Supplementary Information Computational methods using ... - Nature

Supplementary Information Computational methods using genome-wide association studies to predict radiotherapy complications and to identify correlative molecular processes Jung Hun Oh, Sarah Kerns, Harry Ostrer, Simon N. Powell, Barry Rosenstein & Joseph O. Deasy Number of samples used in each tree construction For an unbiased assessment of resulting predictive models, a dataset is split once and for all into two groups: a training dataset (2/3 of samples) and a validation dataset (1/3 of samples). For example, for 365 evaluable patients in an endpoint of rectal bleeding, 243 and 122 samples are used for training and validation, respectively. We employ 5fold cross-validation (CV). At each iteration of CV, 4 folds (243×0.8≈194 samples) are used for modeling and the resulting model is tested using the hold-out validation data. In random forest regression, each tree is constructed using a bootstrapping dataset that is randomly sampled with replacement from the original data, having the same size as the original data. On average, 36.8% samples, called the out-of-bag (OOB) data, are excluded in the process of constructing each tree. Therefore, in each tree construction, the size of out-of-bag (OOB) data is 71 (≈194×0.368) that are used to measure the SNP importance and 123 (≈194×0.632) samples are used for the tree construction.

Use of the pre-conditioned outcomes in place of the binary outcomes in our modeling Let X denote a list of the top ranked SNPs that resulted in the best AUC using k – 1 folds of the training data on cross validation in the model building process of rectal bleeding. Let and denote the binary outcomes and pre-conditioned outcomes that are computed using SNPs in X, respectively. We conducted Spearman’s correlation tests between each SNP in X and the following parameters: , , and the first principal component computed using SNPs in X. Figure S1 is a scatter plot of the comparison of these three correlations, showing linear patterns for each other. In particular, the linear pattern between the correlation of X vs. pre-conditioned outcomes and the correlation of X vs. original outcomes supports our idea of using the preconditioned outcomes in the model building process, implying that it is likely that the residual indicates the denosing effect of the original outcomes.

Figure S1. Comparison of the correlation between each SNP in X and the following parameters: 1) , 2) , and 3) the first principal component resulting from SNPs in X in the model building process of rectal bleeding where X indicates a list of the top ranked SNPs that resulted in the best AUC on the training data; indicates original outcomes; and indicates pre-conditioned outcomes. The value indicates the absolute value of Spearman's correlation coefficient.

Distribution of artifactual “noisy” SNPs It is likely that a portion of SNPs selected in univariate analysis are false positive due to a relaxed p-value cutoff of 0.001. To investigate the distribution of potentially artifactual "noisy" SNPs for rectal bleeding, we generated 60,000 synthetic SNPs using the GWAsimulator (http://biostat.mc.vanderbilt.edu/wiki/Main/GWAsimulator) with HapMap CEU data. With a p-value cutoff of 0.001, 74 SNPs remained. We combined these SNPs with 749 SNPs that were originally chosen in univariate analysis for rectal bleeding and iterated the model building process with the combined 823 SNPs. Figure S2A shows the SNP importance score obtained from the model building process. There was no noisy SNP within the top 26 SNPs, suggesting that the highly ranked SNPs are more likely to be real biomarkers. On the other hand, a broad range of ranking of noisy SNPs implies the possibility of the presence of noisy SNPs among 749 SNPs. Figure S2B shows the cumulative rate of observed SNPs starting from the top one, i.e., the number of observed SNPs/(the number of noisy SNPs + the number of observed SNPs). The rate reached the bottom between the top 400 and 500 SNPs.

Figure S2. For rectal bleeding, (A) the SNP importance score and ranking when noisy SNPs were added in the model building process and (B) the rate of observed SNPs starting from the top SNP.

Comparison of the predictive power of models built using different set of SNPs The model building process was iterated using the top {25%, 50%, 75%, and 100%} of SNPs according to the SNP importance score shown in Figure 3. The below figure shows the performance of predictive models on the hold-out validation data. We chose predictive models constructed using the top 50% of SNPs for both rectal bleeding and erectile dysfunction as final predictive models. Note that we chose the cutoff (50%) by investigating the biological relevance of biological processes to the endpoints, not by the predictive performance. The predictive power was slightly improved from 0.70 to 0.71 AUC for rectal bleeding, whereas there was relatively considerable improvement from 0.62 to 0.65 AUC for erectile dysfunction.

Figure S3. Box plots for the predictive power of the pre-conditioning random forest regression on the hold-out validation data in (A) rectal bleeding and (B) erectile dysfunction when the top {25%, 50%, 75%, and 100%} of SNPs according to the SNP importance score measure in the model building process were used.

Finding a set of optimal SNPs based on biological relevance analysis We identified nearby genes for the top {25%, 50%, 75%, and 100%} of SNPs according to the SNP importance score shown in Figure 3. With these genes, we performed gene ontology enrichment analysis to identify biological processes using the MetaCore software. After perceptual analysis for these biological processes, we decided that those biological processes that are enriched by the genes identified from the top 50% of SNPs are more relevant to both endpoints. For example, muscle tissue development found using the top 25% of SNPs is less likely to be associated with rectal bleeding.

Likewise, regulation of heart contraction and regulation of blood circulation found using the top 75% and 100% of SNPs do not appear to be associated with rectal bleeding. However, genes identified by the top 50% of SNPs seem to act in biological processes more relevant to rectal bleeding. For erectile dysfunction, learning or memory found using the top 75% and 100% of SNPs is less likely to be associated with erectile dysfunction. In contrast, several biological processes including negative regulation of heart contraction, negative regulation of blood circulation, and regulation of muscle contraction, found using the top 50% of SNPs, appear to be more associated with erectile dysfunction than those found using the top 25% of SNPs.

