intron[NM_015011.1]
NA
NA
intron[NM_001846.2]
NA
intron[NM_001846.2]
NA
NA
intron[NM_001846.2]
intron[NM_015011.1]
NA
intron[NM_015011.1]
NA
NA
intron[NM_172370.3]
intron[NM_001846.2]
intron[NM_015011.1]
NA
intron[NM_182614.2]
intron[NM_001845.4]
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs12017058
rs9555773
rs555212
rs4517649
rs1509095
rs1927674
rs7399860
rs192505
rs9549575
rs3814254
rs12021271
rs7983579
rs716504
rs9515076
rs4773340
rs2147686
rs1859756
rs1325372
rs913746
rs475518
rs9577645
rs185792
rs1334586
rs7982576
rs2031837
rs701580
rs2391882
rs6492204
rs953386
rs1163838
109621341
110571109
112804541
107045669
107336856
108874741
113567277
111923787
112560332
113160288
108312802
105957447
106859625
108966763
110747254
110665502
110867758
107431712
109814125
111640795
111893886
112048584
99433607
106844787
108930376
109040392
110377552
108972142
109741693
111001762
0.021
0.021
0.021
0.023
0.023
0.023
0.023
0.024
0.024
0.024
0.025
0.026
0.026
0.026
0.026
0.027
0.027
0.028
0.028
0.028
0.028
0.028
0.029
0.029
0.031
0.031
0.032
0.033
0.033
0.033
0.051
0.019
0.0031
0.98
0.056
0.0076
0.114
0.039
0.3
0.52
0.055
0.72
0.88
0.0103
0.0116
0.04
0.126
0.079
0.052
0.049
0.068
0.26
*
0.28
0.056
0.032
0.16
0.053
0.066
0.075
A/G
A/G
A/G
NA
G/T
C/T
A/C
A/G
C/T
G/T
G/T
G/T
C/G
C/T
A/G
G/T
A/G
C/T
A/C
A/T
A/T
A/G
A/G
C/T
C/T
A/G
C/G
C/T
A/G
A/G
COL4A1
ARHGEF7
NA
NA
NA
NA
LOC100128430
NA
ATP11A
DCUN1D2
MYO16
EFNB2
FAM155A
NA
ARHGEF7
ARHGEF7
NA
NA
COL4A2
NA
NA
NA
ZIC2
FAM155A
NA
NA
NA
NA
COL4A1
NA
33
intron[NM_001845.4]
intron[NM_145735.2]
NA
NA
NA
NA
NA
intron[NM_032189.3]
intron[NM_015011.1]
intron[NM_004093.2]
NA
intron[NM_003899.3]
intron[NM_003899.3]
NA
NA
intron[NM_001846.2]
NA
NA
NA
intron[NM_007129.2]
NA
NA
NA
NA
intron[NM_001845.4]
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs7987644
rs7984847
rs996969
rs7325670
rs4771685
rs2136267
rs9515008
rs4771748
rs913745
rs2296353
rs387298
rs9521694
rs944899
rs4597175
rs2077891
rs195249
rs1328247
rs157008
rs7394
rs754599
rs6602897
rs277796
rs4293272
rs280795
rs2270393
rs9559068
rs3906815
rs1536678
rs954580
rs1935133
112322196
107096864
109040933
109122216
109966952
107332783
108648676
110810722
109683981
110731099
109957629
109775574
111798962
106846695
110197898
108170191
108917530
108556379
110090045
110152789
113501804
108435624
111553204
111914113
113023895
107032518
110203578
112143948
104949855
107126055
0.033
0.034
0.034
0.034
0.034
0.035
0.035
0.035
0.037
0.037
0.038
0.039
0.039
0.04
0.04
0.041
0.041
0.042
0.042
0.042
0.042
0.046
0.046
0.046
0.046
0.048
0.048
0.049
0.05
0.05
0.0096
0.041
0.21
0.028
0.136
0.022
0.29
0.066
0.028
0.085
0.086
0.49
0.81
0.2
0.022
0.28
0.28
0.026
0.104
0.043
0.128
*
0.028
0.49
0.061
0.107
0.065
0.06
0.0096
*
A/G
C/T
A/G
C/T
A/G
A/G
C/T
C/T
A/T
C/G
A/G
A/T
C/T
C/T
A/T
A/G
C/T
A/G
C/T
A/C
C/T
C/T
A/G
A/G
C/T
A/G
G/T
A/G
C/T
A/T
NA
FAM155A
NA
NA
NA
NA
MYO16
NA
COL4A1
ARHGEF7
COL4A2
COL4A2
NA
FAM155A
NA
MYO16
NA
MYO16
FLJ10769
CARS2
FLJ44054
MYO16
NA
NA
LAMP1
FAM155A
NA
NA
NA
FAM155A
34
NA
NA
NA
NA
NA
intron[NM_015011.1]
NA
intron[NM_001845.4]
intron[NM_003899.3]
intron[NM_001846.2]
intron[NM_001846.2]
NA
NA
intron[NM_015011.1]
NA
intron[NM_015011.1]
utr-3[NM_018210.2]
intron[NM_024537.1]
intron[NM_015011.1]
NA
NA
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs942653
rs9549653
rs7328800
rs1473792
rs483838
rs920008
rs4107301
rs4773173
rs1536621
rs2391610
rs277854
rs815176
rs7999900
rs622911
rs11069816
rs1926542
rs157023
rs1325395
rs7325927
rs12016920
rs492560
rs2094700
rs393192
rs3858816
rs1046518
rs2068813
rs188126
rs196141
rs3910315
rs512610
110632032
112767835
107489197
107675630
111660805
109191651
107322224
109823119
110006337
107468407
108564557
111906520
107795019
108666181
109388612
108118919
108575332
107495302
107273514
113474918
109717977
109808269
112507640
108441465
113252370
108341285
111925441
108333318
109156880
110787471
0.05
0.051
0.052
0.052
0.052
0.053
0.054
0.054
0.054
0.055
0.055
0.055
0.056
0.056
0.057
0.058
0.058
0.059
0.06
0.062
0.063
0.064
0.064
0.065
0.065
0.066
0.066
0.067
0.067
0.067
0.2
0.029
0.045
0.091
0.2
0.025
0.16
0.062
0.049
0.28
0.023
0.53
0.021
0.24
0.065
0.044
0.06
0.08
0.146
0.26
*
0.071
0.032
0.4
0.42
0.124
0.94
0.058
0.141
0.087
C/T
C/T
C/G
C/T
C/T
C/T
A/G
A/G
G/T
C/T
C/T
C/G
C/T
C/T
C/T
A/G
G/T
A/G
C/T
A/G
A/G
C/T
A/T
C/T
A/G
C/T
A/G
C/T
C/T
A/G
ARHGEF7
MCF2L
NA
ABHD13
NA
NA
NA
COL4A2
RAB20
NA
MYO16
NA
NA
NA
NA
MYO16
MYO16
NA
FAM155A
NA
COL4A1
COL4A2
ATP11A
MYO16
TMCO3
MYO16
NA
MYO16
NA
C13orf16
35
intron[NM_003899.3]
intron[NM_024979.3]
NA
intron[NM_032859.2]
NA
NA
NA
intron[NM_001846.2]
intron[NM_017817.1]
NA
intron[NM_015011.1]
NA
NA
NA
NA
intron[NM_015011.1]
intron[NM_015011.1]
NA
NA
intron[NM_001845.4]
intron[NM_001846.2]
intron[NM_032189.3]
intron[NM_015011.1]
utr-3[NM_017905.4]
intron[NM_015011.1]
NA
intron[NM_015011.1]
NA
intron[NM_152324.1]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs6422414
