Genome-wide association study confirms extant PD risk loci
among the Dutch.
Javier Simón-Sánchez1,CA, Jacobus J. van Hilten2, Bart van de Warrenburg3, Bart Post3,
Henk W. Berendse4, Sampath Arepalli5, Dena G. Hernandez5, Rob M.A. de Bie6, Daan
Velseboer6, Hans Scheffer7, Bas Bloem3, Karin D. van Dijk4, Fernando Rivadeneira8,9,
Albert Hofman8, André G. Uitterlinden8,9, Patrizia Rizzu1, Zoltan Bochdanovits1, Andrew
B. Singleton5 and Peter Heutink1.
1
Department of Clinical Genetics, Section of Medical Genomics, VU University Medical
Centre, Amsterdam, The Netherlands.
2
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
3
Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen,
The Netherlands.
4
Department of Neurology, VU University Medical Centre, Amsterdam, The
Netherlands.
5
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health,
Bethesda, Maryland, USA.
6
Department of Neurology, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands.
7
Department of Human Genetics, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands.
8
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The
Netherlands
9
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The
Netherlands.
CA
Correspondance should be addressed to Javier Simón-Sánchez. E-mail:
j.simonsanchez@vumc.nl; Telephone: +31-20-5983662; Fax: +31-20-5983596.
SUPPLEMENTARY METHODS
Quality control (QC) procedures
. Controls: Genotyping data from 2,082 control participants from the Rotterdam study III
(ERGO Young) was used as our control population. The dataset provided had already
been submitted to three rounds of QC in Rotterdam. In summary, samples with 10%
failed SNPs and SNPs not successfully genotyped in at least 80% of the samples were
removed in the first QC round. In the second round of QC, heterozygosity (samples with
F values smaller than the mean – (4 x SD)) and homozygosity (samples with F values
higher than the mean + (4 x SD)) outlyers were excluded from the dataset. In the third
round of QC, again the percentage of missing data was checked. Thus, samples with
more than 2.5% failed SNPs and SNPs not successfully genotyped in more than 5% of
the samples were removed.
In the forth round of quality controls IBS/IBD distances between Rotterdam participants
and clustering with reference to 210 HapMap samples was checked to inspect for
population outlayers. Those Rotterdam samples in which the principal components were
bigger or smaller than a border defined by the mean positions (PC1, PC2, PC3 and PC4)
of the CEU clustering (mean ± 4 x SD) were defined as a population outlayer and
removed form further analysis.
In a fifth step of QC pairwise IBD distances were calculate to identify cryptic family
relationships. A pair of each duplicate detected was removed from the dataset.
Finally, gender mismatches were checked using the reported gender and the gender
according to the inbreeding coefficient in chromosome X.
After this extensive QC procedures, the control dataset consisted on 587,388 SNPs
genotyped in a total of 2,082 control individuals from the Rotterdam study.
. Cases: Any samples with a call rate below 98% were repeated on a new DNA aliquot
and if the call rate persisted below this level the sample was excluded from the analysis.
Low-quality genotyping led us to repeat 32 individual samples, of which 9 were
ultimately excluded from the analysis. After this preliminary step of QC, PD cases
underwent QC procedures similar to those used to produce the RS III dataset provided.
First, all samples with more than 10% failed SNPs as well and those SNPs not
successfully genotyped in more than 20% of the samples were removed from further
analyses. This approach led us to remove 2 PD cases and 32,300 SNPs from our cases
dataset.
In a second round of QC, we conducted tests of individual heterozygosity using PLINK4
to detect possible sources of sample contamination. Heterozygosity was determined by
comparing the number of observed homozygotes [O (HOM)] with the number of
expected homozygotes [E (HOM)]. Heterozygosity outliers (samples with evidence for
excess of heterozygosity) were defined as samples with F-values smaller than the mean (4 x SD). A total of 6 heterozygosity outlyers were detected in our dataset.
Finally, all samples with more than 2.5% failed SNPs (0 PD cases) and those SNPs not
successfully genotyped in more than 5% of the samples (958 SNPs), were removed from
further analyses.
After the QC steps explained above, the total number of genotyped cases consisted of 824
individuals genotyped in 559,589 different positions. Since only the SNPs located in the
22 autosomes were included in our association study, the number of SNPs was reduced to
546,155.
. Cases and controls: The first step of these QC was to exclude those SNPs that
significantly failed more in one cohort (cases or controls) than in the other (p < 10-7).
This approach led us to exclude 50,418 SNPs (including those not genotyped in one of
the cohorts). Besides SNPs that presented a MAF below 1% (23,626 SNPs), a genotyping
call rate below 95% (1 SNP) or extreme deviations from Hardy-Weinberg equilibrium
(HWE) in controls (p < 10-4, 1,220 SNPs) were also excluded from further analyses.
In an attempt to detect the presence of population substructure or ethnically mismatched
individuals, IBS distances were calculated. Consequently, IBS distance to its “nearest
neighbor” was calculated for each individual in our cohort. This distribution was
standardized (by the sample mean and variance of nearest neighbor) and inspected for
outliers. For this last purpose Multidimensional scaling (MDS) was performed. Those
individuals deviating more than two standard deviations from the mean, were removed
from further analysis. This analysis led us to remove 23 cases. Recalculating the IBS
distribution for the remaining samples along with 30 trios from Yoruba (Nigeria, YRI),
45 unrelated individuals from the Tokyo area in Japan (JPT), 45 unrelated individuals
from Beijing (China, CHB) and 30 US-resident trios with Northern and Western
European ancestry from the Centre d’Etude du Polymorphisme Humain (CEPH, Paris,
France, CEU); data downloaded from the HapMap website (www.hapmap.org) showed
that our samples clearly shared Caucasian ancestry although they were slightly different
than the CEU samples from HapMap (supplementary figure 1).
The pairwise clustering based on IBS distances (see previous paragraph) is useful for
making estimations of pairwise Identity by Descent (IBD) to find pairs of individuals
who look more similar than expected by chance, in a random sample. By estimating the
probability of sharing 0, 1, or 2 alleles IBD for any two individuals, a proportion of IBD
can be calculated (PI-HAT = P [IBD = 2] + 0.5 x P [IBD = 1]). Using 0.2 as a threshold
for PI-HAT, 78 sample pairs were considered too similar to each other. Thus, one
member of each pair was removed from further SNP association tests (18 cases and 60
controls).
Individuals with gender ambiguity were flagged based on heterozygosity of chromosome
X genotypes (inbreeding coefficient [F] in this chromosome). A male call is made if F is
more than 0.8 and a female call if F is less than 0.2. Samples with an ambiguous F score
or discrepancies between genotyped and reported sex, were considered as problematic.
These samples were analyzed by visual examination of log R ratio and B allele frequency
metrics with the Illumina Genome Viewer (IGV) tool within GenomeStudio software
(www.illumina.com) to rule out whether this discrepancy was caused because of copy
number variation or extended homozygosity in chromosome X. These analyses led to the
exclusion of 11 cases.
Last, after performing the association tests described in the next section, clusters for all
SNPs with an unadjusted p value below 1 x 10-4 were visually inspected. This approach
led us to the removal of 51 improperly clustered SNPs.
After these extensive QC approaches, the final number of fully genotyped samples from
the Netherlands was 2,796 including 772 cases and 2,024 controls. Each of these was
genotyped in a total of 514,799 unique autosomal SNPs.
SUPPLEMENTARY TABLES
Supplementary table 1: Summary statistics for all SNPs located in the SNCA locus in the Dutch
population.