Assessment of population structure effects The following table shows the number of patients with and without toxicities across populations. A chi-square test was performed to investigate whether there is a significant difference in the number of events (toxicities) between populations. As a result, there was no significant difference between populations for both endpoints with p-value = 0.37 and 0.43 for rectal bleeding and erectile dysfunction, respectively. Endpoint Rectal bleeding Erectile dysfunction

Toxicity No Yes No Yes

African American 42 12 9 18

Hispanic Caucasian 28 8 8 16

209 50 81 96

Asian

Unknown

3 3 1 1

9 1 4 2

Algorithm S1. The proposed multi-SNP predictive model algorithm. 1. Split a dataset into 2/3 and 1/3 of samples for training and validation, respectively 2. Using the training dataset, perform k-fold cross validation (CV) Using k – 1 folds whose binary outcomes are , do univariate analysis using logistic regression and calculate AUCU for each of the m SNPs as follows: 2.1 With an increasing number of ranked SNPs based on AUCU, perform principal component analysis (PCA) 2.1.1 Using 1 or 2 principal components, perform logistic regression fitted to 2.1.2 Denote the predicted outcomes as

and calculate AUCM for

and

2.1.3 Exit this loop when AUCM reaches a predefined threshold 2.2 Find the

that produces the best AUCM

2.3 Build a pre-conditioned random forest regression (PRFR) model with the

and m SNPs

2.4 Test the resulting predictive model using the hold-out validation dataset whose binary outcomes are and calculate AUCV for PRFR’s predicted outcomes ( ) and 3. To estimate performance variance, repeat steps 2.1-2.4 and tabulate variability of AUCs on the holdout validation dataset AUCU: AUC in univariate analysis using logistic regression on a given k -fold CV partition AUCM: AUC in logistic regression analysis with the first or first few principal components AUCV: AUC calculated on the hold-out validation dataset : Original binary outcomes (toxicity vs. non-toxicity) for samples belonging to k – 1 folds on CV : Original binary outcomes for the hold-out validation dataset : Pre-conditioned continuous outcomes predicted by logistic regression with the first or first few principal components : Pre-conditioned continuous outcomes that result in the best AUCM : Final PRFR’s predicted outcomes for the hold-out validation dataset

Table S1. Top 10 biological processes identified using each list of genes that were found by the top {25%, 50%, 75%, and 100%} of SNPs according to the SNP importance score measured in the model building process for rectal bleeding.

Ranking 1 2 3 4 5 6 7 8 9 10

Ranking 1 2 3 4 5 6 7 8 9 10

Ranking 1 2 3 4 5 6 7 8 9 10

Top 25% of SNPs GO Processes second-messenger-mediated signaling muscle tissue development positive regulation of calcium ion transport system development striated muscle tissue development synapse organization cGMP biosynthetic process protein localization to synapse membrane repolarization during SA node cell action potential phospholipase C-activating G-protein coupled glutamate receptor signaling pathway Top 50% of SNPs GO Processes regulation of ion transport regulation of potassium ion transport regulation of metal ion transport regulation of cation transmembrane transport regulation of potassium ion transmembrane transport regulation of ion transmembrane transport regulation of transmembrane transport cellular calcium ion homeostasis regulation of system process regulation of ion transmembrane transporter activity Top 75% of SNPs GO Processes regulation of system process regulation of ion transport regulation of heart contraction regulation of blood circulation regulation of cation transmembrane transport regulation of ion transmembrane transport second-messenger-mediated signaling regulation of transmembrane transport regulation of metal ion transport regulation of muscle contraction

FDR 1.033E-03 1.138E-03 5.122E-03 1.325E-02 1.752E-02 1.752E-02 1.752E-02 1.752E-02 1.752E-02 1.752E-02

FDR 4.70E-06 5.33E-06 8.92E-06 1.76E-05 1.89E-05 2.31E-05 5.04E-05 1.27E-04 1.27E-04 1.27E-04

FDR 9.845E-08 3.671E-07 6.915E-07 6.915E-07 1.320E-06 1.320E-06 1.815E-06 3.167E-06 4.303E-06 8.274E-06

Ranking 1 2 3 4 5 6 7 8 9 10

Top 100% of SNPs GO Processes

FDR 8.887E-10 7.061E-09 1.040E-08 2.715E-08 2.715E-08 4.412E-08 4.756E-08 9.550E-08 1.072E-07 1.465E-07

regulation of ion transport regulation of system process regulation of ion transmembrane transport regulation of transmembrane transport second-messenger-mediated signaling regulation of heart contraction regulation of blood circulation regulation of cation transmembrane transport regulation of metal ion transport regulation of transporter activity

Table S2. Top 10 biological processes identified using each list of genes that were found by the top {25%, 50%, 75%, and 100%} of SNPs according to the SNP importance score measured in the model building process for erectile dysfunction.