rs1328240
rs2993342
rs2011035
rs1771138
rs474128
rs9549655
rs6042
rs4773139
rs2391933
rs3742181
rs1931356
rs2391812
rs4772864
rs1556122
rs2479429
rs1571862
rs9577826
rs1151451
rs3858799
rs1408911
rs10492418
rs9559900
rs1924349
rs1022963
rs2391891
rs1359476
rs7998446
rs927606
rs1023168
113646243
108822845
112655072
108688891
107314854
106941677
112773368
112818069
109730194
110823483
110751904
107587302
109554665
106710934
109783608
109975673
110463849
111632380
110936930
107133874
107423256
108178727
110325330
107905294
110296002
110430395
107404941
112658843
108654322
109029934
0.068
0.069
0.07
0.071
0.072
0.074
0.074
0.074
0.075
0.076
0.077
0.079
0.08
0.082
0.083
0.083
0.083
0.083
0.084
0.086
0.086
0.086
0.087
0.088
0.088
0.089
0.09
0.09
0.091
0.091
0.18
0.094
0.148
0.34
0.44
*
0.16
0.36
0.126
0.083
0.129
0.142
0.34
0.066
0.148
0.044
0.039
0.042
0.21
0.34
0.22
0.071
0.093
0.44
0.068
0.17
0.51
0.079
*
0.036
C/T
A/G
G/T
A/G
C/T
C/T
A/G
C/T
A/G
A/C
A/G
C/T
C/T
C/T
C/T
A/G
C/T
A/T
C/T
A/G
C/T
G/T
A/G
A/G
A/G
A/G
C/T
C/T
A/G
A/G
FAM70B
NA
NA
NA
FAM155A
FAM155A
MCF2L
F7 F7 F7
COL4A1
NA
ARHGEF7
NA
NA
FAM155A
COL4A2
RAB20
NA
NA
NA
FAM155A
NA
MYO16
NA
NA
NA
NA
NA
NA
MYO16
NA
36
intron[NM_182614.2]
NA
NA
NA
intron[NM_024979.3]
intron[NM_001845.4]
NA
intron[NM_003899.3]
NA
NA
intron[NM_001846.2]
intron[NM_017817.1]
NA
NA
NA
NA
intron[NM_015011.1]
NA
NA
NA
NA
NA
NA
intron[NM_015011.1]
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs4771678
rs9588436
rs7317784
rs1853861
rs2391887
rs1074866
rs9314891
rs9634589
rs378953
rs7489746
rs9558996
rs7326145
rs4907475
rs1887697
rs3915580
rs8002899
rs7994403
rs992529
rs275944
rs872484
rs912943
rs912947
rs4578513
rs4238277
rs1164133
rs7330570
rs9549845
rs1925888
rs3916968
rs943900
109874941
110881278
109753075
110112905
110420594
111810283
113891307
109359256
112026872
113637032
106740433
109845351
112657291
101214784
107180494
108201934
110523933
108075875
108597821
109506369
110001696
109946660
108177007
110034434
110847931
111660345
111813664
112294946
104925530
110831429
0.091
0.091
0.093
0.093
0.093
0.093
0.093
0.094
0.094
0.094
0.095
0.096
0.097
0.098
0.098
0.099
0.099
0.1
0.1
0.1
0.1
0.101
0.104
0.105
0.105
0.106
0.106
0.106
0.108
0.108
0.025
0.062
0.084
0.32
0.33
0.063
0.034
0.127
0.63
0.18
0.28
0.066
0.68
0.028
0.39
0.08
0.143
0.091
0.097
0.05
0.069
0.034
0.059
0.0093
0.035
0.44
0.047
0.114
0.17
0.31
C/T
A/C
C/T
A/G
C/T
A/G
A/G
C/G
G/T
A/G
C/T
A/C
A/G
C/T
A/G
C/G
G/T
A/T
A/T
A/G
G/T
C/G
A/G
A/G
C/T
C/T
A/G
A/G
A/G
C/T
COL4A2
NA
COL4A1
CARS2
NA
NA
RASA3
NA
NA
FAM70B
FAM155A
COL4A2
NA
FGF14
FAM155A
MYO16
NA
MYO16
MYO16
NA
RAB20
COL4A2
MYO16
NA
NA
NA
NA
NA
DAOA
NA
37
intron[NM_001846.2]
NA
intron[NM_001845.4]
intron[NM_024537.1]
NA
NA
intron[NM_007368.2]
NA
NA
intron[NM_182614.2]
intron[NM_001846.2]
NA
intron[NM_004115.2]
intron[NM_015011.1]
NA
intron[NM_015011.1]
intron[NM_015011.1]
NA
intron[NM_017817.1]
intron[NM_001846.2]
intron[NM_015011.1]
NA
NA
NA
NA
NA
intron[NM_172370.3]
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs9585307
rs715738
rs766974
rs9604456
rs947361
rs958378
rs4444189
rs878538
rs4771635
rs961762
rs7981705
rs7331116
rs9583484
rs3803229
rs8000897
rs943767
rs9521623
rs928543
rs8000376
rs977387
rs9514997
rs1163857
rs1411628
rs1926503
rs958952
rs9520479
rs1224166
rs3923530
rs4773291
rs9520928
99419777
108990492
110015423
112508272
107123121
110542939
106823669
108228609
109013314
106770873
109229892
113103906
109764350
109932781
107630926
108828552
109607383
109396965
100848840
108062451
108609512
110957774
110997322
108148775
109540198
106984579
107765412
108790155
110398933
107990778
0.109
0.109
0.109
0.109
0.11
0.11
0.111
0.111
0.112
0.113
0.115
0.116
0.117
0.119
0.121
0.121
0.123
0.124
0.125
0.126
0.126
0.126
0.126
0.127
0.127
0.128
0.128
0.128
0.128
0.129
0.142
0.062
0.12
0.15
*
0.049
0.34
0.122
0.19
0.108
0.101
0.141
0.071
0.17
0.37
*
0.23
0.103
0.028
0.031
0.34
0.24
0.31
0.029
0.68
0.2
0.076
0.5
0.083
0.016
C/G
A/G
C/T
C/G
C/T
G/T
A/G
A/T
A/G
C/T
C/T
A/G
G/T
C/T
C/T
A/C
A/C
A/G
C/T
C/T
A/G
A/G
A/G
C/T
C/T
C/G
C/T
G/T
A/G
G/T
ZIC5
NA
NA
ATP11A
FAM155A
NA
FAM155A
MYO16
NA
FAM155A
IRS2
NA
COL4A2
COL4A2
NA
NA
COL4A1
NA
NALCN
MYO16
MYO16
NA
NA
MYO16
NA
FAM155A
NA
NA
NA
NA
38
intron[NM_033132.3]
NA
NA
intron[NM_032189.3]
NA
intron[NM_015011.1]
NA
intron[NM_003749.2]
NA
intron[NM_001846.2]
intron[NM_001846.2]
NA
NA
intron[NM_001845.4]
NA
intron[NM_052867.2]
intron[NM_015011.1]
intron[NM_015011.1]
NA
NA
intron[NM_015011.1]
NA
NA
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs1341403
rs7992722
rs1886228
rs4771636
rs4773124
rs1886227
rs4771644
rs7139958
rs4773278
rs966804
rs415756
rs6577046
rs831165
rs776897
rs1323682
rs7326528
rs7991325
rs1223978
rs1041466
104914808
112157732
107067797
109021687
109557712
107063516
109211818
104934733
110371439
108207339
110259218
113140550
110590297
112843672
106909000
108423121