CHR
SNP
BP
position
Minor/Major
alleles
Frequency
affected
Frequency
Unaffected
Chi
square
Chi square
P value
Logistic
regression
P value
OR (C.I 95%)
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
4q22
rs2736990
rs356188
rs3857059
rs11931074
rs2583978
rs2197120
rs356191
rs168552
rs894278
rs3775439
rs1866995
rs2619372
rs3796661
rs2583985
rs2736988
rs3775442
rs12502363
rs3822095
rs11097238
rs10516848
rs11734067
rs6532194
rs7687945
rs3889917
rs2301134
rs3775461
rs1372522
rs1812923
90,897,564
90,910,560
90,894,261
90,858,538
90,969,349
90,948,625
90,907,143
90,862,167
90,953,558
90,928,764
90,950,732
90,955,750
90,906,530
90,974,962
90,995,368
90,934,254
90,932,087
90,955,540
90,965,732
90,994,235
90,843,876
90,999,925
90,983,722
90,935,875
90,977,968
90,960,826
90,984,303
90,958,562
G/A
G/A
G/A
A/C
A/C
A/G
A/G
G/A
C/A
A/G
G/A
A/G
A/G
G/A
A/G
A/G
A/G
G/A
A/G
G/A
A/G
A/G
G/A
G/A
A/G
G/A
A/G
A/C
0.5136
0.1474
0.1101
0.1102
0.1509
0.1492
0.1503
0.3327
0.09156
0.1466
0.06671
0.2053
0.03886
0.2925
0.2843
0.02461
0.4035
0.4093
0.4093
0.4048
0.06412
0.08873
0.4478
0.0557
0.4501
0.05584
0.4603
0.5006
0.4471
0.1875
0.08004
0.08033
0.1892
0.1865
0.1875
0.2916
0.06453
0.1176
0.04743
0.2401
0.02566
0.2683
0.2638
0.0168
0.4209
0.4251
0.4244
0.4174
0.06176
0.08276
0.4653
0.05228
0.4647
0.05336
0.4733
0.4891
19.88
12.23
12.54
12.38
11.19
10.73
10.63
8.915
12.08
8.537
8.313
7.628
6.825
3.279
2.384
3.669
1.401
1.148
1.043
0.7379
0.1064
0.5161
1.365
0.2592
0.9516
0.1347
0.7492
0.5932
8.26 x 10-6
4.60 x 10-4
3.97 x10-4
4.34 x 10-4
8.23 x 10-4
1.05 x 10-3
1.11 x 10-3
2.82 x 10-3
5.09 x 10-4
3.48 x 10-3
3.93 x 10-3
5.74 x 10-3
8.98 x 10-3
0.07
0.123
0.055
0.237
0.284
0.307
0.390
0.744
0.473
0.243
0.611
0.329
0.714
0.387
0.441
1.63 x 10-5
1.78 x 10-3
2.13 x 10-3
2.15 x 10-3
3.01 x 10-3
3.65 x 10-3
3.82 x 10-3
4.27 x 10-3
4.59 x 10-3
0.013
0.017
0.019
0.025
0.05
0.09
0.130
0.197
0.198
0.217
0.276
0.431
0.477
0.489
0.569
0.586
0.630
0.665
0.789
1.31 (0.06 - 1.16)
0.75 (0.08 - 0.64)
1.42 (0.1 - 1.17)
1.42 (0.1 - 1.17)
0.76 (0.08 - 0.65)
0.76 (0.08 - 0.65)
0.77 (0.08 - 0.65)
1.21 (0.06 - 1.07)
1.46 (0.11 - 1.18)
1.29 (0.09 - 1.09)
1.44 (0.13 - 1.12)
0.82 (0.07 - 0.71)
1.54 (0.17 - 1.11)
1.13 (0.07 - 0.99)
1.11 (0.07 - 0.97)
1.48 (0.2 - 0.99)
0.93 (0.06 - 0.83)
0.94 (0.06 - 0.83)
0.94 (0.06 - 0.83)
0.95 (0.06 - 0.84)
1.04 (0.12 - 0.82)
1.08 (0.11 - 0.88)
0.93 (0.06 - 0.83)
1.07 (0.13 - 0.83)
0.94 (0.06 - 0.84)
1.05 (0.13 - 0.81)
0.95 (0.06 - 0.84)
1.05 (0.06 - 0.93)
The chromosome in which is located (CHR), the base pair position (BP position), the Minor and the
Major alleles code, the frequency in the affecteds and the unaffecteds, the Chi square value after
comparison of the minor allele frequency in cases versus controls, the p value corresponding to the
Chi square value, the p value obtained after applying our logistic regression models, the odds ratio
and the 95% confidence interval and the genomic region in which is located are shown for each SNP
in the table.
Supplementary table 2: Logistic regression analysis to test for independence of association between
the two signals detected in the SNCA locus
SNP ID
BP position
SNCA LD block
P value
OR
Conditioned?
Conditioned
P value
Conditioned OR
rs2736990
90,897,564
3'
1.63 x 10-5
1.31
rs356188
6.00 x 10-5
1.29
rs356188
5'
1.78 x 10-3
0.75
rs2736990
9.9 x 10-3
90,910,560
For each most associated SNP in each of the two LD blocks in SNCA, a logistic regression analysis was
0.79
performed using the minor allele dosage of the most associated SNP in the other LD block as a
covariate. Results derived from this analysis slightly changed the results previuolsy obtained after
applying our logistic regression models, indicating that the two signals identified are independent to
each other.
Supplementary table 3: Summary statistics for all SNPs located in the BST1 locus in the Dutch
population.
CHR
SNP
BP position
Minor/Major
alleles
Frequency
affected
Frequency
unaffected
Chi
square
Chi square
P value
Losgistic
regression
P value
OR (C.I 95%)
4p15
4p15
4p15
4p15
4p15
4p15
4p15
4p15
4p15
4p15
4p15
4p15
rs12502586
rs4583752
rs4235380
rs3213710
rs2302467
rs10001565
rs2302464
rs7696938
rs4396986
rs2302465
rs11931532
rs11944132
15,335,662
15,308,103
15,299,026
15,326,419
15,314,137
15,331,671
15,318,350
15,312,675
15,310,928
15,318,290
15,334,864
15,335,012
A/G
G/A
A/G
G/A
C/A
A/G
A/G
A/C
A/G
A/G
G/A
A/G
0.147
0.3381
0.3355
0.4573
0.5097
0.08161
0.02655
0.2293
0.2701
0.1271
0.0272
0.0272
0.1124
0.2913
0.2898
0.4844
0.4753
0.09486
0.0205
0.2479
0.2814
0.1349
0.02544
0.02547
12.51
11.58
11.07
3.311
5.31
2.369
1.887
2.109
0.7101
0.5862
0.1367
0.1327
4.05 x -04
6.67 x -04
8.75 x -04
0.069
0.021
0.124
0.170
0.147
0.399
0.444
0.712
0.716
1.63 x -03
2.63 x -03
3.34 x -03
0.048
0.055
0.243
0.265
0.289
0.356
0.371
0.643
0.646
1.36 (1.15 - 1.62)
1.24 (1.1 - 1.41)
1.24 (1.09 - 1.4)
0.9 (0.8 - 1.01)
1.15 (1.02 - 1.29)
0.85 (0.69 - 1.05)
1.3 (0.89 - 1.9)
0.9 (0.79 - 1.04)
0.95 (0.83 - 1.08)
0.93 (0.78 - 1.11)
1.07 (0.74 - 1.54)
1.07 (0.74 - 1.54)
The chromosome in which is located (CHR), the base pair position (BP position), the Minor and the
Major alleles code, the frequency in the affecteds and the unaffecteds, the Chi square value after
comparison of the minor allele frequency in cases versus controls, the p value corresponding to the
Chi square value, the p value obtained after applying our logistic regression models, the odds ratio
and the 95% confidence interval and the genomic region in which is located are shown for each SNP
in the table.
Supplemenatary table 4: Logistic regression analysis to test for independence of association between
the two signals detected in the BST1 locus
Conditioned P
SNP ID
BP position
BST1 LD block
P value
OR
Conditioned?
Conditioned OR
value
rs4583752
15,308,103
1
2.62 x 10-3
1.22
rs12502586
0.115
1.13
rs12502586
15,335,662
2
1.63 x 10-3
1.34
rs4583752
0.074
1.18
For each most associated SNP in each of the two LD blocks in BST1, a logistic regression analysis was
performed using the minor allele dosage of the most associated SNP in the other LD block as a
covariate. Results derived from this analysis dramatically changed the results previously obtained
after applying our logistic regression models, indicating that the two association signals are tagging
the same risk variant.
Supplementary table 5: Summary statistics for all SNPs located in the GAK/DGKQ locus in the Dutch
population.
