Table 5. Functional and ancestral annotation of potentially pleiotropic single nucleotide polymorphisms in the Population Architecture using Genomics and Epidemiology (PAGE) study.
All PheWAS-identified variants and variants in linkage disequilibrium with the index variant (at r2 ≥ 0.80 based AFR 1000 Genomes Project data) were functionally and ancestrally annotated using HaploReg v4.1, RegulomeDB v1.1, the SNP and CNV Annotation Database (SCAN), and local genetic ancestry. HaploReg v4.1 NHGRI-EBI GWAS Catalog data were augmented using NHGRI-EBI GWAS Catalog data from 2019-06-20, and associations listed are at p<5.0x10-8 unless otherwise noted. Local genetic ancestry, shown as proportion of African-derived alleles, was estimated using LAMP-LD. An asterisk in the direction of effect column indicates an opposite direction of effect for two of the phenotype classes listed. Genomic position given is based on hg38.
| DE | rsID (Chromsome:Position) |
Phenotype classes | CA | Reason on Metabochip | Variant classification (Gene or nearest gene(s)) |
Variants in LD | HaploReg/RegulomeDB/SCAN | Ancestry | ||
|---|---|---|---|---|---|---|---|---|---|---|
| 0 | 1 | 2 | ||||||||
| rs10889334 (chr1:62491528) |
Smoking, LDL-C | C | Fine-mapping Lipids / Triglycerides | Intronic (DOCK7) |
rs10493322 rs10158897 rs3913007 rs4350231 rs12037659 rs11356503 rs1979722 rs10889333 rs10789112 rs10889335 | HaploReg: located within enhancer and promoter regions in multiple cell types; index variant significant eQTL in GTEx transformed fibroblast cells, skin (sun exposed lower leg), tibial artery, and aorta artery tissues; USP1 rs10158897 associated with LDL-C in Chinese population at p = 9.0x10-6 (PMID:24386095); DOCK7 rs4350231 is associated with cardiovascular disease in European populations (PMID:30595370); DOCK7 rs10889333 is associated with total cholesterol in European populations (PMID:28270201) RegulomeDB: rs4350231 likely to affect TF binding and linked to expression of a gene target (DOCK7); rs10493322, rs10158897, rs3913007, rs11356503, rs10889334 minimal TF binding evidence SCAN: Index variant an eQTL in multiple genes in CEU. Associated SNPs rs10493322, rs10158897, rs3913007, rs4350231, rs1979722, rs10889333, rs10889335 also eQTLs in multiple genes, mostly CEU data. Associated rs10889335, is a nonsynonymous enhancer |
7.57 | 43.53 | 48.90 | |
| rs61771778 chr1:72461172) |
CRP, MI | G | Fine-mapping BMI | Intronic (LOC105378797) |
rs4649955 | HaploReg: Index and associated variants significant eQTLs in GTEx from tibial nerve tissue | 42.34 | 52.41 | 5.24 | |
| rs2994429 (chr1:84709901) |
Hemoglobin, Hematocrit | A | Replication Fasting Glucose | Intergenic (SSX2IP/ LPAR3) |
rs2911571 rs2911578 rs2994449 rs1340527 rs1340528 | HaploReg: Index variant is an eQTL in whole blood; associated rs2911571 binds OCT2 and POU2F2 and has promoter and enhancer histone marks in several cell lines RegulomeDB: Associated variant rs2911571 likely to affect TF binding; index variant less likely to affect TF binding; other associated variants have minimal TF binding evidence SCAN: Index and associated variants have eQTL evidence in YRI cell line |
100.00 | 0.00 | 0.00 | |
| rs10798572 (chr1:177821975) |
Hypertension, Smoking | G | Fine-mapping BMI | Intergenic (LOC100506128/ SEC16B) |