Ranking 1 2 3 4 5 6 7 8 9 10

Ranking 1 2 3 4 5

Top 25% of SNPs GO Processes locomotion cell projection morphogenesis neuron development neuron differentiation blood vessel development cell part morphogenesis regulation of endothelial cell migration movement of cell or subcellular component vasculature development anatomical structure formation involved in morphogenesis

Top 50% of SNPs GO Processes negative regulation of heart contraction negative regulation of blood circulation neutrophil chemotaxis neutrophil migration granulocyte chemotaxis

FDR 2.191E-06 2.191E-06 2.191E-06 2.191E-06 2.191E-06 2.191E-06 2.191E-06 2.702E-06 2.889E-06 2.896E-06

FDR 8.376E-10 2.180E-08 5.026E-08 5.883E-08 9.684E-08

6 7 8 9 10

granulocyte migration positive regulation of locomotion regulation of muscle system process regulation of muscle contraction positive regulation of cell migration

1.300E-07 2.631E-07 5.510E-07 5.510E-07 8.960E-07

Ranking 1 2 3 4 5 6 7 8 9 10

Top 75% of SNPs GO Processes negative regulation of heart contraction negative regulation of blood circulation neutrophil chemotaxis neuron differentiation generation of neurons neutrophil migration granulocyte chemotaxis learning or memory neurogenesis granulocyte migration

Ranking 1 2 3 4 5 6 7 8 9 10

Top 100% of SNPs GO Processes activation of phospholipase C activity learning or memory negative regulation of heart contraction positive regulation of phospholipase C activity regulation of phospholipase C activity cognition single-organism behavior positive regulation of phospholipase activity neuron differentiation negative regulation of blood circulation

FDR 5.553E-09 1.423E-07 2.536E-07 2.536E-07 2.536E-07 2.536E-07 4.452E-07 5.003E-07 5.003E-07 5.003E-07

FDR 5.100E-09 5.100E-09 5.100E-09 8.574E-09 1.148E-08 1.151E-08 1.338E-08 7.723E-08 7.769E-08 7.769E-08

Table S3. SNP ranking that was sorted based on the SNP importance score measured in the model building process for rectal bleeding. SNPs were assigned to a gene if they are located within 10kb upstream and downstream of the gene. Ranking SNP 1 rs2825233 2 rs333167 3 rs7008185

Nearby genes NFIA RGS22

Importance score 0.097 0.082 0.080

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

rs10227348 rs2404149 rs2591101 rs10519411 rs1994701 rs12553697 rs747209 rs3850762 rs2551214 rs154238 rs13138652 rs13136965 rs1817124 rs12711386 rs33967331 rs13167578 rs17062849 rs859357 rs12607893 rs6881873 rs3757572 rs6450138 rs4725080 rs862242 rs11877437 rs2551215 rs862245 rs13315469 rs6894520 rs13168035 rs1445587 rs10891664 rs447881 rs11126163 rs7950087 rs7181082 rs13104417 rs7658139 rs1343007 rs11679340 rs16871955 rs2285264 rs5949642

HOMER1

SLC1A1, SPATA6L MICU3 MYT1L SEC13

AGBL1 TBC1D9 OXCT1 C5orf51 TNR OXCT1 TBRG4 FST ATP6AP1L RIT2 MYT1L ATP6AP1L TNIK ATP6AP1L OXCT1 REXO2 CDH12

ADAM29 ADAM29 FRMD4A SLC8A1 OXCT1 MICU3

0.065 0.065 0.065 0.064 0.063 0.063 0.062 0.061 0.061 0.059 0.058 0.058 0.058 0.057 0.057 0.057 0.056 0.056 0.056 0.056 0.056 0.056 0.055 0.055 0.055 0.055 0.054 0.054 0.053 0.053 0.053 0.053 0.053 0.052 0.052 0.052 0.052 0.052 0.052 0.052 0.051 0.051 0.051

47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89

rs7698088 rs1864803 rs2949942 rs2300584 rs12334614 rs17309228 rs7746208 rs9408158 rs11155629 rs17529367 rs2206006 rs734512 rs1944390 rs2219207 rs6072084 rs8013023 rs7281316 rs8103535 rs9866601 rs11750607 rs2822832 rs10990245 rs1995413 rs16923500 rs16905107 rs16871972 rs35672 rs3123390 rs10941556 rs6992117 rs444876 rs11209979 rs294559 rs4700799 rs7322542 rs12188447 rs9926328 rs2328271 rs2278082 rs472587 rs154237 rs2729609 rs197003

TBC1D9 PITPNC1 GCK

TAB2 TAB2 CHM

NXPE1 MAFB JDP2 DPRX OXCT1, C5orf51

UBXN2B, CYP7A1 OXCT1 SEC13, GHRL ZBTB18 OXCT1 TOX NTM MCTP2 ADAMTS2 TNFRSF19 CDH12

CCDC93 DLG2 SEC13 IL1RAPL1

0.051 0.051 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.049 0.049 0.049 0.049 0.049 0.049 0.049 0.049 0.049 0.049 0.048 0.048 0.048 0.048 0.048 0.048 0.048 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.046 0.046 0.046 0.046 0.046

90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

rs6725474 rs2061143 rs6683030 rs11082602 rs16867320 rs264174 rs1028867 rs10519410 rs17458235 rs7615625 rs2639313 rs7649134 rs268706 rs3787255 rs4713926 rs9465923 rs10894446 rs8108694 rs11211945 rs9885072 rs9790641 rs680944 rs7228876 rs3808900 rs4650390 rs2768275 rs1357395 rs11876485 rs1186048 rs9487199 rs1576672 rs12333397 rs1510744 rs9635948 rs12150846 rs11590310 rs516888 rs4794281 rs2457846 rs741038 rs41330144 rs2653648 rs715345

CCDC93 NXPE1

PIEZO2 PALM2

TNIK PDZRN3 TARS EYA2 ADTRP CDKAL1 NTM ZNF543, ZNF304 GUCY1A2 CDH12 RBM47 SH3BGR LHX6, RBM18

CCDC171 GPR63

NTNG1 SH3BGR CA10 FRMD4A GCK

0.046 0.046 0.046 0.046 0.046 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.045 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.044 0.043 0.043 0.043 0.043 0.043 0.043 0.043