113127674
107573163
109042323
0.13
0.131
0.132
0.132
0.132
0.133
0.134
0.135
0.135
0.136
0.136
0.136
0.137
0.138
0.139
0.14
0.141
0.142
0.144
*
0.38
0.35
0.24
0.33
0.66
0.2
0.148
0.43
0.58
0.41
0.16
0.24
0.46
0.38
0.12
0.077
0.17
0.23
A/C
A/G
A/G
C/T
G/T
C/T
A/G
A/T
C/G
C/T
A/G
G/T
A/G
C/T
C/T
C/T
A/C
C/T
C/T
13
rs4773092
109233954
0.144
*
A/G
13
13
13
13
13
13
13
13
13
rs7335928
rs1320517
rs1164132
rs9577503
rs2057504
rs9521184
rs745324
rs9555646
rs4773106
111053199
112636505
110853125
113013177
106895244
108580569
109263298
109364001
109448627
0.145
0.145
0.146
0.147
0.15
0.15
0.15
0.15
0.15
0.076
0.22
0.42
0.114
0.89
0.42
0.45
0.089
0.68
A/G
C/T
A/G
A/C
C/T
C/T
C/T
C/T
A/G
DAOA
NA
FAM155A
NA
NA
FAM155A
IRS2
DAOA
NA
MYO16
NA
ADPRHL1
ARHGEF7
F10
FAM155A
MYO16
ADPRHL1
NA
NA
IRS2 LOC728767
LOC728767
NA
NA
NA
LAMP1
FAM155A
MYO16
NA
NA
NA
39
NA
NA
NA
intron[NM_003749.2]
intron[NM_172370.3]
NA
intron[NM_015011.1]
NA
intron[NM_199162.1]
intron[NM_145735.2]
intron[NM_000504.3]
intron[NM_015011.1]
intron[NM_199162.1]
NA
NA
NA
NA
NA
intron[NM_015011.1]
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs9521666
rs867790
rs11619712
rs11618595
rs9549656
rs9520447
rs11839232
rs7324846
rs1536675
rs336230
rs927793
rs12856863
rs9604573
rs9520396
rs9301247
rs719185
rs10492417
rs592398
rs9301388
rs4773218
rs912937
109695445
110249709
111611762
111741481
112773759
106902104
108496987
108608164
108861771
109268342
109998017
113050384
113571085
106791742
107071857
107079922
108181642
108677223
108934565
110028734
110048882
0.15
0.15
0.15
0.15
0.15
0.16
0.16
0.16
0.16
0.16
0.16
0.16
0.16
0.17
0.17
0.17
0.17
0.17
0.17
0.17
0.17
0.38
0.36
0.018
0.106
0.22
0.27
0.038
*
0.106
0.079
0.21
0.072
0.53
0.58
0.042
0.31
0.35
0.066
0.3
0.133
0.091
A/G
C/T
A/G
C/T
A/T
A/G
A/G
A/G
G/T
A/G
A/G
A/G
C/T
C/T
C/T
C/T
G/T
C/T
C/T
C/G
C/T
13
rs2296354
110668038
0.17
0.89
A/G
13
13
13
13
13
13
13
rs753178
rs7325678
rs383353
rs915047
rs726449
rs1926510
rs9514995
111665322
112183509
112527549
107648692
107949490
108153556
108602549
0.17
0.17
0.17
0.18
0.18
0.18
0.18
0.68
0.81
0.35
0.94
0.81
0.33
0.18
C/T
A/G
A/G
A/G
A/G
G/T
A/C
COL4A1
NA
NA
NA
MCF2L
FAM155A
MYO16
MYO16
NA
NA
RAB20
GRTP1
GAS6
FAM155A
FAM155A
FAM155A
MYO16
NA
NA
NA
NA
ARHGEF7 ARHGEF7
ARHGEF7
NA
NA
ATP11A
NA
NA
MYO16
MYO16
40
intron[NM_001845.4]
NA
NA
NA
intron[NM_024979.3]
intron[NM_015011.1]
intron[NM_015011.1]
NA
NA
intron[NM_017817.1]
intron[NM_024719.2]
intron[NM_000820.1]
intron[NM_015011.1]
NA
NA
NA
NA
NA
NA
intron[NM_032189.3]
NA
NA
intron[NM_015011.1]
intron[NM_015011.1]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs4462453
rs627527
rs2391876
rs947170
rs1923740
rs927855
rs4386002
rs984299
rs1328250
rs1410424
rs885339
rs7331778
rs884708
rs1278775
rs474810
rs7320143
rs9562080
rs9521369
rs2391777
rs1411553
rs2119480
rs9522149
rs9588435
rs928194
rs1041385
rs9604566
rs2181506
rs1341373
rs4772955
rs12428930
109049329
109713136
110354344
111039063
111594867
108080073
108219137
108254079
108856632
108976282
110487236
110681068
110813104
112595200
112828911
113046455
113941879
108880688
109056244
109108212
110141889
110625168
110880978
111902203
112354883
113533961
101272738
107230495
107597307
107737706
0.18
0.18
0.18
0.18
0.18
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.21
0.21
0.21
0.21
0.5
0.37
0.38
0.31
0.19
0.082
*
0.79
0.16
0.84
0.24
0.09
0.31
0.56
0.65
0.12
0.113
0.136
0.125
0.38
0.29
0.5
0.24
0.18
0.49
0.18
*
0.49
0.55
0.6
A/G
C/T
A/T
A/G
A/C
A/C
NA
A/G
C/T
C/T
A/G
A/G
C/T
A/G
C/T
C/T
C/G
A/G
A/G
G/T
A/G
C/T
A/G
A/C
C/T
G/T
A/G
C/T
A/C
A/C
NA
COL4A1
ANKRD10
NA
NA
MYO16
NA
MYO16
NA
NA
NA
ARHGEF7
NA
NA
F10
GRTP1
NA
NA
NA
NA
CARS2
ARHGEF7
NA
NA
C13orf35
NA
FGF14
FAM155A
NA
TNFSF13B
41
NA
intron[NM_001845.4]
intron[NM_017664.2]
NA
NA
intron[NM_015011.1]
NA
intron[NM_015011.1]
NA
NA
NA
intron[NM_003899.3]
NA
NA
intron[NM_000504.3]
intron[NM_024719.2]
NA
NA
NA
NA
intron[NM_024537.1]
intron[NM_145735.2]
NA
NA
intron[NM_207440.1]
NA
intron[NM_004115.2]
NA
intron[NM_006573.3]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs1360051
rs162563
rs9301412
rs7337597
rs529041
rs1923742
rs7318319
rs7317198
rs12561491
rs766106
rs4344597
rs406685
rs157000
rs7981385
rs9559849
rs9559981
rs11841484
rs4907561
rs4907623
rs9514649
rs3858806
rs9514840
rs196159
rs7328960
rs2993305
rs1323672
rs7321280
rs9520836
rs2181766
rs12585282
108709716
109095564
109256477
109454492
109658220
111595306
113882946
106723017
107602960
107787699
108000287
108425587
108551465
109105063
110041737
110548126
110771589
112615675
113071402
106742081
107264370
107816155
108308282
112376717
112726831
106870516
107297419
107755064
107855110
108857114
0.21
0.21
0.21
0.21
0.21
0.21
0.21
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.23
0.23
0.23
0.23
0.23
0.23
0.24
0.24
0.24
0.24
0.24
0.0097
0.3
0.19
0.24
0.137
0.055
0.38
0.137
0.3
0.07
0.22
0.53
*
*
0.36
0.009
0.084
0.28
0.059
0.068
0.0058
0.39
0.41
0.83
0.096