HaploReg: associated with HMGN1, PTGES2, and SNX29 gene expression in peripheral blood monocytes SCAN: eQTL evidence across multiple genes in YRI cell line |
0.00 | 1.06 | 98.94 | ||
| rs943763 (chr1:177867129) |
LDL-C, Smoking | C | Fine-mapping BMI | Intergenic (LOC100506128/ SEC16B) |
rs3131318 | RegulomeDB: Index variant has minimal TF binding evidence SCAN: Index variant is eQTL with multiple genes in YRI cell line |
50.75 | 35.36 | 13.89 | |
| rs1052238 (chr1:198665496) |
CRP, Diabetes | G | Replication BMI | Intronic (PTPRC) |
rs1926230 rs12401369 rs6686725 rs1326272 rs3820484 rs16843591 rs201584212 rs57114949 rs59147127 rs3767735 rs56272733 rs6428473 rs2182418 rs2148314 rs6428474 rs3754096 rs1326274 rs1326275 rs1326276 rs1052240 | Haploreg: Index variant is eQTL for PTPRC in whole blood; associated rs2148314 is strong and weak enhancer in multiple cell lines. RegulomeDB: Index variant and associated variants rs6686725, rs6428474, rs1326272, rs56272733, rs3754096, rs1052240 have minimal TF binding evidence; associated variants rs1926230, rs2182418, rs2148314 less likely to affect TF binding |
59.00 | 40.92 | 0.08 | |
| rs568938 (chr2:21080744) |
LDL-C, Smoking | A | Fine-mapping Lipids/LDL | Intergenic (APOB/ LOC100129278) |
rs563290 rs668948 rs201027918 rs541041 rs478588 rs577584 rs614303 rs503105 | HaploReg: Index and associated variants rs478588 APOB eQTL in QTEx heart-left ventricle tissue; associated variants are weak to strong enhancers in cell lines; multiple proteins bound to associated rs201027918 and rs503105; index and associated variants rs563290, rs668948, rs541041 associated with LDL-C, triglycerides, and total cholesterol in multiple populations (PMID:29507422); associated rs577584 associated with LDL-C in multiple populations (PMID:30275531); associated rs541041 associated with response to statin therapy in European-descent populations at p = 8x10-6 (PMID:20339536) RegulomeDB: Associated rs201027918 likely to affect TF binding; minimal TF binding evidence for associated rs503105, rs563290, rs577584 SCAN: Index variant and associated rs563290, rs668948, rs201027918, rs541041, rs478588, rs577584, rs614303, rs503105 eQTLs for several genes in CEU cell line |
22.79 | 64.53 | 12.68 | |
| * | rs56197751 (chr2:27835291) |
Insulin, Height | A | Fine-mapping Lipids/Triglycerides | Intronic (RBKS) |
HaploReg: Strong and weak enhancer across multiple cell lines RegulomeDB: minimal TF binding evidence |
||||
| * | rs6760908 (chr2:27855874) |
Insulin, Height | A | Fine-mapping Lipids/Triglycerides | Intronic (RBKS) |
rs6722366 rs140932929 rs116259477 rs138952225 rs147803188 rs114117339 rs142916112 rs116767574 rs6752310 rs111456535 rs144150514 rs141914200 rs145123975 | HaploReg: Index and associated variants strong and weak enhancers across multiple cell lines; associated rs138952225 is a missense variant RegulomeDB: Associated rs142916112 likely to affect TF binding; index variant and associated variants rs140932929, rs138952225, rs114117339, rs116767574, rs111456535, rs141914200, rs116259477, rs147803188 have minimal TF binding evidence |
0.00 | 8.73 | 91.27 |
| rs12622858 (chr2:50130369) |
Hemoglobin, Hematocrit | A | Replication Triglycerides | Intronic (NRXN1) |