133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175

rs979220 rs2812510 rs4073251 rs1061615 rs17087870 rs2852949 rs1593054 rs16976240 rs1153744 rs4928149 rs10833229 rs1459920 rs10483303 rs934882 rs430924 rs9828340 rs10023965 rs12670403 rs17471738 rs2889548 rs6795317 rs3862777 rs12439884 rs1773015 rs9571314 rs2562126 rs17782181 rs1999468 rs2714656 rs12482280 rs6807031 rs10505560 rs10512542 rs4808203 rs3875341 rs10102682 rs9613021 rs17053449 rs6413472 rs2870749 rs6671294 rs12425885 rs13354232

CACNA1D C10orf35 PDPN

NDUFS4, FST PPP1R1C FILIP1L NAV2

CDH12 GABRB1 AHR SGIP1 ADCY8 SCHIP1 DLG2

HERPUD1 DOCK9

MITF ADCY8 GATAD2A

MYO18B SGCD CTH

BTBD11

0.043 0.043 0.043 0.043 0.043 0.043 0.043 0.043 0.043 0.043 0.043 0.043 0.043 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.042 0.041 0.041 0.041 0.041 0.041 0.041 0.041 0.041 0.041 0.041 0.041 0.041 0.041

176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218

rs2449447 rs7226130 rs934207 rs284732 rs2251301 rs2230600 rs12618287 rs550830 rs16969506 rs16860627 rs10891647 rs715346 rs11981812 rs7699581 rs10010361 rs2616072 rs4653062 rs4402749 rs17080199 rs834771 rs715347 rs1008695 rs6787045 rs12353518 rs6424638 rs2916498 rs6943978 rs10809832 rs10470587 rs473005 rs7797162 rs7098507 rs6717960 rs2385833 rs2019991 rs9317478 rs17573253 rs17049410 rs12278023 rs6072196 rs159319 rs11899768 rs3793753

SPAG9

MTMR9 PTPN13 HRH4 MGAT5B NNMT DPP6 GRID2, ATOH1 C10orf35

GFPT2

LRP1B MAGI1

CTNNA2 SDK1

TMEM165 ELMO1

CCT4 DLG2 CCL13, CCL1 PIP4K2A

0.041 0.041 0.041 0.041 0.041 0.041 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.040 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039

219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261

rs12150848 rs2714657 rs13337852 rs17078797 rs6480585 rs12452891 rs12693239 rs515092 rs1941378 rs16997454 rs10914991 rs12449066 rs11187371 rs16860030 rs17552411 rs7120482 rs3776763 rs2609836 rs17011727 rs532753 rs631376 rs6774615 rs7944514 rs11613346 rs344404 rs10861733 rs2072070 rs159290 rs7333447 rs13265608 rs159289 rs13086738 rs12638862 rs4237397 rs2283380 rs7612205 rs10505102 rs6775136 rs6925604 rs1449720 rs1490706 rs6553586 rs11713968

PRKG1 MGAT5B BLID TENM4 TSHZ2 WWOX MYOF AHCYL2 STK10 FAM107B CNTNAP5 MGAT5B ALKBH8 SLC6A6 POLD3 TMEM132D CNTN4 BTBD11 CCL13, CCL1 CCL1 SUGT1P3 CCDC26 CCL1 TERC RGS6 IGSF10 ANGPT1 REPS1

0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.039 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038

262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304

rs17142569 rs979438 rs4794194 rs13084396 rs4653061 rs13266795 rs2835862 rs17142556 rs1806190 rs10959478 rs159313 rs1863042 rs1825792 rs7210332 rs155783 rs1346376 rs10419912 rs10916762 rs10157706 rs1805609 rs159291 rs10485365 rs638196 rs11890841 rs2087930 rs17555239 rs264536 rs2147384 rs3861854 rs6072163 rs1958059 rs1033098 rs2279827 rs17136316 rs6587388 rs344651 rs2122061 rs10010675 rs4696975 rs9812042 rs2853559 rs896313 rs4727070

SPAG9

CSMD1 KCNJ6

CCL13 CCDC93 CDH12 NDUFS4 SPOCK3 GATAD2A VWA5B1 GADD45A CCL1

DPP10

KIAA0141 NPAS3 DRD3, ZNF80 ZNF75A OR2T8, OR2W3 LHFPL2 GRID2, ATOH1 KCNIP4 VDR DLG2 ZNF777

0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.036 0.036 0.036 0.036 0.036 0.036

305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343

rs12196063 rs10873205 rs10255878 rs17719830 rs2630182 rs4689626 rs12546003 rs4982398 rs1186387 rs2094520 rs10796186 rs2178333 rs1350836 rs4457339 rs1341739 rs10794203 rs7485210 rs275010 rs2303329 rs6677050 rs2548649 rs10970529 rs8089756 rs3729904 rs2975272 rs16976243 rs11593477 rs9567894 rs583173 rs4838988 rs10517596 rs1169475 rs2332329 rs754574 rs13390621 rs10938039 rs12038219 rs1184913 rs17668620

344 345 346

rs10800279 rs7653813 rs9473031

PLEKHH1 KIAA1468 FHIT SORCS2 NDRG2 CCDC171 CCDC171 REPS1 TNKS CCDC171 ADGRD1 CCDC93 PTPN14 SNX18 RFX3 PRKCB ZNF250, ZNF16

NLGN1 MAGI3 LRAT CCDC171 GNB4 ANTXR1, GFPT1 CD247, CREG1 CCDC171 PTPRD NOS1AP, OLFML2B TNFRSF21

0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.036 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035