CHR
SNP
BP position
Minor/Major
alleles
Frequency
affected
Frequency
unaffected
Chi
square
Chi square
P value
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
rs2242235
rs4690296
rs1564282
rs6599389
rs873785
rs11248060
rs2290403
rs6838241
rs4690187
rs2061846
rs2290402
rs2242233
rs4690281
rs3755963
rs11722977
rs3755959
rs935965
rs11726508
rs4234853
rs2279186
rs1531583
rs13130034
rs17165046
rs3822023
rs7376288
rs7687129
rs10004503
rs9332466
rs11248042
rs1078139
745,210
722,261
842,313
929,113
915,149
954,359
932,006
746,686
693,813
842,484
931,518
745,025
743,944
884,255
780,757
891,672
918,684
878,937
725,150
865,887
734,972
745,496
803,393
886,486
731,742
929,883
783,929
734,098
802,598
818,148
G/A
G/A
A/G
A/G
G/A
A/G
A/G
C/A
A/G
G/A
A/G
A/G
A/G
G/A
C/A
G/A
A/G
A/G
A/G
A/G
A/C
G/A
A/G
G/A
A/G
A/G
A/G
G/A
G/A
C/A
0.100
0.100
0.121
0.097
0.325
0.134
0.308
0.319
0.279
0.188
0.178
0.258
0.304
0.257
0.455
0.402
0.306
0.146
0.240
0.226
0.037
0.089
0.054
0.370
0.318
0.316
0.050
0.273
0.356
0.314
0.068
0.070
0.097
0.073
0.368
0.110
0.349
0.286
0.316
0.160
0.153
0.286
0.331
0.287
0.422
0.425
0.325
0.129
0.265
0.256
0.051
0.075
0.065
0.352
0.299
0.322
0.044
0.280
0.349
0.316
15.680
13.400
6.880
8.506
8.790
6.185
8.271
5.935
7.147
6.279
5.181
4.105
3.817
5.118
4.911
2.451
1.760
3.014
3.446
5.317
4.715
3.011
2.522
1.708
1.877
0.155
0.817
0.331
0.224
0.024
7.49 x 10-05
2.52 x 10-04
8.71 x 10-03
3.54 x 10-03
3.03 x 10-03
0.013
4.03 x 10-03
0.015
7.51 x 10-03
0.015
0.008
0.012
0.023
0.043
0.051
0.024
0.027
0.117
0.185
0.083
0.063
0.021
0.030
0.083
0.112
0.191
0.171
0.694
0.366
0.565
Logistic
regression
P value
1.23 x 10-04
2.02 x 10-04
7.56 x 10-03
8.17 x 10-03
9.77 x 10-03
0.013
0.018
0.021
0.027
0.034
0.049
0.056
0.060
0.065
0.072
0.077
0.090
0.090
0.093
0.099
0.109
0.164
0.191
0.243
0.253
0.420
0.437
0.446
0.472
0.475
OR (C.I 95%)
1.51 (1.23 - 1.86)
1.47 (1.19 - 1.8)
1.28 (1.06 - 1.54)
1.36 (1.11 - 1.67)
0.83 (0.73 - 0.94)
1.25 (1.05 - 1.49)
0.83 (0.73 - 0.94)
1.17 (1.03 - 1.33)
0.84 (0.74 - 0.95)
1.22 (1.04 - 1.42)
1.2 (1.03 - 1.4)
0.87 (0.76 - 1)
0.88 (0.78 - 1)
0.86 (0.75 - 0.98)
1.14 (1.02 - 1.29)
0.91 (0.81 - 1.02)
0.92 (0.81 - 1.04)
1.16 (0.98 - 1.37)
0.88 (0.77 - 1.01)
0.85 (0.74 - 0.98)
0.72 (0.53 - 0.97)
1.2 (0.98 - 1.49)
0.81 (0.63 - 1.05)
1.09 (0.96 - 1.23)
1.09 (0.96 - 1.24)
0.98 (0.86 - 1.11)
1.14 (0.86 - 1.49)
0.96 (0.84 - 1.1)
1.03 (0.91 - 1.16)
0.99 (0.87 - 1.12)
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
4p16
rs7336
rs2290405
rs2127168
rs17164972
rs17165032
rs2306251
rs6964
rs3755964
rs17781378
rs17781348
rs4690309
rs6810428
rs1044147
rs755447
rs7677766
rs1134921
rs4076064
rs9328758
rs2306245
rs17165026
rs764324
rs9328757
rs17165156
rs936551
750,258
936,974
820,601
737,810
788,817
776,401
833,184
881,098
870,094
868,746
746,377
749,709
753,077
855,227
785,890
833,508
702,222
799,787
852,156
788,511
857,866
799,593
889,143
811,490
A/C
G/A
A/G
A/G
A/G
G/A
A/G
A/G
G/A
A/G
A/G
G/A
A/G
A/G
A/G
A/G
G/A
G/A
G/A
A/G
G/A
A/G
A/G
A/G
0.264
0.441
0.314
0.057
0.032
0.357
0.316
0.029
0.475
0.115
0.332
0.407
0.044
0.046
0.290
0.160
0.235
0.490
0.352
0.102
0.441
0.337
0.047
0.488
0.277
0.425
0.316
0.048
0.028
0.349
0.305
0.030
0.488
0.118
0.322
0.401
0.045
0.049
0.299
0.155
0.230
0.488
0.359
0.103
0.451
0.343
0.049
0.483
1.037
1.256
0.026
1.707
0.834
0.284
0.544
0.140
0.835
0.090
0.432
0.170
0.052
0.274
0.388
0.183
0.125
0.010
0.240
0.004
0.432
0.200
0.088
0.152
0.636
0.877
0.309
0.263
0.872
0.191
0.361
0.594
0.461
0.709
0.361
0.764
0.511
0.680
0.820
0.601
0.533
0.669
0.723
0.921
0.625
0.948
0.511
0.655
0.477
0.479
0.481
0.482
0.489
0.566
0.598
0.663
0.664
0.677
0.698
0.703
0.710
0.745
0.754
0.757
0.761
0.764
0.908
0.911
0.913
0.919
0.926
0.940
0.93 (0.82 - 1.07)
1.07 (0.95 - 1.2)
0.99 (0.87 - 1.12)
1.19 (0.92 - 1.54)
1.17 (0.83 - 1.64)
1.03 (0.91 - 1.17)
1.05 (0.92 - 1.19)
0.94 (0.66 - 1.33)
0.95 (0.84 - 1.07)
0.97 (0.81 - 1.17)
1.04 (0.92 - 1.18)
1.03 (0.91 - 1.16)
0.97 (0.73 - 1.29)
0.93 (0.7 - 1.23)
0.96 (0.84 - 1.09)
1.04 (0.88 - 1.22)
1.03 (0.89 - 1.18)
1.01 (0.89 - 1.13)
0.97 (0.86 - 1.1)
0.99 (0.82 - 1.21)
0.96 (0.85 - 1.08)
0.97 (0.86 - 1.1)
0.96 (0.73 - 1.26)
1.02 (0.91 - 1.15)
The chromosome in which is located (CHR), the base pair position (BP position), the Minor and the
Major alleles code, the frequency in the affecteds and the unaffecteds, the Chi square value after
comparison of the minor allele frequency in cases versus controls, the p value corresponding to the
Chi square value, the p value obtained after applying our logistic regression models, the odds ratio
and the 95% confidence interval and the genomic region in which is located are shown for each SNP
in the table.
Supplementary table 6: Logistic regression analysis to test for independence of association between
the two signals detected in the GAK/DGKQ locus.
SNP ID
BP position
GAK/DGKQ LD block
P value
OR
Conditioned?
Conditioned P
value
Conditioned OR
rs2242235
745,210
1
1.23 x 10-4
1.51
rs4690296
0.325
1.082
rs4690296
15,335,662
2
2.02 x 10-4
1.47
rs2242235
0.49
1.119
For each most associated SNP in each of the two LD blocks in GAK/DGKQ, a logistic regression
analysis was performed using the minor allele dosage of the most associated SNP in the other LD
block as a covariate. Results derived from this analysis dramatically changed the results previously
obtained after applying our logistic regression models, indicating that the two association signals are
tagging the same risk variant.
Supplementary table 7: Summary statistics for all SNPs in the HLA region that were nominally
associated with PD after our logistic regression models.