rs1452778 rs4971554 rs1452781 rs1452783 rs12477934 rs1961358 rs2011317 rs12474335 rs1377233 rs10490241 rs921573 rs1452768 rs930752 rs72878120 rs72878122 rs72878124 rs4971648 rs12469244 rs17039848 rs4971556 rs57366806 rs9917277 rs17039863 rs6744441 rs896683 rs896684 rs1880075 rs896685 rs1840074 rs11898302 rs11887484 rs12479057 rs1037428 rs72878159 rs12151722 rs12151727 rs11125288 rs11883844 rs12622858 rs12465888 rs12478732 rs17039935 | HaploReg: Index variant NRXN1 eQTL for GTEx testis tissue; associated variants strong enhancers across multiple cell lines RegulomeDB: Minimal TF binding evidence for associated rs17039863, rs1452778, rs72878124, rs4971648, rs896683, rs11898302, rs1452783, rs12477934, rs1377233, rs72878120, rs72878122, rs17039848, rs57366806, rs1880075, rs1037428, rs11125288, rs12478732 SCAN: Index and associated variants rs1452778, rs1452783, rs1961358, rs1377233, rs10490241, rs921573, rs930752, rs4971648, rs896683, rs896684, rs12478732 eQTLs for multiple genes in YRI and CEU cell lines |
37.62 | 62.38 | 0.00 | |
| rs17033788 (chr2:67566015) |
Hormone Use, Hypertension | C | Replication Diastolic Blood Pressure | Intronic (LOC102724373/LOC105374786) |
rs11686555 rs17033787 rs17033788 rs4671187 rs4671188 rs60735969 rs2270342 rs2270344 rs2270346 rs5831889 rs12624204 rs12616261 rs1107595 rs2270348 rs12619942 rs10490721 rs72621572 rs4671189 rs4671808 rs723712 rs4444509 rs11679082 rs150584652 rs2861650 rs2861651 rs149039938 rs148027161 rs143593647 rs2902020 rs11680926 | HaploReg: Index and associated variants rs11686555, rs17033787, rs17033788, rs4671187, rs4671188, rs60735969, rs12619942, rs72621572, rs4671189, rs4671808, rs723712, rs11679082, rs143593647, rs2902020, rs11680926 eQTLs for GTEx testis tissue; index variant strong enhancer across multiple cell lines. RegulomeDB: Index variant and associated rs4671187, rs4671188, rs2270344, rs2270342, rs17033787 have minimal binding TF evidence; associated rs60735969 likely to affect TF binding |
95.74 | 4.26 | 0.00 | |
| * | rs13186242 (chr5:136857921) |
Smoking, Hypertension | A | Replication Fasting Glucose | Intergenic (LOC391834) |
53.59 | 46.41 | 0.00 | ||
| rs4958487 (chr5:151684113) |
Glucose, Hypertension | A | Replication Mean Platelet Volume | Intronic (SPARC) |
HaploReg: Strong promoter and enhancer in several cell lines; eQTL for GTEx tibial artery and skeletal muscle tissues RegulomeDB: minimal TF binding evidence. SCAN: eQTL for several genes in CEU and YRI cell lines |
62.82 | 37.12 | 0.06 | ||
| * | rs9349379 (chr6:12903725) |
Smoking, Diabetes, Hypertension | G | Fine-mapping Myocardial Infarction, Replication Diastolic Blood Pressure, Replication Systolic Blood Pressure | Intronic (PHACTR1) |
HaploReg: Strong enhancer in several cell lines; eQTL for GTEx aorta artery, coronary artery, and tibial artery tissues; associated with coronary heart disease in European and South Asian populations (PMID:21378988; PMID:21846871), in a Lebanese population (PMID:22745674), and in Han Chinese (PMID:22751097); coronary artery calcification in European populations (PMID:22144573); cervical artery dissection in European populations (PMID:25420145); migraine (PMID:23793025) (PMID:22683712), migraine without aura (PMIS:2379025), and clinic-based migraine (PMID:23793025) in European populations; headache in British population (PMID:29397368); alcohol consumption in European-descent populations (PMID:30643258); systolic and diastolic blood pressure in multiple populations (PMID:27618447; PMID:30595370; PMID:30578418); pulse pressure in multiple populations (PMID:27618447; PMID:30578418; PMID:27841878) RegulomeDB: minimal TF binding evidence |