347 348 349 350

rs6799873 rs11123477 rs1868606 rs16977561

351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388

rs5747295 rs7917012 rs10030477 rs1169476 rs7199566 rs868031 rs17041944 rs6800052 rs17101326 rs1254729 rs4694846 rs17140083 rs874869 rs1787318 rs582096 rs153398 rs11042789 rs6449150 rs7013751 rs133553 rs17298157 rs17142139 rs4964576 rs11876970 rs15047 rs896739 rs10773460 rs11187345 rs11082590 rs1118823 rs1787319 rs249621 rs6449973 rs3136681 rs12571538 rs10490128 rs7708775 rs13393217

CGNL1 ATP6V1E1, BCL2L13

CCDC171 SNTB2 CTNNA2 CNTN6 WDR89 GABRB1 RBFOX1 FBXO11 MYO5B MGAT5B SREK1 AMPD3 CC2D2A CDH17

BTBD11 PRMT2

FGG, FGA MYO5B

CCL13, CCL1 RBM17, PFKFB3 PJA2 HDAC4

0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.035 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034

389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431

rs4744313 rs3961050 rs3732477 rs7619608 rs11136920 rs6755898 rs11187341 rs6779873 rs1550353 rs4791610 rs12637201 rs4904509 rs9625253 rs6651056 rs10508824 rs17638180 rs2624917 rs1860164 rs1393735 rs12465358 rs12464424 rs6857138 rs17841189 rs1866069 rs7042626 rs6058224 rs1293114 rs5943527 rs7916658 rs355820 rs7067945 rs17691848 rs6501805 rs12515663 rs17513709 rs7181796 rs12734251 rs13180690 rs133204 rs10508823 rs2812509 rs10452607 rs2434781

PTPDC1 CPN2 ECT2 SP110 CNTN6 GRID2, ATOH1 CDRT7 ECT2 FOXN3

AKAP13 UPP2 CA10 UPP2 GRID2, ATOH1 SH3GL3 TTC41P UQCC1, EIF6 IL1RAPL1

KIAA0195 PCDH1 NSUN7 AKAP13 CHD5 PDE4D LRP5L C10orf35 TRERF1, MRPS10 CDH18

0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.034 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.033 0.032 0.032 0.032 0.032

432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461

rs2692815 rs9294979 rs7139809 rs10497826 rs6943606 rs3741044 rs6632412 rs9806191 rs6971319 rs12918362 rs882733 rs7846356 rs4316801 rs2670199 rs5912422 rs7652461 rs17541282 rs12655617 rs16967577 rs9960012 rs4888901 rs1582007 rs2096823 rs7903506 rs1927060 rs17082323 rs1680887 rs931950 rs514253 rs17461863

462 463 464 465 466 467 468 469 470 471 472 473

rs9576167 rs738633 rs313438 rs3816432 rs2299262 rs7847020 rs6765863 rs1379257 rs6716246 rs11662963 rs10816139 rs11102736

SFMBT2 THBS2

AMPD3 CFAP47 DAPK2 MKLN1 NSUN7 MYOM2 CA10 FAM46D

PDE4D

WWOX

DLG5 CHMP1B2P SYNE1 BRE, FLJ31356 CLUL1, CETN1 GABRB1 SUPT20H, CSNK1A1L RBX1 YPEL2 PON1 ECT2, SPATA16 CEP70 KIAA1468 PTPRD SYT6

0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.032 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031

474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516

rs1347064 rs6933331 rs17059161 rs188025 rs2878682 rs7937598 rs6113032 rs5913245 rs423779 rs9862461 rs1128272 rs6854244 rs12215832 rs187615 rs1680885 rs7230449 rs12027327 rs7553348 rs12723898 rs9494089 rs13169888 rs16948801 rs10816138 rs6482959 rs4978888 rs17034615 rs17006475 rs9946520 rs543977 rs1684900 rs10450540 rs17247902 rs3095634 rs1778214 rs565610 rs973877 rs2449448 rs9303606 rs870570 rs12199325 rs11783232 rs3103161 rs2711078

CHMP1B2P MAS1L, UBD

CFAP47 TSPAN18 CHMP1B2P CACNA1E RAB7A GKN2

SYT6 TNNI3K TUFT1 UBTD2 WWOX PTPRD FOXI2 C9orf152 KIF1B PLAC8, COPS4 PIGN CCDC6 CAMK1D AKTIP PIGN

CDH12 PKP4

0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030 0.030

517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559

rs17509502 rs2333856 rs17045259 rs17801966 rs1747649 rs7314936 rs7644832 rs10903923 rs6106629 rs241798 rs17289606 rs7296628 rs261076 rs7436353 rs6756459 rs2065841 rs12703626 rs7206996 rs10896 rs2446830 rs11251645 rs7377646 rs4825704 rs457062 rs7377670 rs11251481 rs17289585 rs428786 rs17130592 rs7253030 rs17512637 rs1805502 rs7634745 rs2284428 rs10836419 rs10219717 rs7824301 rs9987094 rs2179538 rs4464774 rs11662257 rs12099529 rs1383879

IPCEF1 AKTIP

CMKLR1 FAM196B RXFP1 NFIA TPK1 YPEL2 MEF2BNB CDH17 RXFP1 CUL4B, MCTS1 DENND4C RXFP1

WLS RBM47 GRIN2B CEP70 GRIN2B PAMR1 CCDC63 ZFAT IPCEF1 LOXHD1

0.030 0.030 0.030 0.030 0.030 0.030 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.029 0.028 0.028 0.028 0.028 0.028