CHR
SNP
BP
position
Minor/Major
alleles
Frequency
affected
Frequency
unaffected
Chi
square
Chi square
P value
Losgistic
regression P
value
6p21.3
rs4248166
32,474,399
G/A
0.2137
0.1665
16.92
3.89 x 10-05
4.39 x 10-05
6p21.3
rs17202259
32,465,467
C/A
0.177
0.1337
16.82
4.11 x 10-05
6.22 x 10-05
6p21.3
rs2294884
32,475,237
C/A
0.214
0.1682
15.85
6.86 x 10-05
6.72 x 10-05
6p21.3
rs12529049
32,465,693
A/G
0.1783
0.1354
16.42
5.08 x 10-05
7.98 x 10-05
6p21.3
rs17533090
32,698,700
A/C
0.2088
0.1663
13.83
0.0002004
0.000162
6p21.3
rs10484561
32,773,398
C/A
0.1541
0.1166
14.21
0.0001632
0.0004507
6p21.3
rs13192471
32,779,081
G/A
0.1822
0.1447
11.98
0.000538
0.0007642
6p21.3
rs2856683
32,763,196
C/A
0.2349
0.1921
12.52
0.0004021
0.0009567
6p21.3
rs1794275
32,779,226
A/G
0.2208
0.1829
10.26
0.001357
0.0009647
6p21.3
rs7755224
32,760,295
G/A
0.1514
0.1166
12.23
0.0004695
0.001242
6p21.3
rs9391858
32,449,376
G/A
0.1852
0.1485
11.32
0.0007669
0.004349
6p21.3
rs2858331
32,789,255
G/A
0.3965
0.3622
5.62
0.01776
0.005378
6p21.3
rs13209234
32,523,953
A/G
0.1838
0.1487
10.29
0.001335
0.007262
6p21.3
rs10947262
32,481,290
A/G
0.09132
0.07362
4.843
0.02776
0.01074
6p21.3
rs3763313
32,484,449
C/A
0.2124
0.1818
6.8
0.009114
0.0119
6p21.3
rs9275439
32,779,499
G/A
0.2698
0.2383
5.926
0.01492
0.01494
6p21.3
rs9275424
32,778,554
G/A
0.2708
0.2403
5.545
0.01853
0.02009
6p21.3
rs9275582
32,788,048
A/G
0.239
0.2095
5.714
0.01683
0.02215
6p21.3
rs9275425
32,778,852
A/C
0.2698
0.24
5.314
0.02116
0.02222
6p21.3
rs7774434
32,765,556
G/A
0.3763
0.3469
4.207
0.04026
0.02241
6p21.3
rs9275595
32,789,333
G/A
0.2383
0.2096
5.428
0.01982
0.02255
6p21.3
rs17211510
32,710,408
A/C
0.3288
0.296
5.647
0.01748
0.02286
6p21.3
rs9275428
32,778,956
G/A
0.2698
0.2406
5.09
0.02406
0.02568
6p21.3
rs9275406
32,777,933
A/C
0.2694
0.2407
4.928
0.02642
0.02804
6p21.3
rs9275371
32,776,274
G/A
0.2694
0.241
4.841
0.02778
0.02842
6p21.3
rs9275388
32,777,062
G/A
0.2694
0.2411
4.796
0.02853
0.02928
6p21.3
rs9275390
32,777,134
G/A
0.2694
0.2411
4.796
0.02853
0.02928
OR (C.I 95%)
1.361(1.175 1.576)
1.394(1.189 1.634)
1.347(1.163 1.56)
1.386(1.183 1.624)
1.324(1.141 1.535)
1.381(1.167 1.634)
1.317(1.126 1.539)
1.291(1.121 1.488)
1.266(1.096 1.462)
1.352(1.141 1.602)
1.304(1.117 1.522)
1.157(1.026 1.305)
1.289(1.104 1.506)
1.265(1.026 1.559)
1.214(1.049 1.404)
1.181(1.033 1.35)
1.174(1.027 1.342)
1.185(1.031 1.362)
1.17(1.024 1.337)
1.136(1.006 1.283)
1.18(1.027 1.357)
1.165(1.027 1.321)
1.166(1.02 1.333)
1.163(1.018 1.329)
1.162(1.016 1.328)
1.161(1.016 1.327)
1.161(1.016 1.327)
6p21.3
rs9275393
32,777,417
A/G
0.2694
0.2411
4.796
0.02853
0.02928
6p21.3
rs9275407
32,778,015
A/C
0.2694
0.2411
4.796
0.02853
0.02928
6p21.3
rs9275374
32,776,504
A/G
0.2694
0.2412
4.755
0.02921
0.02983
6p21.3
rs9275418
32,778,222
G/A
0.2694
0.2412
4.755
0.02921
0.02987
6p21.3
rs9275427
32,778,893
A/G
0.2694
0.2415
4.67
0.03069
0.03216
6p21.3
rs2858332
32,789,139
A/C
0.4832
0.4592
2.578
0.1083
0.03801
6p21.3
rs9276291
32,810,791
A/G
0.228
0.2515
3.332
0.06794
0.04296
6p21.3
rs7770048
32,442,732
A/G
0.169
0.1467
4.292
0.03829
0.0459
6p21.3
rs2073048
32,443,411
A/G
0.169
0.1467
4.292
0.03829
0.0459
1.161(1.016 1.327)
1.161(1.016 1.327)
1.16(1.015 1.326)
1.16(1.015 1.326)
1.159(1.014 1.324)
1.101(0.979 1.238)
0.8789(0.765 1.01)
1.183(1.009 1.387)
1.183(1.009 1.387)
The chromosome in which is located (CHR), the base pair position (BP position), the Minor and the
Major alleles code, the frequency in the affecteds and the unaffecteds, the Chi square value after
comparison of the minor allele frequency in cases versus controls, the p value corresponding to the
Chi square value, the p value obtained after applying our logistic regression models, the odds ratio
and the 95% confidence interval and the genomic region in which is located are shown for each SNP
in the table.
Supplementary table 8: Logistic regression analysis to test for independence of association between
the two signals detected in the HLA locus.
SNP ID
BP position
HLA LD block
P value
OR
Conditioned?
Conditioned P
value
Conditioned OR
rs17202259
32,465,467
3
6.22 x 10-5
1.39
rs4248166
0.437
1.147
4
10-5
1.36
rs17202259
0.204
1.228
rs4248166
32,474,399
4.39 x
For each most associated SNP in blocks 3 and 4 in the HLA region, a logistic regression analysis was
performed using the minor allele dosage of the most associated SNP in the other LD block as a
covariate. Results derived from this analysis dramatically changed the results previously obtained
after applying our logistic regression models, indicating that the two association signals are tagging
the same risk variant.
Supplementary table 9: Logistic regression analysis to test for independence of association between
the two signals detected in the HLA locus.
SNP ID
BP position
HLA LD block
P value
OR
Conditioned?
Conditioned P
value
Conditioned OR
rs4248166
32,465,467
3
4.39 x 10-5
1.36
rs17533090
0.032
1.23
4
10-4
1.32
rs4248166
0.102
1.18
rs17533090
32,474,399
1.62 x
For each most associated SNP in blocks 3 and 4 in the HLA region, a logistic regression analysis was
performed using the minor allele dosage of the most associated SNP in the other LD block as a
covariate. Results derived from this analysis dramatically changed the results previously obtained
after applying our logistic regression models, indicating that the two association signals are tagging
the same risk variant.
Supplementary table 10: Summary statistics for the nominally associated SNPs in the MAPT locus.
CHR
SNP
BP position
Minor/Major
alleles
Frequency
affected
Frequency
unaffected
Chi
square
Chi
square P
value
Logistic
regression P
value
OR (C.I 95%)
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
17q21
rs3785880
rs11869096
rs12185268
rs17563986
rs1981997
rs8070723
rs12373139
rs2532274
rs393152
rs2532269
rs11012
rs2668692
rs1158660
rs12938476
rs8327
rs7224296
rs1526123
rs4792893
rs7215239
rs11867549
41349204
41300889
41279463
41347100
41412603
41436901
41279910
41602941
41074926
41605885
40869224
41648797
41301077
41168668
40828290
42155230
41139123
41341550
41123556
41369064
C/A
A/G
G/A
G/A
A/G
G/A
A/G
G/A
G/A
G/A
A/G
A/G
A/G
G/A
G/A
G/A
G/A
A/G
G/A
G/A
0.492
0.481
0.196
0.199
0.198
0.199
0.199
0.203
0.200
0.200
0.159
0.199
0.334
0.371
0.284
0.257
0.436
0.137
0.225
0.296
0.449
0.441
0.232
0.234
0.233
0.234
0.233
0.238
0.233
0.233
0.183
0.230
0.306
0.410
0.251
0.287
0.466
0.117
0.253
0.269
8.114
7.333
8.130
7.907
7.895
7.813
7.497
7.919
7.314
6.850
4.694
6.037
4.281
7.075
6.208
4.865
4.048
3.941
4.670
4.216
4.39 x -03
6.77 x -03
4.35 x -03
4.92 x -03
4.96 x -03
5.19 x -03
6.18 x -03
4.89 x -03
6.84 x -03
8.86 x -03
0.030
0.014
0.039
0.008
0.013
0.027
0.044
0.047
0.031
0.040
1.90 x -03
2.44 x -03
6.86 x -03
7.65 x -03
7.69 x -03
8.64 x -03
8.86 x -03
9.16 x -03
9.45 x -03
0.014
0.020
0.020
0.020
0.020
0.026
0.032
0.038
0.038
0.045
0.045
1.19 (1.06 - 1.33)
1.18 (1.05 - 1.32)
0.81 (0.7 - 0.94)
0.81 (0.7 - 0.94)
0.81 (0.7 - 0.94)
0.81 (0.7 - 0.94)
0.82 (0.71 - 0.94)
0.81 (0.7 - 0.94)
0.82 (0.71 - 0.95)
0.82 (0.71 - 0.95)
0.84 (0.72 - 0.98)
0.83 (0.72 - 0.96)
1.14 (1.01 - 1.29)
0.85 (0.75 - 0.96)
1.18 (1.04 - 1.35)
0.86 (0.75 - 0.98)
0.89 (0.79 - 1)
1.19 (1 - 1.42)
0.86 (0.75 - 0.99)
1.15 (1.01 - 1.3)
For each SNP, the chromosome in which is located (CHR), the base pair position (BP position), the
Minor and the Major alleles code, the frequency in the affecteds and the unaffecteds, the Chi square
value after comparison of the minor allele frequency in cases versus controls, the p value
corresponding to the Chi square value, the p value obtained after applying our logistic regression
models, the odds ratio and the 95% confidence interval and the genomic region in which is located is
shown.