13.30 | 29.44 | 57.26 | |
| rs79239785 (chr6:20602709) |
Alcohol, Hypertension | A | Fine-mapping Type 2 Diabetes | Intronic (CDKAL1) |
rs116186936 rs182046163 | HaploReg: Associated rs116186936 active promoter across multiple cell lines RegulomeDB: Index and associated variants have minimal TF binding evidence |
100.00 | 0.00 | 0.00 | |
| rs1728312 (chr7:23231308) |
Smoking, Alcohol | G | Replication HDL | Intronic (LOC101927890) |
rs75143479 rs199354 | HaploReg: Index variant strong enhancer and promoter in multiple cell lines; Index and associated variants are eQTLs for GTEx whole blood; index variant and associated rs75143479 are eQTLs for GTEx subcutaneous adipose tissues; associated 199354 is a synonymous variant RegulomeDB: Associated rs199354 is less likely to affect TF binding |
36.41 | 62.61 | 0.98 | |
| rs2390859 (chr7:23995928) |
Smoking, Heart arterial surgery | A | Intergenic (STK31/ NPY) |
rs9655243 rs9655244 rs10447618 rs2390859 rs7783960 rs7784349 rs67876243 rs873186 rs1072098 rs10243572 rs10257228 rs70939867 rs6943764 rs6947634 rs7801000 rs2390860 rs7802938 rs202074308 rs7807099 rs112444386 rs4719751 rs4722315 rs6461766 rs6461767 rs4722316 rs4719752 rs4719753 rs6977179 rs12700507 rs7810381 rs7791318 rs7791476 rs199821255 rs11417764 rs12670613 rs12670671 rs7801241 rs7784401 rs7801557 rs6461771 rs6461772 rs7788937 rs7788943 rs6461773 rs6461774 rs6974395 rs6974276 rs6956710 rs6978673 rs6978761 | HaploReg: Index variant promoter in one cell line; associated variants weak and strong enhancers and promoters in multiple cell lines RegulomeDB: Index and associated variants rs10243572, rs10447618, rs199821255, rs200555303, rs202074308, rs4719752, rs4722316, rs6461767, rs6461771, rs6461772, rs6461773, rs67876243, rs6943764, rs6956710, rs6974276, rs6974395, rs6977179, rs6978673, rs6978761, rs7801557, rs7802938, rs7807099, rs9655243, rs9655244 have minimal evidence for TF binding SCAN: Associated variants rs9655243, rs10447618, rs6943764, rs7802938, rs4719752, rs12700507, rs7791476, rs7801241, rs7801557, rs7788937, rs6461774, rs6974395 eQTLs for several genes in YRI cell line |
36.22 | 62.66 | 1.12 | ||
| rs2106922 (chr7:27969614) |
Hemoglobin, Hematocrit | A | Fine-mapping Type 2 Diabetes | Intronic (JAZF1) |
rs17695685 rs34389716 | HaploReg: Index and associated variants enhancers in several cell lines and eQTL in lymphoblastoid EUR cell lines RegulomeDB: Minimal TF binding evidence for associated rs17695685 and rs34389716 SCAN: Index and associated variant rs17695685 eQTLs for several genes in CEU and YRI cell line |
100.00 | 0.00 | 0.00 | |
| rs114374279 (chr7:44532122) |
Alcohol, Smoking | G | Fine-mapping Lipids, LDL | Synonymous (NPC1L1) |
HaploReg: Enhancer for several cell lines RegulomeDB: minimal TF binding evidence |
0.00 | 4.35 | 95.65 | ||
| rs11983880 (chr7:73708374) |
Glucose, Diabetes | A | Fine mapping Lipids/Triglycerides | Intronic (STX1A) |
rs11973069 | HaploReg: Index and associated rs11973069 enhancers for several cell lines RegulomeDB: Index and associated rs11973069 have minimal TF binding evidence |
80.68 | 19.30 | 0.02 | |
| rs10974448 (chr9:4308010) |
Hematocrit, Hemoglobin | A | Fine Mapping Fasting Glucose | Intergenic (GLIS3) |