560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602

rs7830390 rs10759078 rs6632414 rs16865763 rs7089611 rs6629021 rs12582270 rs9342869 rs10991000 rs17383845 rs3801004 rs11578843 rs11251641 rs2859481 rs6709269 rs17216862 rs10505625 rs2041102 rs17062816 rs2239253 rs17023680 rs4665631 rs697702 rs900973 rs10772506 rs17107113 rs923074 rs306536 rs4629440 rs7519127 rs17563756 rs1965670 rs1419644 rs17755728 rs3790227 rs10977800 rs17000271 rs11848155 rs7659958 rs17054187 rs11176735 rs4502644 rs2546589

LRRCC1 PTPRD CFAP47 KIAA1217 CFAP47 SOX5

SHC4 FSCN1

BATF RAB11FIP5 ZFAT OR7A5, OR7C1 RGS6 CNTN4

SLC14A2 ETV6 JAKMIP2 SLC14A2 DDX31 TTLL7 PJA2 MAS1L, UBD TENM4 SLC24A3 PTPRD

MAN2B2

0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.028 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027 0.027

603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645

rs10903922 rs11174192 rs12082808 rs10979437 rs2417923 rs7049635 rs2268129 rs7705858 rs739854 rs11104497 rs1495008 rs12652757 rs7902402 rs2685257 rs9360487 rs5749006 rs877387 rs10903925 rs955245 rs4869474 rs12683129 rs9930917 rs7105434 rs3772932 rs7849713 rs16909281 rs1931365 rs5934426 rs10990940 rs10761206 rs10889769 rs6021721 rs17013484 rs1924529 rs4809721 rs2942135 rs1480053 rs7775829 rs6824699 rs17104350 rs1045392 rs1438631 rs7133438

FAM19A2

GRIN2B NADK2, RANBP3L

ADRB2

CECR3

RANBP3L HACD4, IFNB1

GAP43 HACD4, IFNB1 FAM135B WNK2 VCX3B WNK2 DEPDC1, RPE65 ZFP64

PREX1 PLEKHA6 PHACTR2 ESRRB FAM173B GAP43 NOS1

0.027 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.026 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.024 0.024 0.024 0.024

646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688

rs7788756 rs2575515 rs12107704 rs1952052 rs12549436 rs17484734 rs10511277 rs11765212 rs17155665 rs5934151 rs7269050 rs8063167 rs11859377 rs10888857 rs7849485 rs7163029 rs6744735 rs709188 rs11614312 rs13097883 rs7329268 rs6640144 rs2046902 rs10899964 rs9537297 rs12084736 rs9838500 rs9932807 rs5968699 rs11994169 rs16885752 rs6096776 rs8133540 rs12109225 rs1380813 rs7158201 rs4732418 rs6815858 rs7134341 rs4772838 rs1585687 rs6535972 rs6497853

NALCN

CACNA2D1

RMI2 IRX3 ACOT11 HACD4, IFNB1 LINGO1

MED13L CCDC39 VCX3B ASIC2

SKI PDCD6IP NAA60, C16orf90 CHM C5orf67 ZFP64 RCAN1 WDR70, NUP155 KCNIP4 ADAM20, MED6 CACNA2D1 SRRM4 COL23A1

0.024 0.024 0.024 0.024 0.024 0.024 0.024 0.024 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.023 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.022 0.021 0.021

689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731

rs7521055 rs2834772 rs16967866 rs17729263 rs8090945 rs9576769 rs7983935 rs11166624 rs6927607 rs12451314 rs16944395 rs2628644 rs17771094 rs4710979 rs11794984 rs17770070 rs16987857 rs11056813 rs8095200 rs11897377 rs8052035 rs4762546 rs2633674 rs12213204 rs9459317 rs6500685 rs7644156 rs11714171 rs7609420 rs1919561 rs2047201 rs2036936 rs17081861 rs2741607 rs3860271 rs1434364 rs7181017 rs10937080 rs10955035 rs4950128 rs17628762 rs224671 rs12712927

RSPO1, C1orf109 GRB2, KIAA0195 DCC

ZFAT ASIC2

ZFAT

ZFAT HS1BP3 SLC15A5 GCFC2 ANKS1B POU1F1

ERC2 GCFC2 SPATA5

DBNDD2, TP53TG5

KLHL25 RAB11FIP1

SIX3

0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.020 0.020 0.020 0.020 0.020 0.020 0.020 0.020 0.020 0.019 0.019 0.019 0.019 0.019 0.019 0.019 0.019 0.019 0.019 0.019 0.018 0.018 0.018 0.018 0.018 0.018 0.018 0.018 0.018 0.018 0.017 0.017

732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749

rs11829822 rs11743007 rs17074756 rs17629141 rs224666 rs10064691 rs9296115 rs7746427 rs11832465 rs1196348 rs10488742 rs452755 rs6929303 rs11578753 rs9356730 rs9358331 rs2037177 rs2095268

TMPO, SLC25A3 ERGIC1

TBCA, OTP PACSIN1 SRRM4 SNX27

SAYSD1

NEK11 EVI5

0.017 0.017 0.017 0.017 0.017 0.017 0.016 0.016 0.016 0.016 0.016 0.016 0.016 0.016 0.015 0.015 0.015 0.013

Table S4. SNP ranking that was sorted based on the SNP importance score measured in the model building process for erectile dysfunction. SNPs were assigned to a gene if they are located within 10kb upstream and downstream of the gene. Ranking 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

SNP rs319460 rs463295 rs17232178 rs4255740 rs7149188 rs11017104 rs10829695 rs10764930 rs7082126 rs10829696 rs17775328 rs723187 rs6950259 rs7333648 rs4791505 rs7748820