*
0.56
0.81
0.99
0.29
A/G
A/G
A/G
C/T
A/G
A/G
A/G
C/T
A/C
A/G
C/T
G/T
A/G
C/T
A/G
A/T
C/T
A/G
A/G
C/T
C/T
C/G
A/G
C/T
C/T
C/T
A/G
A/G
C/T
C/T
NA
NA
LOC728767
NA
COL4A1
NA
RASA3
FAM155A
NA
NA
NA
MYO16
MYO16
NA
NA
NA
C13orf16
NA
NA
FAM155A
FAM155A
NA
MYO16
C13orf35
MCF2L
FAM155A
FAM155A
TNFSF13B
NA
NA
42
NA
NA
NA
intron[NM_001845.4]
NA
intron[NM_007368.2]
NA
NA
NA
intron[NM_015011.1]
intron[NM_015011.1]
NA
NA
NA
intron[NM_152324.1]
NA
NA
NA
intron[NM_015011.1]
intron[NM_207440.1]
intron[NM_024979.3]
intron[NM_006573.3]
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs6492232
rs7320618
rs1933204
rs984300
rs9521112
rs9522032
rs7319901
rs1887649
rs3024731
rs9525275
rs2893357
rs4773116
rs7140030
rs1467652
rs2243928
rs876505
rs4343137
rs530085
rs11618091
rs1408563
rs1581031
rs7321660
rs9515395
rs9515446
rs1046793
rs7989319
rs7327124
rs1431273
rs3803233
rs1541110
109383171
109695293
112629826
108253836
108414403
110424256
111151026
112122229
112866709
113905078
109461227
109511453
109862160
109985751
110779708
110922638
111113593
111649700
113524235
106775852
107447597
108321913
110670274
111015109
112587895
113132512
114071257
108486591
109917147
110500205
0.24
0.24
0.24
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.26
0.26
0.26
0.26
0.26
0.26
0.26
0.26
0.26
0.27
0.27
0.27
0.27
0.27
0.27
0.27
0.27
0.28
0.28
0.28
0.16
0.41
0.3
0.67
0.39
0.062
0.91
0.3
0.53
0.2
0.25
0.088
0.33
0.18
0.21
0.033
0.47
0.16
0.27
0.28
0.27
0.22
0.65
0.56
0.19
0.24
0.23
0.23
0.138
0.26
C/T
C/T
C/T
C/T
A/G
A/G
A/G
A/C
A/T
C/T
C/T
C/T
A/G
A/G
C/G
A/G
C/T
A/G
C/T
C/T
A/G
C/T
A/C
A/G
C/T
A/G
C/T
C/T
A/T
A/T
NA
COL4A1
NA
MYO16
MYO16
NA
NA
C13orf28
PROZ
RASA3
NA
NA
COL4A2
RAB20
C13orf16
NA
NA
NA
FLJ44054
FAM155A
NA
MYO16
ARHGEF7
NA
ATP11A
ADPRHL1
UPF3A
MYO16
COL4A2
NA
43
NA
intron[NM_001845.4]
NA
intron[NM_015011.1]
intron[NM_015011.1]
NA
NA
intron[NM_145248.3]
intron[NM_003891.1]
intron[NM_007368.2]
NA
NA
intron[NM_001846.2]
intron[NM_017817.1]
intron[NM_152324.1]
NA
NA
NA
NA
intron[NM_015011.1]
intron[NM_003899.3]
NA
utr-3[NM_032189.3]
intron[NM_199162.1]
intron[NM_080687.1]
intron[NM_015011.1]
intron[NM_001846.2]
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs9559738
rs2318058
rs571564
rs4907674
rs7338610
rs7329468
rs9590410
rs3916906
rs4771568
rs9520569
rs7139848
rs1224096
rs869913
rs167952
rs754730
rs1888845
rs7332266
rs3813739
rs9550176
rs2224904
rs816960
rs7985095
rs4772972
rs1579520
rs912196
rs9994
rs11069734
rs997702
rs4129052
rs4907715
109582412
111622992
111773792
111900674
112381685
113514092
114065802
100679778
106697442
107200552
107259958
107701073
108721817
109072232
109151514
110520432
111768387
112291289
112317128
106746123
107320522
107479131
107908415
108524944
112781336
112932302
107800359
110934168
111562394
112155252
0.29
0.29
0.29
0.29
0.29
0.29
0.29
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.31
0.31
0.31
0.31
0.31
0.31
0.31
0.32
0.32
0.32
0.32
0.036
0.31
0.88
0.59
0.23
0.26
0.099
0.51
0.32
0.4
0.43
0.78
0.26
0.19
0.99
0.094
0.26
0.38
0.52
0.19
0.5
0.27
*
0.2
0.2
0.99
0.095
0.73
0.28
0.59
C/T
C/T
C/T
G/T
C/T
A/G
A/T
C/T
A/G
C/T
C/G
C/T
C/T
A/G
C/T
A/G
A/G
A/C
C/T
C/T
A/G
C/T
C/T
C/T
A/G
C/T
C/T
C/T
A/C/G/T
A/G
NA
NA
SOX1
NA
C13orf35
FLJ44054
UPF3A
NALCN
FAM155A
FAM155A
FAM155A
NA
NA
NA
NA
NA
SOX1
NA
NA
FAM155A
NA
NA
NA
MYO16
MCF2L
CUL4A
NA
NA
NA
NA
44
NA
NA
utr-3[NM_005986.2]
NA
utr-5[NM_207440.1]
intron[NM_080687.1]
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
intron[NM_015011.1]
intron[NM_024979.3]
NA
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs816999
rs231604
rs1019865
rs4773039
rs2076914
rs496916
rs4771754
rs7317997
rs9521321
rs1550042
rs2148079
rs1224147
rs1224174
rs1328238
rs7996888
rs4773301
rs9560063
rs7320365
rs7998746
rs2476773
rs2296845
rs1106028
rs2152929
rs14067
rs3905075
rs732974
rs8000882
rs1411766
rs9301405
rs1888247
107308417
107524007
108237056
108749019
109139017
109649015
110907300
113781019
108795406
109189696
109989414
107754759
107777044
108866662
108978756
110492072
110886536
111848671
111948132
106931175
109898948
111078373
112642865
113158661
107261220
108213759
108940576
109050161
109144217
109164787
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.33
0.34
0.34
0.34
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.35
0.36
0.36
0.36
0.36
0.36
0.37
0.37
0.37
0.37
0.37
0.37
0.83
0.113
0.26
0.22
0.76
0.85
0.37
0.45
0.42
0.17
0.59
0.145
0.73
0.106
0.121
0.43
0.87
0.39
0.31
0.93
0.116
0.16
0.54
0.52
0.65
0.25
0.19
0.81
0.68
0.26
A/T
C/T
G/T
A/G
C/T
C/G
A/G
A/G
C/T
A/T
A/G
C/T
C/T
C/T
C/T
C/T
A/T
C/G
C/T
C/T
A/C
A/G
C/G
C/T
C/T
C/T
C/G
C/T
A/G
C/T
FAM155A
NA
MYO16
NA
NA
COL4A1
NA
RASA3
NA
NA
RAB20
TNFSF13B
NA
NA
NA
NA
NA
NA
NA
FAM155A
COL4A2
NA
NA
DCUN1D2
FAM155A
MYO16
NA
NA
NA
NA
45
NA
intron[NM_015011.1]
NA
NA
intron[NM_001845.4]
NA
intron[NM_007368.2]
NA
NA
intron[NM_017817.1]
intron[NM_006573.3]
NA
NA
NA
NA
NA
NA
NA
intron[NM_001846.2]
NA