HaploReg: Enhancer for several cell lines RegulomeDB: minimal TF binding evidence SCAN: eQTL for several genes in YRI cell line |
5.18 | 66.94 | 27.89 | ||
| rs2756916 (chr9:101915669) |
BMI, CRP | C | Intergenic (GRIN3A/ ARL2BPP7) |
rs10448294 rs143133298 rs143437487 rs201788915 rs200346607 rs150008750 rs823919 rs823915 rs146165843 rs2756916 rs2795380 rs823911 rs10739817 rs2995211 rs3012590 rs2995212 rs2995215 rs78207849 rs147999115 rs149109326 rs139794562 rs149531772 rs143226478 rs181646361 rs144087235 rs140683088 | HaploReg: Index variant associated with exon level expression of GRIN3A RegulomeDB: Index and associated variants rs146165843, rs2995212, rs78207849, rs143226478, rs10448294, rs2795380, rs823911, rs10739817, rs147999115, rs149109326, rs139794562, rs140683088 have minimal TF binding evidence SCAN: Associated variants rs823911, rs2995211, rs2995212 eQTLs for several genes in CEU cell line |
99.52 | 0.48 | 0.00 | ||
| rs7923036 (chr10:1433616) |
MI, Smoking | G | Replication BMI | Intronic (ADARB2) |
HaploReg: Promoter and enhancer across multiple cell lines RegulomeDB: Minimal TF binding evidence |
29.50 | 70.50 | 0.00 | ||
| rs787037 (chr10:26504353) |
Smoking, HDL-C | G | Intronic (APBB1IP) |
HaploReg: Promoter and enhancer across multiple cell lines RegulomeDB: Minimal TF binding evidence SCAN: eQTL for multiple genes in YRI cell line |
17.56 | 81.95 | 0.49 | |||
| rs17875327 (chr10:92515052) |
Insulin, Triglycerides | G | Fine-mapping Type 2 Diabetes | Intronic (IDE) |
rs201503938 | HaploReg: Index and associated variant MARK2P9 eQTL in GTEx aorta artery, cerebellum brain, transformed fibroblast cells, muscularis esophagus, lung, skeletal muscle, pancreas, suprapubic skin not sun exposed, lower leg skin sun exposed, thyroid tissues RegulomeDB: Index and associated variant have minimal TF binding evidence |
100.00 | 0.00 | 0.00 | |
| rs942008 (chr10:96397655) |
Hypertension, SBP | G | Replication Fasting Glucose | Intronic (TLL2) |
HaploReg: Promoter and enhancer across several cell lines RegulomeDB: Minimal TF binding evidence |
100.00 | 0.00 | 0.00 | ||
| rs76394293 (chr11:17372388) |
Insulin, Glucose | A | Fine-mapping Type 2 Diabetes | Missense (B7H6) |
rs148825479 rs11024270 rs12269839 rs147111794 | HaploReg: Associated rs11024270, rs12269839, rs147111794 promoter and enhancers across multiple cell lines RegulomeDB: Minimal TF binding evidence for index and associated variants rs11024270, rs12269839, rs147111794 |
0.00 | 44.61 | 55.39 | |
| rs1939120 (chr11:64537243) |
Smoking, Hematocrit | A | Replication HDL | Intergenic (ARL2BPP7/ SLC22A11) |
HaloReg: Promoter and enhancer across multiple cell lines RegulomeDB: Likely to affect TF binding and linked to expression of a gene target SCAN: eQTL for multiple genes in YRI cell line |
19.37 | 80.59 | 0.05 | ||
| rs17376366 (chr12:20339790) |
Stroke, Creatinine | G | Replication Diastolic Blood Pressure | Intergenic (LOC100506393/ PDE3A) |
rs71463092 | HaploReg: Index variant PDE3A eQTL in GTEx skeletal muscle | 99.51 | 0.48 | 0.02 | |
| rs115487129 (chr12:89395852) |
Smoking, Alcohol | C | Fine Mapping Systolic Blood Pressure | Intergenic (DUSP6/ POC1B) |
HaploReg: Enhancer and promoter in multiple cell lines RegulomeDB: Minimal TF binding evidence |
2.90 | 20.14 | 76.96 | ||
| * | rs7139221 (chr12:110853890) |