Nearby genes ATP8B1 ATP8B1 GLRX3 MAP2K1 GLRX3 GLRX3 GLRX3 GLRX3 GLRX3

Importance score 0.139 0.135 0.131 0.127 0.126 0.126 0.126 0.125 0.124 0.124 0.124 0.124 0.124 0.123 0.114 0.113

17 18 19 20 21 22 23

rs317835 rs1535904 rs301571 rs8080976 rs6846909 rs317838 rs10113394

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58

rs9525326 rs1432441 rs9678284 rs865332 rs7245988 rs4697682 rs4726411 rs16949924 rs2239865 rs815718 rs641461 rs598207 rs3760629 rs4803781 rs319461 rs16949879 rs4984390 rs8031897 rs7517337 rs11633291 rs11683069 rs4541064 rs1554931 rs755267 rs1344293 rs11694842 rs183733 rs756603 rs574079 rs10237950 rs16959604 rs819238 rs9349145 rs12030578 rs1171594

ATP8B1

DNAH17 ATP8B1 CHAMP1, UPF3A MAP2K1 ITK, FAM71B NLRP11 DPP6 MAP2K1 MTMR7 COL8A1 CXCR5 CLPTM1 CLPTM1 ATP8B1 MAP2K1 MCTP2 TIPIN MCTP2

DNMT3A SEMA5A MTMR7 DAB2IP PRKCA ITK USP48 MRLN

0.111 0.111 0.109 0.108 0.104 0.104 0.104 0.103 0.103 0.103 0.103 0.102 0.102 0.102 0.102 0.101 0.101 0.100 0.100 0.100 0.100 0.098 0.097 0.097 0.097 0.096 0.096 0.095 0.094 0.094 0.094 0.094 0.093 0.093 0.092 0.092 0.092 0.092 0.092 0.092 0.091 0.091

59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101

rs9822615 rs10472290 rs41007 rs7737213 rs514075 rs12470828 rs11683506 rs1024969 rs4705493 rs6556502 rs6492521 rs2682966 rs1022308 rs8036023 rs11869821 rs1750240 rs924506 rs4921309 rs2836892 rs11871291 rs13430914 rs2075620 rs4982676 rs3093998 rs4354715 rs2063972 rs2839241 rs4712300 rs9854419 rs9369181 rs261218 rs7292527 rs1554930 rs528526 rs11856789 rs4346455 rs16930371 rs6935608 rs17291801 rs11635009 rs4235754 rs6678912 rs12550499

ATP10B OPCML SMARCAL1 ATP10B ATP10B FHIT DLG2 MAP2K1 PRKCA ANKS1B ATP10B PRKCA CLPTM1 SLC7A7 MICB DLG2 PCNT CAP2 CNTN4

DLEU7 CERS3 SSPN PKHD1 CERS3

0.091 0.091 0.091 0.090 0.090 0.090 0.090 0.090 0.089 0.089 0.089 0.089 0.089 0.089 0.089 0.089 0.089 0.088 0.088 0.088 0.088 0.087 0.087 0.087 0.087 0.087 0.086 0.086 0.086 0.086 0.086 0.085 0.085 0.085 0.084 0.084 0.084 0.084 0.084 0.083 0.083 0.083 0.083

102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144

rs4624634 rs12537077 rs10798052 rs6853616 rs7766099 rs11952011 rs10979039 rs671549 rs10041627 rs1890473 rs6885587 rs667046 rs6880938 rs953018 rs751853 rs12027256 rs12907997 rs1003271 rs9551134 rs1860994 rs11639209 rs2220746 rs4902923 rs10476200 rs9408677 rs10496216 rs7666487 rs10926895 rs2156973 rs9364707 rs956211 rs2605897 rs4681620 rs6041590 rs3095341 rs10499676 rs917012 rs17278578 rs1440487 rs611954 rs9553395 rs9553394 rs7988031

CUX1 TBC1D9 PDE4D DLEU7 CTNND2 EFCAB14 CTNND2 EFCAB2 CTNND2 SEMA5A

SMAD3

TSPAN17 KANK1 GABRB1 FHIT CERS3 TSC22D2

ABCA13 CTNND2 EFCAB14

0.083 0.082 0.082 0.082 0.082 0.082 0.082 0.082 0.082 0.082 0.082 0.082 0.082 0.081 0.081 0.081 0.081 0.081 0.081 0.081 0.081 0.080 0.080 0.079 0.079 0.079 0.079 0.079 0.079 0.078 0.078 0.078 0.078 0.078 0.078 0.078 0.078 0.078 0.078 0.077 0.077 0.077 0.077

145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187

rs1922660 rs11670380 rs10749863 rs7980124 rs33980476 rs2839258 rs601060 rs1012695 rs9380975 rs4673021 rs6114768 rs11148196 rs10947907 rs16918884 rs11721076 rs11156961 rs9837013 rs4508584 rs12621723 rs5910076 rs6049771 rs5945702 rs6935166 rs2237182 rs10897895 rs665478 rs11933507 rs7824784 rs2900724 rs6859323 rs9829886 rs5629 rs894910 rs10505638 rs17482340 rs721992 rs6078121 rs208867 rs10950076 rs7620877 rs1533896 rs1877796 rs4557574

EFCAB14

PCNT TEX38

SGPP2 SYNDIG1

OPRK1 PDZRN3

SGPP2

SYNDIG1 ARHGAP18 ATXN1 EFCAB2 FRAS1 THG1L THG1L FHIT PTGIS

MYOF CCDC6

CCDC6

0.077 0.077 0.077 0.077 0.076 0.076 0.076 0.076 0.076 0.075 0.075 0.075 0.075 0.075 0.074 0.074 0.074 0.073 0.073 0.073 0.073 0.073 0.073 0.073 0.073 0.073 0.073 0.072 0.072 0.072 0.072 0.072 0.072 0.072 0.072 0.072 0.072 0.072 0.071 0.071 0.071 0.071 0.071