NA
intron[NM_015011.1]
NA
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs336209
rs1192198
rs9515299
rs1028974
rs942339
rs1320526
rs4630437
rs4772985
rs9284246
rs189878
rs9515341
rs1025662
rs4468469
rs9301356
rs3098728
rs9324305
rs12871648
rs9559125
rs9555639
rs9555673
rs1018643
rs7320173
rs9514828
rs954335
rs11616523
rs2391898
rs7323757
rs1163852
rs7989477
rs7995181
109346846
109609579
110283570
110873083
111734909
112608380
112998037
108080882
108125789
108250430
110450160
111862700
106816536
108644425
110208803
112180463
113018663
107108857
109296335
109587487
109894926
112207188
107719374
109516892
110234671
110454440
110631622
110962872
111137392
112014794
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.38
0.38
0.38
0.38
0.38
0.39
0.39
0.39
0.39
0.39
0.4
0.4
0.4
0.4
0.4
0.41
0.41
0.41
0.41
0.41
0.41
0.41
0.41
0.095
0.97
0.101
0.57
0.91
0.54
0.72
0.84
0.26
0.22
0.17
0.85
*
0.91
0.45
*
0.59
0.121
0.67
0.95
0.127
0.53
0.97
0.98
0.47
0.53
0.87
0.57
0.63
0.66
G/T
C/T
C/T
C/T
A/G
C/T
C/T
C/T
C/T
A/G
A/C
C/T
C/T
C/T
C/T
C/T
A/C
A/T
A/G
A/T
C/T
A/G
C/T
C/T
A/G
A/G
G/T
C/T
A/G
A/C
NA
COL4A1
NA
NA
NA
NA
LAMP1
MYO16
MYO16
MYO16
NA
NA
FAM155A
MYO16
NA
NA
LAMP1
FAM155A
NA
NA
COL4A2
TUBGCP3
TNFSF13B
NA
NA
NA
ARHGEF7
NA
NA
NA
46
NA
intron[NM_001845.4]
NA
NA
NA
NA
intron[NM_015011.1]
intron[NM_015011.1]
intron[NM_015011.1]
NA
NA
intron[NM_015011.1]
NA
NA
intron[NM_005561.3]
NA
NA
intron[NM_001846.2]
intron[NM_006322.4]
NA
NA
NA
intron[NM_003899.3]
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs7323586
rs4907617
rs157024
rs7323041
rs2025905
rs4771726
rs421595
rs1890202
rs7991547
rs11069721
rs1924322
rs1924345
rs4771591
rs7139390
rs680484
rs2183850
rs1183184
rs1933199
rs2993282
rs9577556
rs9557751
rs10508190
rs9514827
rs8181791
rs1924326
rs630943
rs4447275
rs9549433
rs7995838
rs2183246
112526655
113061932
108575504
109911609
109982257
110518979
112494223
112603051
99417463
107625853
107859630
107987033
108034018
109433529
109679086
110513987
110839550
112630131
112681797
113164163
101341004
107242528
107717404
107732046
107848056
109675047
109780420
111571966
112309830
113919290
0.41
0.41
0.42
0.42
0.42
0.42
0.42
0.42
0.43
0.43
0.43
0.43
0.43
0.43
0.43
0.43
0.43
0.43
0.43
0.43
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.44
0.86
0.3
0.74
0.06
0.44
0.096
0.52
0.32
0.22
0.114
0.44
0.65
0.072
*
0.133
0.64
0.42
0.64
0.21
0.83
0.018
*
0.83
0.51
0.71
0.32
0.84
0.49
0.78
0.92
C/G
A/G
A/G
G/T
C/G
A/G
C/T
A/G
A/G
C/T
A/G
C/T
C/T
A/G
A/C
A/G
A/G
C/T
A/G
A/G
A/G
C/T
C/T
A/G
C/T
C/T
A/G
A/C
A/G
C/T
ATP11A
GRTP1
MYO16
COL4A2
RAB20
NA
ATP11A
NA
ZIC5
NA
NA
NA
NA
NA
COL4A1
NA
NA
NA
NA
DCUN1D2
FGF14
FAM155A
NA
TNFSF13B
NA
COL4A1
COL4A2
NA
NA
NA
47
intron[NM_032189.3]
intron[NM_024719.2]
intron[NM_001846.2]
intron[NM_017817.1]
NA
intron[NM_032189.3]
NA
intron[NM_033132.3]
NA
NA
NA
NA
NA
intron[NM_001845.4]
NA
NA
NA
NA
intron[NM_004115.2]
NA
intron[NM_006573.3]
NA
intron[NM_001845.4]
intron[NM_001846.2]
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs980044
rs1931355
rs4284503
rs328825
rs1183680
rs744134
rs2146952
rs868284
rs10492412
rs1034104
rs418543
rs1007260
rs1001843
rs1952109
rs12867405
rs9520758
rs4907563
rs6577026
rs755993
rs990181
rs4238266
rs2083567
rs9588495
rs1571621
rs9549757
rs9577874
rs12584299
rs831150
rs7337905
rs871388
106702668
107579727
109922256
110278453
110855749
106922322
106952456
107652214
108298004
109203128
109977797
112056109
108477359
112304134
113331064
107516512
112621373
112761672
113053814
106726884
108779132
110223844
111127395
112367707
113076752
113595154
107612825
110571317
112376526
112572551
0.45
0.45
0.45
0.45
0.45
0.46
0.46
0.46
0.46
0.46
0.46
0.46
0.47
0.47
0.47
0.48
0.48
0.48
0.48
0.49
0.49
0.49
0.49
0.49
0.49
0.49
0.5
0.5
0.5
0.5
*
0.35
0.65
0.24
0.75
0.86
*
0.75
0.52
0.21
0.74
0.82
0.48
0.38
0.82
0.56
0.29
0.28
0.71
0.072
*
0.29
0.28
0.62
0.16
0.64
0.55
0.99
0.66
0.48
C/T
A/C
A/G
C/T
A/G
A/G
A/G
C/T
G/T
C/G
C/T
C/G
A/G
A/G
A/G
A/G
C/T
G/T
A/C
A/C
A/T
C/T
A/G
C/T
A/G
C/T
A/G
C/G
A/G
A/G
FAM155A
NA
COL4A2
NA
NA
FAM155A
FAM155A
NA
MYO16
IRS2
RAB20
NA
MYO16
NA
TFDP1
NA
NA
MCF2L
GRTP1
FAM155A
NA
NA
NA
C13orf35
NA
NA
NA
ARHGEF7
C13orf35
ATP11A
48
NA
intron[NM_001846.2]
NA
NA
NA
intron[NM_015011.1]
intron[NM_017817.1]
NA
intron[NM_015011.1]
NA
intron[NM_007111.3]
NA
NA
intron[NM_024979.3]
intron[NM_024719.2]
NA
NA
NA
intron[NM_207440.1]
NA
NA
NA
intron[NM_145735.2]
intron[NM_207440.1]
intron[NM_032189.3]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs9577283
rs7321414
rs913947
rs3742207
rs2196579
rs4883652
rs7994151
rs4483719
rs677532
rs1235133
rs1925391
rs1408725
rs2257442
rs3825491
rs7998604
rs9515326
rs2182921
rs282620
rs4074317
rs7331571
rs4771627
rs4287436
rs10220229
rs9583500
rs523042
rs1926717
rs1555754
rs942341
rs1888297
rs10508195
113274387
107805127
109154732
109616599
111816835
113913667
114056981
106828307
106994363
107550437
107555920
110703433
113176783