Insulin, Smoking | A | Fine-mapping Myocardial Infarction | Intronic (CCDC63) |
rs61944267 rs112189206 rs113945414 | HaploReg: Index variant is ARPC3, TCTN1, VPS29 eQTL for BRCA tissue RegulomeDB: Index and associated variant rs113945414 likely to affect TF binding; minimal TF binding evidence for associated rs61944267 and rs112189206 SCAN: Index variant eQTL in two genes in YRI cell line |
0.00 | 9.98 | 90.02 |
| rs10774711 (chr12:113697994) |
SBP, MI | A | Replication QT Interval | Intergenic (LOC100506452/ LOC100506465) |
rs28723444 rs28519077 rs28578425 rs12297352 rs4767114 rs4767115 rs4767116 rs7978617 rs2384312 rs2384313 | HaploReg: Index and associated variants have strong to weak enhancer evidence RegulomeDB: Index and associated variants rs28723444, rs28519077, rs28578425, rs4767114, rs4767115, rs4767116, rs7978617, rs2384312, rs2384313) have minimal evidence of TF binding |
17.01 | 47.60 | 35.39 | |
| rs60136502 (chr15:90965307) |
Insulin, Total Cholesterol | C | Fine-mapping Type 2 Diabetes | Intergenic (RCCD1/PRC1) |
HaploReg: Weak enhancer RegulomeDB: minimal TF binding evidence |
2.39 | 61.58 | 36.03 | ||
| rs11865790 (chr16:47399623) |
Alcohol, CRP | G | Replication Fasting Glucose | Intronic (ITFG1) |
rs13335171 rs7197586 rs113161991 rs7202716 rs73543108 rs73543111 rs16945353 rs11860257 |
HaploReg: Index and associated variants weak enhancers; Associated rs7202716 and rs11860257 eQTLs of Hs.42217 in YRI cell lines RegulomeDB: Index and associated variants rs13335171, rs113161991, rs73543108, rs73543111 minimal TF binding evidence SCAN: Index and associated variants rs7202716, rs16945353, rs11860257 eQTLs for one to two genes in YRI cell line |
96.58 | 3.42 | 0.00 | |
| rs8058543 (chr16:53096347) |
Heart Arterial Surgery, MI | A | Replication Two Hour Glucose Challenge | Intronic (CHD9) |
HaploReg: Weak to strong enhancer RegulomeDB: Minimal TF binding evidence SCAN: eQTL for genes in CEU cell line |
34.84 | 43.71 | 21.46 | ||
| * | rs2926143 (chr16:64224173) |
Hypertension, Smoking | G | Replication Diastolic Blood Pressure | Intergenic (RPS15AP34/ LOC729217) |
rs1016891 rs889424 | HaploReg: Associated rs889424 weak enhancer Regulome DB: Index and associated variants have minimal TF binding evidence |
62.47 | 37.31 | 0.22 |
| rs4260044 (chr16:85238638) |
BMI, CRP | A | Replication HDL, Replication Triglycerides | Intergenic (LOC100506467/ LINC00311) |
HaploReg: Evidence of weak and strong enhancer across different cell lines. RegulomeDB: Minimal TF binding evidence SCAN: eQTL for two genes in YRI cell line |
30.88 | 69.09 | 0.03 | ||
| * | rs4334353 (chr17:55374378) |
Smoking, MI | A | Replication HDL | Intergenic (HLF) |
rs9911896 rs11079163 rs11079164 rs28619477 | HaploReg: Index and associated rs9911896, rs11079163, rs11079164 weak enhancers RegulomeDB: Minimal TF binding evidence for associated variants SCAN: Index and associated rs9911896, rs11079163, rs11079164 eQTLs for several genes in YRI cell line |
90.23 | 9.69 | 0.08 |
Abbreviations: body mass index (BMI), C-reactive protein (CRP), coded allele (CA), direction of effect (DE), high density lipoprotein cholesterol (HDL-C), expression quantitative trait locus (eQTL), linkage disequilibrium (LD), low density lipoprotein cholesterol (LDL-C), myocardial infarction (MI), systolic blood pressure (SBP), transcription factor (TF)