Supplementary table 11: Two-locus association results of rs1981997 and the most associated SNPs
in the MAPT locus.
H1-H2 htSNP
rs1981997
rs1981997
Associated SNP
rs3785880
rs3785880
Haplotype
GC
AA
Frequency
0.461
0.223
OR
1.22
0.814
STAT
10.4
7.39
P value
0.00127
0.00655
D'
r^2
rs1981997
rs1981997
rs3785880
rs11869096
GA
GA
0.316
0.452
0.94
1.22
0.893
9.75
0.345
0.00179
0.997
0.245
rs1981997
rs1981997
rs11869096
rs11869096
AG
GG
0.224
0.324
0.811
0.948
7.65
0.667
0.00569
0.414
1
0.238
rs1981997
rs1981997
rs12185268
rs12185268
AG
GA
0.221
0.777
0.809
1.24
7.67
8.12
0.00561
0.00437
0.995
0.99
rs1981997
rs1981997
rs17563986
rs17563986
AG
GA
0.223
0.776
0.812
1.23
7.54
7.63
0.00603
0.00575
0.999
0.995
rs1981997
rs1981997
rs8070723
rs8070723
AG
GA
0.223
0.775
0.817
1.24
7.08
7.78
0.00781
0.00528
0.996
0.989
rs1981997
rs1981997
rs12373139
rs12373139
AA
GG
0.223
0.776
0.816
1.23
7.19
7.62
0.00735
0.00577
0.995
0.99
rs1981997
rs1981997
rs2532274
rs2532274
AG
GA
0.223
0.771
0.821
1.23
6.76
7.54
0.0093
0.00603
0.997
0.971
rs1981997
rs393152
AG
0.223
0.816
7.19
0.00735
rs1981997
rs393152
GA
0.775
1.23
7.5
0.00618
0.995
0.988
A two-locus haplotype association analysis was performed using our logistic regression models for
rs1981997 and the most associated SNPs (P < 0.01) in the MAPT locus. The frequency of the tested
haplotype, the odds ratio exerted by that same haplotype, the statistic and the p value for that
statistic is displayed. Linkage disequilibrium between both SNPs of the two-locus haplotype is
displayed in D’ and r^2 values.
Supplementary table 12: Summary statistic and comparison with previous GWAS in PD of SNPs
located in chromosome 13q31 locus.
CHR
SNP
BP
Minor
allele
Dutch GWAS
P value
German/American GWAS
Myers - Foroud GWAS
OR (c.i. 95%)
P value
OR (c.i. 95%)
P value
OR (c.i. 95%)
-6
13
rs7995973
79503787
C
5.42 x 10
0.72 (0.63 - 0.83)
0.254
1.05 (0.97 - 1.14)
0.448
0.93 (0.79 - 1.1)
13
rs9574547
79529418
A
4.20 x 10-5
0.71 (0.61 - 0.83)
0.566
0.97 (0.88 - 1.07)
-
-
A
9.43 x 10
-5
0.75 (0.65 - 0.86)
0.740
1.02 (0.93 - 1.11)
0.774
1.02 (0.88 - 1.18)
1.17 x 10
-4
0.73 (0.63 - 0.85)
0.165
1.13 (0.95 - 1.33)
-
-
-4
13
13
rs1215451
rs7990503
79613894
79518643
A
13
rs8001401
79621013
C
1.63 x 10
0.74 (0.64 - 0.86)
0.566
0.97 (0.89 - 1.07)
0.409
1.01 (0.89 - 1.16)
13
rs1215470
79604456
G
2.75 x 10-4
0.77 (0.67 - 0.88)
0.854
1.01 (0.92 - 1.1)
-
-
G
3.96 x 10
-4
0.78 (0.68 - 0.89)
0.729
1.02 (0.93 - 1.11)
-
-
7.82 x 10
-4
0.8 (0.7 - 0.91)
0.085
1.13 (0.98 - 1.31)
-
-
-3
13
13
rs1237259
rs9318669
79618143
79541644
A
13
rs475743
79665183
G
1.53 x 10
0.78 (0.67 - 0.9)
0.188
0.94 (0.85 - 1.03)
0.402
1.07 (0.91 - 1.26)
13
rs537435
79655311
A
2.16 x 10-3
0.82 (0.72 - 0.93)
0.763
1.01 (0.93 - 1.1)
0.756
1.02 (0.89 - 1.17)
A
2.67 x 10
-3
0.81 (0.72 - 0.93)
0.211
0.95 (0.87 - 1.03)
0.202
0.91 (0.79 - 1.05)
3.59 x 10
-3
0.82 (0.71 - 0.93)
0.392
0.96 (0.88 - 1.05)
0.025
0.85 (0.74 - 0.98)
13
13
rs504122
rs348008
79809526
79702503
A
13
rs9574546
13
rs7988352
79526139
79555356
A
3.95 x 10-3
0.82 (0.72 - 0.94)
0.878
0.99 (0.91 - 1.08)
-
-
C
4.50 x 10
-3
1.2 (1.06 - 1.36)
0.767
0.99 (0.91 - 1.07)
0.827
0.99 (0.86 - 1.13)
-3
13
rs9545412
79836100
G
5.37 x 10
1.2 (1.06 - 1.36)
0.317
1.04 (0.96 - 1.13)
-
-
13
rs9545323
79554383
C
5.59 x 10-3
1.2 (1.06 - 1.35)
0.569
0.98 (0.9 - 1.06)
-
-
G
6.40 x 10
-3
1.22 (1.06 - 1.4)
0.666
0.97 (0.83 - 1.13)
-
-
7.58 x 10
-3
0.84 (0.74 - 0.95)
0.495
0.97 (0.9 - 1.05)
0.808
0.98 (0.86 - 1.13)
-3
13
rs9545330
13
rs4885692
79597167
79538223
A
13
rs9545409
79822349
A
8.16 x 10
1.19 (1.05 - 1.35)
0.318
1.04 (0.96 - 1.13)
0.935
1.01 (0.88 - 1.16)
13
rs2117906
79709010
G
8.32 x 10-3
0.71 (0.56 - 0.91)
0.460
0.94 (0.8 - 1.1)
0.666
0.94 (0.72 - 1.23)
-3
0.84 (0.75 - 0.96)
0.574
0.98 (0.9 - 1.06)
-
-
13
rs12431307
79542619
A
9.29 x 10
13
rs541731
79817713
A
0.012
0.85 (0.75 - 0.96)
0.486
0.97 (0.89 - 1.06)
0.165
0.91 (0.79 - 1.04)
13
rs942233
79599849
G
0.012
1.18 (1.04 - 1.34)
0.058
1.08 (1 - 1.18)
0.778
1.02 (0.89 - 1.17)
13
rs722023
79781647
A
0.013
0.85 (0.75 - 0.96)
0.296
0.96 (0.88 - 1.04)
0.240
0.92 (0.8 - 1.06)
13
rs2329154
79647173
A
0.017
0.85 (0.75 - 0.97)
0.797
1.02 (0.88 - 1.17)
-
-
13
rs9545324
79558416
A
0.017
1.22 (1.04 - 1.43)
0.025
1.12 (1.01 - 1.24)
-
-
13
rs9565541
79493467
A
0.018
1.17 (1.03 - 1.33)
0.159
0.94 (0.87 - 1.02)
0.459
1.06 (0.92 - 1.21)
13
rs679805
79645702
G
0.020
1.16 (1.03 - 1.32)
0.884
0.99 (0.92 - 1.08)
0.540
1.04 (0.91 - 1.19)
13
rs1212082
79024769
A
0.021
1.16 (1.03 - 1.32)
0.101
1.08 (0.99 - 1.17)
0.986
1 (0.87 - 1.15)
13
rs7997069
79503536
G
0.021
1.19 (1.03 - 1.38)
0.647
0.98 (0.89 - 1.08)
0.396
1.07 (0.91 - 1.25)
13
rs9318679
79588136
A
0.022
1.17 (1.03 - 1.34)
0.519
1.03 (0.94 - 1.12)
-
-
13
rs3850067
79490205
A
0.022
0.86 (0.76 - 0.98)
0.691
0.98 (0.91 - 1.07)
0.238
0.92 (0.8 - 1.05)
13
rs9574595
79670436
A
0.022
1.23 (1.04 - 1.46)
0.870
1.01 (0.9 - 1.14)
-
-
13
rs1215465
79589353
A
0.023
1.16 (1.02 - 1.32)
0.433
1.03 (0.95 - 1.12)
0.680
1.03 (0.9 - 1.18)
13
rs496932
79831609
G
0.028
0.87 (0.76 - 0.98)
0.507
0.97 (0.9 - 1.06)
0.877
0.99 (0.86 - 1.13)
13
rs1327314
79581626
A
0.028
1.16 (1.02 - 1.31)
0.301
1.05 (0.96 - 1.14)
0.681
1.03 (0.9 - 1.19)
13
rs1575900
79574705
C
0.031
1.16 (1.02 - 1.32)
0.097
1.07 (0.99 - 1.17)
0.868
1.01 (0.88 - 1.16)
13
rs7336627
79543079
A
0.032
1.19 (1.02 - 1.39)
0.357
1.05 (0.95 - 1.16)
0.979
1 (0.84 - 1.18)
13
rs8001641
79590812
G
0.044
1.14 (1.01 - 1.29)
0.085
0.93 (0.86 - 1.01)
0.860
-
For each nominally associated SNP in the chromosome 13q31 locus, the P value after running our
logistic regression models and the odds ratio is displayed. This values are compared with those
obtained (if applicable) in two previous GWAS in Caucasian populations 7, 8.