108459360
110401364
110414704
112137851
112533327
113765289
113898451
108726456
108738864
109803934
109919621
111672186
110242642
110692672
111736532
112470411
107270556
0.5
0.51
0.51
0.51
0.51
0.51
0.51
0.52
0.52
0.52
0.52
0.52
0.52
0.53
0.53
0.53
0.53
0.53
0.53
0.53
0.54
0.54
0.54
0.54
0.54
0.55
0.55
0.55
0.55
0.56
0.108
0.85
0.29
0.82
0.54
0.68
0.7
0.42
0.55
0.0118
0.97
0.86
0.45
0.43
0.73
0.63
0.85
0.71
0.33
0.51
0.32
0.6
0.32
0.27
0.67
0.39
0.092
0.56
0.54
*
NA
A/G
C/T
A/C
A/G
A/G
A/G
A/G
G/T
A/G
C/T
C/G
C/T
C/G
A/C
A/G
A/C
C/T
C/G
C/T
A/G
C/T
C/G
C/T
A/G
C/G
A/C
C/T
A/G
C/T
NA
NA
NA
COL4A1
NA
RASA3
NA
FAM155A
FAM155A
NA
NA
ARHGEF7
DCUN1D2
MYO16
NA
NA
NA
ATP11A
RASA3
RASA3
NA
NA
COL4A2
COL4A2
NA
NA
ARHGEF7
NA
ATP11A
FAM155A
49
NA
NA
NA
NA
intron[NM_007368.2]
NA
NA
NA
intron[NM_003899.3]
NA
NA
NA
intron[NM_032189.3]
intron[NM_007368.2]
NA
NA
intron[NM_001846.2]
NA
NA
intron[NM_145735.2]
NA
intron[NM_032189.3]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs7322498
rs7317745
rs1184475
rs445307
rs367910
rs1467761
rs2274545
rs4771730
rs726455
rs2183443
rs7321084
rs701567
rs7324250
rs7997328
rs2296851
rs4771699
rs2304767
rs914037
rs387934
rs1151449
rs13378888
rs559054
rs942335
rs2382725
rs1151403
rs2873579
rs957788
rs1924338
rs7983084
rs9301376
107670522
110289758
110891543
113948457
108290417
108517439
109943311
110563847
111699501
111918207
107971966
104939996
110966878
113554521
109936256
110059268
110138343
111033309
110275369
110931714
111867657
112848623
111751180
113927626
107656374
111837270
107055221
107868993
108819564
108821974
0.56
0.56
0.56
0.56
0.57
0.57
0.57
0.57
0.57
0.57
0.58
0.59
0.59
0.59
0.6
0.6
0.6
0.6
0.61
0.61
0.61
0.61
0.62
0.62
0.63
0.63
0.64
0.64
0.64
0.64
0.4
0.24
0.106
0.143
0.17
0.29
0.95
0.138
0.17
0.41
0.2
0.62
0.67
0.98
0.56
0.73
0.61
0.3
0.82
0.29
0.75
0.61
0.42
0.43
0.92
0.19
0.42
0.67
*
*
C/T
C/T
C/T
A/G
C/T
A/G
G/T
C/T
C/T
A/G
A/G
A/G
A/C
C/T
C/T
C/T
C/T
C/T
A/T
G/T
A/G
C/T
C/T
A/G
C/T
A/G
A/G
C/T
C/T
C/T
ABHD13
NA
NA
NA
MYO16
MYO16
COL4A2
ARHGEF7
NA
NA
NA
DAOA
NA
GAS6
COL4A2
NA
CARS2
NA
NA
NA
NA
F10
NA
NA
LIG4
NA
FAM155A
NA
NA
NA
50
intron[NM_032859.2]
NA
NA
NA
intron[NM_015011.1]
intron[NM_015011.1]
intron[NM_001846.2]
NA
NA
NA
intron[NM_172370.3]
NA
intron[NM_000820.1]
intron[NM_001846.2]
NA
NA
NA
NA
NA
intron[NM_000504.3]
NA
NA
NA
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs7982209
rs7322849
rs9603917
rs3211770
rs473270
rs3905069
rs9520974
rs1544085
rs1106723
rs2146752
rs1151457
rs1925887
rs4578540
rs12429529
rs6492116
rs157014
rs1024306
rs3211764
rs6602908
rs915017
rs568315
rs1536760
rs1324668
rs7325027
rs191796
rs336239
rs3803230
rs9604408
rs4907582
rs157027
109531103
111907830
112332192
112841850
110776266
107206398
108162318
108857993
111049123
112797476
110941191
112341502
112752333
106688601
107951372
108560008
109326859
112840391
113561904
109427779
110797463
113931779
106784743
107608084
108338223
109293324
109917397
112420942
112768781
108578747
0.64
0.64
0.64
0.64
0.65
0.66
0.66
0.66
0.66
0.66
0.67
0.67
0.67
0.68
0.68
0.68
0.68
0.68
0.68
0.69
0.69
0.69
0.7
0.71
0.71
0.71
0.71
0.71
0.71
0.72
0.77
0.23
0.72
0.28
0.97
0.72
0.36
0.08
0.89
0.58
0.34
*
0.52
0.38
0.84
0.52
0.5
0.78
0.43
0.98
0.93
*
0.5
0.83
0.33
0.98
0.86
0.52
0.7
*
A/G
C/T
C/T
A/G
A/G
C/T
A/G
A/G
A/G
C/T
A/G
C/T
A/G
C/G
C/T
C/T
G/T
C/G
A/G
A/C
A/G
C/T
A/G
C/T
A/G
G/T
C/G
A/G
C/G
C/T
NA
NA
NA
F10
C13orf16
FAM155A
MYO16
NA
NA
NA
NA
NA
MCF2L
FAM155A
NA
MYO16
NA
F10
GAS6
NA
NA
NA
FAM155A
NA
MYO16
NA
COL4A2
ATP11A
MCF2L
MYO16
51
NA
NA
NA
intron[NM_000504.3]
intron[NM_152324.1]
intron[NM_015011.1]
NA
NA
NA
NA
NA
intron[NM_024979.3]
NA
intron[NM_015011.1]
NA
intron[NM_000504.3]
intron[NM_000820.1]
NA
NA
NA
NA
intron[NM_015011.1]
NA
intron[NM_032189.3]
intron[NM_024979.3]
intron[NM_015011.1]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs9521585
rs9549507
rs204218
rs1556124
rs9514719
rs2391690
rs648705
rs188166
rs2993310
rs9562187
rs10508198
rs2993334
rs2015775
rs419244
rs11617870
rs10508199
rs1330540
rs626444
rs7986656
rs7139897
rs9577173
rs3751411
rs538540
rs2391677
rs7320567
rs7984269
rs2281968
rs4772995
rs4255644
rs831168
109496262
112044119
112079844
109789190
107108078
108223447
109654154
112403499
112730789
114059427
107740789
112618996
107640156
109974394
113289228
107879693
109172131
109662397
113157383
107879625
111654211
112902561
107003052
108377845
112172000
112633899
109952161
108208934
109887574
110594974
0.72
0.72
0.73
0.74
0.75
0.75
0.75
0.75
0.75
0.75
0.76
0.76
0.77
0.77
0.78
0.79
0.79
0.79
0.79
0.8
0.8
0.8
0.81
0.81
0.81
0.81
0.82
0.83
0.83
0.83
0.017
0.56
0.57
0.88
0.9
0.79
0.94
1
0.56
0.78
0.61
0.91
0.47
0.62
0.23
0.31
0.31
0.86
0.48
0.85
0.84
0.75
0.25
0.53
0.51
0.63
0.62
0.58
0.8
0.83
G/T
A/G
C/T
A/G
C/T
A/G
A/C
C/T
C/G
G/T
C/G
C/T
A/C
A/G
A/G
C/T
A/G
C/T
C/T
A/G
C/T
A/G
A/C
G/T
C/T
A/G
C/T
C/T
A/G
A/G
NA
NA
C13orf28
COL4A2
FAM155A
MYO16
COL4A1
ATP11A
MCF2L
NA