188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230

rs10073056 rs1935474 rs10520849 rs11738432 rs6850841 rs896025 rs2073221 rs9935982 rs7025024 rs632676 rs7830977 rs7913010 rs6596147 rs10504070 rs10947863 rs1426535 rs2225692 rs4959710 rs16860083 rs6970554 rs10749338 rs9373088 rs1321168 rs680507 rs9328123 rs1321169 rs17391661 rs4959711 rs6919449 rs1999898 rs17771145 rs2586072 rs10151135 rs3913521 rs2163895 rs6856348 rs17737996 rs6577695 rs183805 rs764077 rs11696845 rs3106324 rs17547120

CTNND2 PCDH15 LSM11

EFCAB2 MYOF, CEP55 C8orf22

MYLK4 GABRB1

SGK1 FYN EFCAB2 MYLK4 FYN MYOF MYLK4 MYLK4 PRKCA ATXN3

KCNK15 MAML3

0.070 0.070 0.070 0.070 0.069 0.069 0.069 0.069 0.068 0.068 0.068 0.068 0.068 0.068 0.068 0.068 0.068 0.067 0.067 0.067 0.066 0.066 0.066 0.066 0.066 0.066 0.065 0.065 0.065 0.065 0.065 0.064 0.064 0.064 0.064 0.064 0.064 0.063 0.063 0.063 0.063 0.063 0.063

231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273

rs17076170 rs11882682 rs12126074 rs7062726 rs12991495 rs1478001 rs11022045 rs1450138 rs16984110 rs17576620 rs10432780 rs877688 rs17050442 rs7827724 rs3913523 rs6922692 rs3913520 rs16984115 rs5907426 rs2168546 rs2666483 rs4743859 rs17348299 rs11674467 rs6922617 rs17712825 rs6907281 rs2728475 rs7084796 rs12109911 rs5964318 rs741661 rs4082418 rs4347920 rs725834 rs11751940 rs10826386 rs2153368 rs11055460 rs17592556 rs3914623 rs505699 rs2075774

ARHGEF18

DNMT3A ASCL2

KANK4

TLL2

CLYBL

CRTAC1 ANGEL1

0.063 0.063 0.063 0.063 0.063 0.062 0.062 0.061 0.061 0.061 0.060 0.060 0.060 0.059 0.059 0.059 0.059 0.059 0.059 0.059 0.058 0.058 0.058 0.058 0.058 0.058 0.058 0.058 0.058 0.058 0.057 0.057 0.057 0.057 0.057 0.056 0.056 0.056 0.056 0.056 0.055 0.055 0.055

274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316

rs1872692 rs795678 rs12125740 rs7739977 rs8102377 rs10820913 rs1341937 rs12491489 rs2385127 rs7590760 rs16954046 rs17712566 rs2585607 rs10770822 rs467797 rs4779131 rs16954047 rs6489341 rs11857724 rs1201888 rs1201886 rs12315726 rs2238128 rs10518015 rs1423576 rs685909 rs10830363 rs1868677 rs10830291 rs12242465 rs11018662 rs7074375 rs6543012 rs12526130 rs11726512 rs4142494 rs12366176 rs2388105 rs13059806 rs12930508 rs6543013 rs11178702 rs10830288

ZNF331

C8orf22 DNMT3A

SPX

DCP1B

ETV6 ETV6 IL31RA TRIM77 ADGRG1 CRTAC1

TBC1D8 PALLD NOX4

TBC1D8

0.055 0.055 0.055 0.054 0.054 0.054 0.054 0.054 0.054 0.053 0.053 0.053 0.053 0.053 0.053 0.053 0.053 0.053 0.053 0.053 0.053 0.052 0.052 0.052 0.051 0.051 0.051 0.051 0.051 0.050 0.050 0.050 0.050 0.049 0.049 0.049 0.049 0.049 0.049 0.049 0.049 0.049 0.048

317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359

rs12444374 rs1036140 rs11686210 rs765304 rs11055430 rs11847171 rs4890018 rs2407053 rs2922350 rs10009101 rs4425129 rs6055916 rs11055431 rs17330228 rs9787725 rs10826385 rs11076365 rs3848264 rs3885635 rs10830359 rs10830321 rs11018670 rs12146625 rs16906883 rs2917533 rs983263 rs11018751 rs291090 rs4685330 rs1201893 rs3757536 rs2031309 rs13419011 rs11755040 rs7879159 rs17762851 rs12142899 rs11007656 rs13356161 rs322896 rs2180958 rs877069 rs17604435

DGKB

CPSF2 RNF213

C4orf19 ZNF806 PLCB1 KCNH7 PCDH15

MPP7 TRIM77

FOLH1B NOX4 TRIM77 PIGR RFTN1 CADPS2

GPLD1 MAP3K15 AUTS2 SVIL ADCY2

ADCY2

0.048 0.048 0.048 0.048 0.048 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.047 0.046 0.046 0.046 0.046 0.046 0.046 0.045 0.045 0.045 0.045 0.045 0.044 0.044 0.044 0.044 0.043 0.043 0.042 0.041 0.041 0.040 0.040 0.039 0.038 0.038 0.037 0.037 0.036

360 361 362 363 364 365 366 367

rs921574 rs10508357 rs5957142 rs10912092 rs7555613 rs1777604 rs1484623 rs12012376

OAF

CTTNBP2NL IL1RAPL1

0.036 0.035 0.035 0.032 0.031 0.030 0.030 0.025