Supplementary table 10: Summary statistics of the top 100 associated SNPs in the Dutch population.
CHR
SNP
BP position
Minor/Major
alleles
Frequency
affected
Frequency
unaffected
Chi
square
Chi square
P value
Logistic
regression
P value
OR (C.I 95%)
Gene
13
rs7995973
27,839,060
C/A
0.2895
0.3515
19.32
1.11E-05
5.42E-06
0.95 (0.66 - 0.85)
FLT1
10
rs7918386
71,839,631
A/G
0.2157
0.2806
24.35
8.03E-07
6.39E-06
0.71 (0.61 - 0.81)
EIF4EBP2
15
rs4347602
89,917,111
A/C
0.2468
0.1907
21.45
3.63E-06
8.78E-06
1.4 (1.21 - 1.6)
Intergenic
3
rs11915523
108,411,619
G/A
0.04286
0.01828
27.59
1.50E-07
1.36E-05
2.12 (1.72 - 3.37)
Intergenic
15
rs2412777
41,361,016
A/G
0.1088
0.07146
20.73
5.30E-06
1.51E-05
1.6 (1.3 - 1.94)
TGM5/TGM7
4
rs2736990
90,897,564
G/A
0.5136
0.4471
19.88
8.26E-06
1.63E-05
1.33 (1.16 - 1.47)
SNCA
2
rs10497310
167,717,651
G/A
0.1258
0.08697
18.88
1.39E-05
2.22E-05
1.52 (1.25 - 1.82)
XIRP2
8
rs10504139
53,607,407
A/C
0.4424
0.5054
17.8
2.46E-05
2.65E-05
0.76 (0.69 - 0.87)
FAM150A
4
rs304347
169,056,796
G/A
0.263
0.2083
19.28
1.13E-05
2.72E-05
1.37 (1.18 - 1.56)
Intergenic
20
rs6057657
29,427,491
G/A
0.1516
0.1089
19.12
1.23E-05
2.77E-05
1.48 (1.23 - 1.73)
DEFB118/DEFB119
4
rs10014961
169,059,847
G/A
0.263
0.2086
19.02
1.30E-05
3.11E-05
1.36 (1.18 - 1.55)
Intergenic
14
rs12586334
100,958,615
C/A
0.2105
0.2627
16.12
5.93E-05
3.18E-05
0.72 (0.65 - 0.86)
Intergenic
7
rs12704998
98,137,093
A/G
0.3962
0.3395
15.52
8.16E-05
3.31E-05
1.31 (1.13 - 1.44)
Intergenic
9
rs2383025
17,480,559
G/A
0.3918
0.4501
15.43
8.57E-05
3.61E-05
0.76 (0.7 - 0.89)
CNTLN
4
rs1444943
169,023,487
A/G
0.2636
0.2096
18.72
1.51E-05
3.71E-05
1.36 (1.18 - 1.55)
Intergenic
13
rs9574547
79,547,247
A/C
0.1736
0.2237
16.92
3.90E-05
4.20E-05
0.97 (0.63 - 0.85)
Intergenic
6
rs4248166
32,474,399
G/A
0.2137
0.1665
16.92
3.89E-05
4.39E-05
1.39 (1.18 - 1.58)
BTNL2
5
rs1217770
71,343,136
G/A
0.3394
0.2796
19.13
1.22E-05
4.44E-05
1.32 (1.17 - 1.5)
Intergenic
15
rs17782975
41,585,331
G/A
0.1086
0.07277
18.84
1.42E-05
4.46E-05
1.56 (1.27 - 1.9)
MAP1A/TP53BP1
2
rs8446
35,855,677
A/G
0.2351
0.294
19.31
1.11E-05
5.17E-05
1.01 (0.64 - 0.85)
Intergenic
15
rs524908
41,975,283
C/A
0.3353
0.2796
16.62
4.57E-05
5.52E-05
1.32 (1.15 - 1.47)
FRMD5
11
rs11235365
87,295,787
A/G
0.1058
0.07161
17.52
2.84E-05
5.58E-05
1.56 (1.25 - 1.88)
Intergenic
2
rs17049848
59,037,627
A/G
0.1247
0.08873
16.21
5.67E-05
6.20E-05
1.51 (1.22 - 1.76)
Intergenic
6
rs17202259
32,465,467
C/A
0.177
0.1337
16.82
4.11E-05
6.22E-05
1.42 (1.19 - 1.63)
BTNL2/C6orf10
21
rs8132225
33,431,025
A/G
0.1405
0.1023
16.35
5.26E-05
6.49E-05
1.08 (1.2 - 1.71)
Intergenic
4
rs2250175
175,739,587
A/G
0.4202
0.4802
16.16
5.82E-05
6.50E-05
0.77 (0.7 - 0.88)
Intergenic
6
rs2294884
32,475,237
C/A
0.214
0.1682
15.85
6.86E-05
6.72E-05
1.38 (1.16 - 1.56)
BTNL2
14
rs12184950
102,269,834
C/A
0.1341
0.184
19.76
8.78E-06
6.91E-05
0.69 (0.58 - 0.81)
RCOR1
1
rs6693597
61,355,134
C/A
0.1017
0.146
18.94
1.35E-05
7.01E-05
0.67 (0.55 - 0.8)
NFIA
6
rs7765333
169,182,781
A/G
0.4158
0.4738
15.15
9.91E-05
7.10E-05
0.77 (0.7 - 0.89)
Intergenic
15
rs2255663
41,616,300
A/G
0.3361
0.2799
16.97
3.81E-05
7.15E-05
1.32 (1.15 - 1.48)
MAP1A/HISPPD2A
18
rs10502510
24,479,614
G/A
0.1667
0.1277
14.2
1.64E-04
7.17E-05
1.42 (1.16 - 1.61)
Intergenic
Intergenic
3
rs9823496
813,711
C/A
0.3459
0.4036
15.7
7.41E-05
7.90E-05
0.98 (0.69 - 0.88)
15
rs4932557
89,919,267
A/C
0.2824
0.2316
15.56
7.98E-05
7.93E-05
1.32 (1.14 - 1.49)
Intergenic
6
rs12529049
32,465,693
A/G
0.1783
0.1354
16.42
5.08E-05
7.98E-05
1.41 (1.18 - 1.62)
BTNL2/C6orf10
15
rs2602141
41,511,938
C/A
0.3446
0.2877
17.1
3.55E-05
8.00E-05
1.31 (1.15 - 1.48)
TP53BP1
15
rs689797
41,613,849
A/G
0.3355
0.2796
16.76
4.24E-05
8.03E-05
1.31 (1.15 - 1.48)
HISPPD2A/MAP1A
21
rs2823324
15,817,704
A/C
0.03433
0.01658
16.75
4.27E-05
8.35E-05
2.21 (1.46 - 3.04)
Intergenic
3
rs7641837
28,994,596
G/A
0.08355
0.05287
18.28
1.91E-05
8.37E-05
1.64 (1.3 - 2.05)
Intergenic
1
rs696958
206,700,625
A/G
0.3833
0.3281
15.1
1.02E-04
8.88E-05
1.3 (1.13 - 1.44)
Intergenic
12
rs11177355
67,434,789
A/G
0.1101
0.07609
16.54
4.75E-05
8.95E-05
1.52 (1.23 - 1.83)
NUP107/SLC35E3
9
rs11265951
91,633,334
G/A
0.4041
0.4583
13.26
2.71E-04
9.35E-05
0.78 (0.71 - 0.9)
Intergenic
4
rs6832140
91,391,461
G/A
0.01816
0.006917
14.23
1.62E-04
9.42E-05
3.08 (1.57 - 4.5)
MGC48628
13
rs1215451
79,613,894
A/G
0.2513
0.3061
16.26
5.52E-05
9.43E-05
0.75 (0.67 - 0.87)
Intergenic
22
rs4819594
16,366,811
G/A
0.2455
0.2003
13.58
2.28E-04
9.52E-05
1.35 (1.13 - 1.49)
CECR2
4
rs440380
169,060,340
A/G
0.3089
0.2542
16.99
3.76E-05
9.76E-05
1.32 (1.15 - 1.49)
Intergenic
14
rs10134155
46,895,886
G/A
0.2008
0.2531
16.83
4.08E-05
1.01E-04
0.74 (0.64 - 0.86)
MDGA2
8
rs7814156
140,334,776
A/G
0.09003
0.1299
16.99
3.75E-05
1.04E-04
0.66 (0.54 - 0.81)
Intergenic
2
rs1551951
70,449,795
G/A
0.3867
0.3344
13.43
2.47E-04
1.07E-04
1.29 (1.11 - 1.42)
Intergenic
1
rs6687686
209,341,916
A/G
0.4054
0.4698
18.72
1.52E-05
1.08E-04
0.78 (0.68 - 0.87)
KCNH1
15
rs6493084
41,434,919
G/A
0.3452
0.2888
16.81
4.14E-05
1.10E-04
1.3 (1.15 - 1.47)
ADAL/TUBGCP4/ZSCAB29
15
rs9920879
33,748,546
G/A
0.3452
0.2888
16.81
4.14E-05