TNFSF13B
NA
NA
RAB20
TFDP1
NA
NA
COL4A1
DCUN1D2
NA
NA
PCID2
FAM155A
MYO16
NA
NA
COL4A2
MYO16
COL4A2
ARHGEF7
52
NA
NA
intron[NM_145248.3]
intron[NM_001846.2]
intron[NM_015011.1]
intron[NM_001845.4]
intron[NM_032189.3]
intron[NM_024979.3]
NA
intron[NM_006573.3]
NA
NA
intron[NM_007111.3]
NA
NA
intron[NM_001845.4]
NA
NA
intron[NM_018386.1]
intron[NM_015011.1]
NA
NA
intron[NM_001846.2]
intron[NM_015011.1]
intron[NM_001846.2]
intron[NM_145735.2]
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs4907532
rs1278114
rs5960
rs2391340
rs7320494
rs1033871
rs2391883
rs7994242
rs4390461
rs3858807
rs1317507
rs1163654
rs192530
rs816976
rs1410421
rs1417782
rs2391643
rs3926864
rs3809340
rs9555776
rs7998896
rs12020931
rs9515212
rs6577102
rs4772974
rs443079
rs753623
rs7982180
rs750991
rs9520594
112177246
112193789
112849738
105971754
108020975
108629670
110386968
111048395
108757611
107267996
112679781
111044768
112436304
107368910
108905828
107103265
107883579
109306820
110603526
110608828
111599869
113654541
109885564
112358548
107926181
108303141
109112770
109451667
112141635
107280986
0.83
0.83
0.83
0.84
0.84
0.84
0.84
0.84
0.85
0.86
0.86
0.87
0.87
0.88
0.88
0.89
0.89
0.89
0.89
0.89
0.89
0.89
0.9
0.9
0.91
0.91
0.91
0.91
0.91
0.92
0.93
0.81
0.77
*
0.56
0.49
0.95
0.66
0.96
0.93
0.66
0.9
0.29
0.76
0.79
0.066
0.56
0.97
0.99
0.132
0.36
0.79
0.27
0.73
0.57
0.15
0.53
0.8
0.46
0.69
A/G
C/T
C/T
G/T
A/G
C/T
C/T
C/T
C/T
A/G
G/T
C/G
C/T
C/T
C/T
A/G
G/T
A/T
A/T
A/C
A/G
A/C
A/G
G/T
C/T
C/T
C/G
A/G
A/G
A/G
NA
TUBGCP3
F10
EFNB2
NA
MYO16
NA
NA
NA
FAM155A
NA
NA
ATP11A
NA
NA
FAM155A
NA
NA
ARHGEF7
ARHGEF7
NA
NA
COL4A2
C13orf35
NA
MYO16
NA
NA
NA
FAM155A
53
NA
intron[NM_006322.4]
intron[NM_004093.2]
NA
intron[NM_015011.1]
NA
NA
NA
NA
NA
intron[NM_032189.3]
NA
NA
NA
NA
intron[NM_145735.2]
intron[NM_003899.3]
NA
NA
intron[NM_001846.2]
intron[NM_207440.1]
NA
intron[NM_015011.1]
NA
NA
NA
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
13
rs7332707
rs1547178
rs1022876
rs9550221
rs1417907
rs4238264
rs2391713
rs7322495
rs1151430
rs4611350
rs8001806
rs4773042
rs1970331
rs7985192
rs953260
rs4907726
rs7338868
rs4883676
rs4505177
rs3933329
rs7996853
rs686746
rs1887124
rs4145072
rs9550193
rs778294
rs4397971
rs6492073
rs2211312
rs9514806
107898025
110329886
106785383
112525346
107144507
108060380
108656651
109789286
110901155
112065161
113111630
108801494
111876993
112076742
110971686
112267159
113479759
113861908
107875386
109337568
113488470
109643506
108159193
109697956
112372325
104940236
106838608
107185360
107203928
107482525
0.92
0.92
0.93
0.93
0.94
0.94
0.94
0.94
0.94
0.94
0.94
0.95
0.95
0.95
0.96
0.96
0.96
0.96
0.97
0.97
0.97
0.98
0.99
0.99
0.99
*
*
*
*
*
0.68
0.69
0.61
0.95
0.78
0.61
0.32
0.74
0.99
0.71
0.79
0.2
*
0.73
*
0.84
0.81
0.9
0.93
0.2
0.8
0.85
0.67
0.2
0.98
0.19
0.81
0.56
*
0.33
C/T
G/T
C/T
C/T
A/G
C/T
C/T
C/T
A/G
C/T
A/G
C/T
A/G
A/G
C/T
A/G
A/C
C/T
C/G
A/G
A/G
A/G
A/G
C/T
G/T
A/G
A/T
C/T
A/C
A/G
NA
ANKRD10
FAM155A
ATP11A
FAM155A
MYO16
MYO16
COL4A2
NA
NA
NA
NA
NA
C13orf28
NA
TUBGCP3
NA
RASA3
NA
NA
FLJ44054
COL4A1
MYO16
COL4A1
C13orf35
DAOA
FAM155A
FAM155A
FAM155A
NA
54
NA
utr-3[NM_017664.2]
intron[NM_032189.3]
intron[NM_015011.1]
intron[NM_015011.1]
intron[NM_001846.2]
NA
NA
NA
NA
NA
NA
intron[NM_006322.4]
NA
intron[NM_007368.2]
NA
NA
intron[NM_001845.4]
intron[NM_015011.1]
intron[NM_001845.4]
intron[NM_207440.1]
intron[NM_172370.3]
NA
13
13
13
13
13
13
13
13
rs9559211
rs1325382
rs719737
rs4771645
rs1414320
rs1335808
rs1133219
rs1111859
107486706
107545226
109148350
109225129
109333093
109486141
109611710
111092169
*
*
*
*
*
*
*
*
0.31
0.34
0.68
*
0.47
0.54
0.87
0.8
A/C
C/T
C/T
A/C
C/T
A/T
C/T
A/G
NA
NA
NA
IRS2
NA
NA
COL4A1
NA
Highlighted are the SNPs that were followed up in Rutgers and US samples
55
NA
NA
NA
intron[NM_003749.2]
NA
NA
NA
Supplementary Table 3
MarkerName
rs9284246
rs7989802
rs1475142
rs732974
rs9521010
rs7986961
rs7330740
rs9301328
rs927856
rs9521011
rs9521072
rs932678
rs7984431
rs7327834
rs7328053
rs6492149
rs9520990
rs9587632
rs16972918
rs1926542
rs4291792
rs8002348
rs9520981
rs1933220
rs10492420
Allele1
a
t
t
a
a
c
a
t
a
t
t
a
t
t
a
a
t
a
a
a
t
t
t
t
a
Allele2
g
c
c
g
g
g
t
c
g
c
c
c
c
c
c
g
c
t
c
g
c
c
c
c
t
Weight
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
8784
56
P-value
1.9E-03
8.0E-03
8.6E-03
9.0E-03
1.1E-02
1.2E-02
1.3E-02
1.3E-02
1.4E-02
1.5E-02
1.5E-02
1.6E-02
1.7E-02
1.8E-02
1.9E-02
2.1E-02
2.6E-02
3.4E-02
3.6E-02
3.7E-02
3.8E-02
4.0E-02
4.3E-02
4.4E-02
4.9E-02
Direction
++
++---+
-+
-+
-++
-+
++
++
++
++
++
-++
-++
++
--++
++
P-Het
8.5E-01
8.7E-02
1.0E-01
7.5E-02
2.1E-02
1.1E-01
1.2E-01
1.2E-01
5.2E-02
1.9E-02
1.2E-01
1.6E-02
1.8E-01
5.0E-02
5.0E-02
4.3E-01
1.4E-02
4.0E-02
9.6E-01
2.1E-01
2.3E-01
2.0E-01
8.9E-02
7.1E-02
3.4E-01
Supplementary Table 4
CHR BP
Variant
ID
REF ALT AF
EXON_ID T_SA U_SA OR P1
T_SA+US U_SA+US OR
13 109318370 rs117770145 G
A
0.006
2
1
1 1.00 1.000
1
1 1.00
13 109379844 .