1.10E-04
0.89 (1.15 - 1.47)
ADAL
11
rs11021762
11,272,650
C/A
0.3031
0.3582
15.05
1.05E-04
1.12E-04
0.76 (0.69 - 0.88)
GALNTL4
7
rs17133451
138,393,521
C/A
0.1062
0.1472
16.01
6.30E-05
1.12E-04
0.68 (0.57 - 0.83)
ZC3HAV1
15
rs506120
41,589,316
A/G
0.3361
0.2808
16.39
5.15E-05
1.12E-04
1.3 (1.14 - 1.47)
MAP1A/TP53BP1
8
rs984309
99,656,923
G/A
0.5123
0.4496
17.67
2.63E-05
1.12E-04
0.93 (1.14 - 1.45)
STK3
15
rs3087657
41,851,151
G/A
0.3223
0.2703
14.83
1.18E-04
1.13E-04
1.31 (1.13 - 1.46)
ELL3/PDIA3
15
rs2927071
41,706,373
G/A
0.3148
0.2614
15.95
6.51E-05
1.16E-04
1.31 (1.14 - 1.48)
CATSPER2/STRC
13
rs7990503
41,498,003
A/C
0.1898
0.2394
15.74
7.26E-05
1.17E-04
0.95 (0.64 - 0.86)
Intergenic
15
rs3809482
41,449,094
G/A
0.345
0.2888
16.67
4.44E-05
1.18E-04
1.3 (1.15 - 1.47)
TUBGCP4/ZSCAN29
15
rs663214
41,901,074
A/C
0.3232
0.271
14.93
1.12E-04
1.22E-04
1.31 (1.13 - 1.46)
HYPK/MFAP1/WDR76
9
rs10116554
91,629,499
G/A
0.4067
0.4602
12.95
3.21E-04
1.23E-04
0.78 (0.71 - 0.91)
Intergenic
4
rs2242235
745,210
G/A
0.09974
0.06818
15.68
7.49E-05
1.23E-04
1.55 (1.23 - 1.86)
PCGF3
2
rs10182247
173,802,391
G/A
0.1749
0.2248
16.74
4.29E-05
1.24E-04
0.73 (0.63 - 0.85)
ZAK
2
rs2362540
30,306,463
C/A
0.408
0.3466
18.23
1.95E-05
1.27E-04
1.29 (1.15 - 1.47)
LBH
11
rs4757023
19,971,796
A/G
0.3184
0.365
10.61
1.12E-03
1.28E-04
0.77 (0.72 - 0.92)
NAV2
3
rs12486302
35,962,448
G/A
0.2766
0.2281
14.31
1.55E-04
1.29E-04
1.32 (1.13 - 1.48)
Intergenic
15
rs12912283
34,648,515
A/G
0.2902
0.2384
15.87
6.80E-05
1.30E-04
1.32 (1.15 - 1.49)
C15orf41
11
rs716667
19,954,380
G/A
0.3459
0.3928
10.45
1.23E-03
1.31E-04
0.77 (0.72 - 0.92)
NAV2
11
rs4132508
40,701,344
A/G
0.3601
0.4184
15.81
6.99E-05
1.36E-04
0.78 (0.69 - 0.88)
Intergenic
6
rs9347562
162,255,457
A/G
0.4184
0.4784
16.13
5.92E-05
1.39E-04
1.22 (0.7 - 0.88)
PARK2
2
rs13021125
56,988,745
A/G
0.5117
0.4533
15.28
9.28E-05
1.40E-04
1.28 (1.12 - 1.42)
Intergenic
9
rs10512296
104,033,493
G/A
0.09132
0.06299
13.63
2.23E-04
1.41E-04
1.56 (1.21 - 1.85)
Intergenic
3
rs164214
32,473,158
G/A
0.3983
0.459
16.68
4.42E-05
1.44E-04
0.78 (0.69 - 0.88)
CMTM7
20
rs6060617
29,313,313
A/C
0.1749
0.1318
16.85
4.06E-05
1.46E-04
1.39 (1.19 - 1.64)
DEFB115
21
rs459513
21,048,981
A/G
0.08614
0.1213
13.91
1.92E-04
1.56E-04
0.66 (0.56 - 0.84)
Intergenic
13
rs1163829
110,944,195
A/C
0.4462
0.3903
14.48
1.42E-04
1.59E-04
1.28 (1.12 - 1.42)
Intergenic
2
rs4439987
75,140,614
G/A
0.4579
0.5091
11.74
6.12E-04
1.61E-04
0.78 (0.72 - 0.92)
TACR1
6
rs17533090
32,698,700
A/C
0.2088
0.1663
13.83
2.00E-04
1.62E-04
1.36 (1.14 - 1.54)
HLA-DQA1
13
rs8001401
2,341,647
C/A
0.2098
0.2582
14.11
1.73E-04
1.63E-04
0.93 (0.66 - 0.88)
Intergenic
22
rs136351
29,471,239
G/A
0.3174
0.2693
12.75
3.56E-04
1.71E-04
1.3 (1.11 - 1.43)
OSBP2
3
rs9875310
31,660,402
G/A
0.3297
0.2777
14.62
1.32E-04
1.71E-04
1.11 (1.13 - 1.45)
OSBPL10/STT3B
20
rs6121224
29,324,345
G/A
0.1749
0.1322
16.52
4.82E-05
1.77E-04
1.39 (1.19 - 1.63)
DEFB115
9
rs10759245
109,424,200
A/G
0.2789
0.2313
13.65
2.20E-04
1.80E-04
1.31 (1.13 - 1.47)
Intergenic
4
rs1523553
162,207,355
A/G
0.121
0.08583
15.66
7.59E-05
1.81E-04
1.45 (1.21 - 1.77)
Intergenic
6
rs366904
13,375,660
A/G
0.1036
0.07475
12.27
4.60E-04
1.86E-04
1.51 (1.17 - 1.75)
PHACTR1
1
rs1995662
152,946,191
G/A
0.07328
0.1062
13.82
2.01E-04
1.87E-04
0.64 (0.54 - 0.83)
KCNN3
13
rs1537418
93,704,538
C/A
0.4696
0.419
11.65
6.42E-04
1.91E-04
1.28 (1.09 - 1.38)
GPC6
2
rs11125665
56,946,863
A/C
0.4566
0.5131
14.27
1.59E-04
1.93E-04
0.78 (0.71 - 0.9)
Intergenic
4
rs2612655
175,730,164
G/A
0.4338
0.4901
14.19
1.65E-04
1.93E-04
0.79 (0.71 - 0.9)
Intergenic
8
rs4440614
140,333,910
G/A
0.09262
0.1315
15.9
6.66E-05
1.94E-04
0.67 (0.55 - 0.82)
Intergenic
10
rs1740721
34,229,984
A/G
0.4585
0.5109
12.25
4.65E-04
1.95E-04
0.78 (0.72 - 0.91)
Intergenic
5
rs323565
40,884,560
G/A
0.4171
0.4753
15.24
9.45E-05
1.95E-04
0.79 (0.7 - 0.89)
CARD6/RPL37
22
rs136354
29,464,390
A/G
0.3171
0.2695
12.48
4.11E-04
1.96E-04
1.3 (1.11 - 1.43)
OSBP2
20
rs6056552
9,257,713
C/A
0.1457
0.1099
13.58
2.29E-04
1.96E-04
1.42 (1.16 - 1.64)
PLCB4
2
rs12467061
56,981,784
G/A
0.5246
0.4654
15.69
7.47E-05
1.97E-04
1.27 (1.13 - 1.43)
Intergenic
10
rs12264514
100,092,721
G/A
0.0842
0.1157
11.59
6.64E-04
1.99E-04
0.66 (0.57 - 0.86)
Intergenic
19
rs6510774
3,792,051
A/G
0.1205
0.0872
14.2
1.65E-04
2.01E-04
1.46 (1.19 - 1.73)
ZFR2
8
rs7832724
53,579,504
A/G
0.5097
0.449
16.55
4.75E-05
2.01E-04
1.27 (1.13 - 1.44)
Intergenic
For each SNP the chromosome in which is located is shown (CHR), the base pair position (BP
position), the Minor and the Major alleles code, the frequency in the affecteds and the unaffecteds,
the Chi square value after comparison of the minor allele frequency in cases versus controls, the p
value corresponding to the Chi square value, the p value obtained after applying our logistic
regression models, the odds ratio and the 95% confidence interval and the genomic region in which
is located.
Supplementary table 13: Logistic regression results for the 6 SNPs in the BST1 locus in the American
and German samples from Simon-Sanchez et al (Nature Genetics, 2009).
P value
Odds Ratio
Americans
Germans
Americans
Germans