C
T
0.010
4
2
2 1.00 1.000
2
2 1.00
13 109438084 rs911973
T
A
0.031
5
5
7 0.71 0.564
13
11 1.18
13 109472733 rs41308564 G
A
0.020
8
3
3 1.00 1.000
8
10 0.80
13 109475600 rs61742194 C
T
0.010
4
1
0 NA
13 109496694 .
T
C
0.011
5
1
0 NA
0.317
1
0 NA
13 109496813 rs16973313 T
C
0.118
5
31
33 0.94 0.803
43
53 0.81
13 109518578 rs9559428
T
C
0.122
7
37
22 1.68 0.051
53
39 1.36
13 109550367 rs76952704 G
A
0.018
10
5
6 0.83 0.763
5
7 0.71
13 109550439 .
T
G
0.014
10
1
0 NA
0.317
1
0 NA
13 109562437 rs61743216 A
C
0.012
4
5
1 5.00 0.103
6
6 1.00
13 109613970 rs112439513 C
T
0.010
6
1
0 NA
13 109661359 rs3825491
C
G
0.366
10
67
60 1.12 0.535
100
102 0.98
13 109672243 .
T
C
0.007
11
0
2 0.00 0.157
0
2 0.00
13 109704760 rs2303965
C
T
0.016
13
0
3 0.00 0.083
4
4 1.00
13 109704761 .
A
T
0.012
13
2
1 2.00 0.564
2
1 2.00
13 109707457 .
A
G
0.011
26
0
1 0.00 0.317
2
1 2.00
13 109707827 rs9521141
T
C
0.138
27
31
36 0.86 0.541
53
59 0.90
13 109772767 .
A
T
0.010
29
1
0 NA
0.317
1
0 NA
13 109777503 rs157024
A
G
0.154
30
39
38 1.03 0.909
58
61 0.95
13 109779906 rs3815983
C
T
0.382
19
53
53 1.00 1.000
81
93 0.87
13 109779910 .
G
A
0.009
19
2
1 2.00 0.564
2
1 2.00
13 109793009 .
C
T
0.053
32
0
9 0.00 0.003
3
16 0.19
13 109793177 .
G
A
0.026
32
3
5 0.60 0.480
8
10 0.80
13 109793246 rs80260507 G
C
0.084
32
19
20 0.95 0.873
36
38 0.95
13 109793424 rs113648411 G
T
0.087
32
20
16 1.25 0.505
36
30 1.20
13 109793474 rs28705148 T
C
0.998
32
1
0 NA
0.317
1
1 1.00
13 109793635 .
G
A
0.012
32
13 109793720 rs7986595
A
C
0.994
32
3
2 1.50 0.655
4
2 2.00
13 109817258 .
C
T
0.014
33
1
0 NA
0.317
1
0 NA
13 109859071 .
G
A
0.007
35
1
1 1.00 1.000
1
1 1.00
13 109859130 .
G
A
0.009
35
1
0 NA
Note:
SA
case
trios
sample
size=143.
Control
trios
sample
size=34.
US
case
trios
sample
size=88
CHR:
Chromosome
BP:
Base
Pair
position
VariantID:
rs
number
when
applicable
REF:
Reference
allele
ALT:
Alternative
allele
AF:
Allele
Frequency
EXON_ID:
Exon
ID
by
SNPEFF
T_SA:
Number
of
alleles
transmitted
to
the
affected
proband
in
South
African
trios
U_SA:
Number
of
alleles
untransmitted
to
the
affected
proband
in
South
African
trios
P1:
P
value
of
the
test
transmitted/untransmitted
alleles
in
SA
T_SA+US:
Number
of
alleles
transmitted
to
the
affected
proband
in
South
African
and
US
trios
U_SA+US:
Number
of
alleles
untransmitted
to
the
affected
proband
in
South
African
and
US
trios
57
P2
parent_count case_count cntrl_count Prediction
1.000
2
1
0
1.000
4
2
0
0.683
32
13
1 TOLERATED
0.637
20
7
2 TOLERATED
0.317
1
1
0
0.317
1
1
0
0.307
116
44
9 TOLERATED
0.144
115
53
13
0.564
17
5
2 TOLERATED
0.317
1
1
0 TOLERATED
1.000
13
6
0 TOLERATED
0.317
1
1
0
0.888
307
132
24 TOLERATED
0.157
4
1
0 TOLERATED
1.000
9
4
1
0.564
3
2
0 DAMAGING
0.564
3
2
0 TOLERATED
0.571
139
59
10
0.317
1
1
0 DAMAGING
0.783
152
68
12 TOLERATED
0.363
309
126
23
0.564
3
2
0 NA
0.003
30
8
2
0.637
21
8
3
0.816
86
38
1
0.460
82
42
7 TOLERATED
1.000
527
229
36
1
0
1 DAMAGING
0.414
530
229
36
0.317
1
1
0 DAMAGING
1.000
2
1
0 TOLERATED
0.317
1
1
0
SNPEFF_FUNCTIONAL_CLASS
SILENT
SILENT
MISSENSE
MISSENSE
SILENT
SILENT
MISSENSE
SILENT
MISSENSE
MISSENSE
MISSENSE
SILENT
MISSENSE
MISSENSE
SILENT
MISSENSE
MISSENSE
SILENT
MISSENSE
MISSENSE
SILENT
MISSENSE
SILENT
SILENT
SILENT
MISSENSE
SILENT
MISSENSE
SILENT
MISSENSE
MISSENSE
SILENT
OR:
Odds
ratios
P2:
P
value
of
the
test
transmitted/untransmitted
alleles
in
SA+US
parent_count:
Number
of
parents
with
the
ALT
allele
case_count:
Number
of
cases
with
the
ALT
allele
cntrl_count:
Number
of
controls
with
the
ALT
allele
Prediction
SNPEFF_FUNCTIONAL_CLASS:
Functional
class
predicted
by
SNPEFF
58
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