4p15
rs11931532
15334864
0.2893
0.02205
1.172
0.6237
4p15
rs12502586
15335662
0.1797
0.004826
1.133
1.291
4p15
rs12645693
15338632
0.2812
0.02716
1.176
0.6339
4p15
rs4698412
15346446
0.7055
0.03362
0.9789
0.8776
4p15
rs4538475
15347035
0.5415
0.1802
1.047
0.8915
4p15
rs12646913
15348374
0.01592
0.575
0.7708
0.9362
Each SNP was tested for association with PD using a logistic regression analysis following an additive
CHR
SNP
BP
model. The chromosome (CHR) the SNP id (SNP) the base pair location within chromosome 4 (BP)
the P value and the odds ratio is shown for each SNP in both the American and the German samples
from the study by Simon-Sanchez et al (Nature Genetics, 2009).
Supplementary table 14: Minor allele frequencies in cases and controls of the Dutch, the German and
Dutch
Germans
North Americans
the American cohort of the 6 selected SNPs in the BST1 locus.
CHR
4p15
4 p15
4p15
4p15
4p15
4p15
CHR
4p15
4p15
4p15
4p15
4p15
4p15
CHR
4p15
4p15
4p15
4p15
4p15
4p15
SNP
rs11931532
rs12502586
rs12645693
rs4698412
rs4538475
rs12646913
SNP
rs11931532
rs12502586
rs12645693
rs4698412
rs4538475
rs12646913
SNP
rs11931532
rs12502586
rs12645693
rs4698412
rs4538475
rs12646913
A1
C
A
A
G
G
G
A1
C
A
A
G
G
G
A1
G
A
A
G
G
G
A2
T
G
G
A
A
A
A2
T
G
G
A
A
A
A2
A
G
G
A
A
A
MAF cases
0.03706
0.1041
0.03656
0.4339
0.1674
0.06856
MAF cases
0.01954
0.1314
0.01954
0.4151
0.1412
0.06941
MAF cases
0.0272
0.147
0.02659
0.4131
0.1651
0.06299
MAF controls
0.03163
0.09304
0.0311
0.4391
0.161
0.08672
MAF controls
0.03123
0.1041
0.03075
0.4469
0.1558
0.07383
MAF controls
0.02525
0.1124
0.02541
0.4457
0.1693
0.07207
For each SNP, the chromosome (CHR) in which they are located the minor allele
(A1) the major allele (A2) and the minor allele frequency in cases (MAF cases) and
controls (MAF controls) is displayed. Highlighted in red are the results for
rs12502586, which was found to be associated with PD in the Dutch and the
German cohorts.
SUPPLEMENTARY FIGURES
Supplementary Figure 1: Multidimensional Scaling (MDS) plots for pair-wise
Identity by State (IBS) showing the population substructure of our cohort. A:
Population substructure of the Dutch cohort. Cases (black) and controls (red) are
scattered following the same pattern. B: Population substructure of the Dutch
cohort clustered with the CEU (black) samples of the second phase of the HapMap
project. A slight difference between our samples and those from the HapMap is
detected. C: Population substructure of the Dutch cohort clustered with the CEU
(black), CHB (red), JPT (red) and YRI (cyan) samples from the second phase of the
HapMap project. This analysis shows that our samples clearly share European
ancestry.
Supplementary figure 2: Power estimates for the Dutch GWAS. Power to detect
association (Y axis) is plotted against the minor allele frequency (X axyis) with
different thresholds of Odds ratios (OR).
Supplementary figure 3: Quantile-quantile plots showing the distribution of
observed versus expected p values in the Dutch population. The left panel plots the
observed p values without adjusting for any of the covariates included in our model.
The right panel plots the p values after adjusting for age, sex and the two first
component of the Multidimensional Scaling (MDS). Distribution under the null
hypothesis is represented by a red line. A slight deviation of our data with respect to
the null distribution is detected. Lambda = 1.06.
Supplementary figure 4: LD structure across the SNCA locus in the Dutch population.
SNCA is within to haplotype blocks delimited at intron 4.
Supplementary figure 5: Risk exerted (expressed in Odds Ratio [OR]) by each of the
haplotypes present in the two LD blocks identified in the SNCA locus. Each
haplotype is represented by a single line which is wider according to that haplotype
frequency.
Supplementary figure 6: Risk exerted (expressed in Odds Ratio [OR]) by each of the
haplotypes present in the two LD blocks identified in the BST1 locus. Each haplotype
is represented by a single line which is wider according to that haplotype frequency.
Supplementary figure 7: Manhattan plot displaying the results obtained in the
GAK/DGKQ locus.
Supplementary figure 8: Risk exerted (expressed in Odds Ratio [OR]) by each of the
haplotypes present in LD blocks identified in the GAK/DGKQ locus. Each haplotype is
represented by a single line, which is wider according to that haplotype frequency.
Supplementary figure 9: Manhattan plot displaying the results obtained in the HLA
region.
Supplementary figure 10: Risk exerted (expressed in Odds Ratio [OR]) by each of the
haplotypes present in LD blocks identified in the HLA region. Each haplotype is
represented by a single line, which is wider according to that haplotype frequency.
Supplementary figure 11: Pairwise linkage disequilibrium values expressed in r^2
are displayed between the most associated SNPs (P < 0.01) in the MAPT locus. Each
square contains the hundredth of each pairwise r^2 value. The shades of grey are
proportional to the r^2 value with darker color representing higher r^2 values.
Supplementary Figure 12: Manhattan plot across the chromosome 13q31 locus