Interethnic analyses of blood pressure loci in populations of East Asian and European descent

ARTICLE In e e hnic analyses o blood p essu e loci in popula ions o Eas Asian and Eu opean descen Fumihiko Takeuchi1,2, Masa o Akiyama3, Nana Ma oba3, Tomohi o Ka suya4,5, Masahi o Naka ochi6, Yasuha u Taba a e al. # Blood p essu e (BP) is a majo isk ac o o ca dio ascula disease and mo e han 200 gene ic loci associa ed wi h BP a e known. He e, we pe o m a mul i-s age genome-wide associa ion s udy o BP (max N=289,038) p incipally in Eas Asians and me a-analysis in Eas Asians and Eu opeans. We epo 19 new gene ic loci and ances y-specific BP a ian s, con o ming o a common ances y-specific a ian associa ion model. A 10 unique loci, dis inc non- a e ances y-specific a ian s colocalize wi hin he same linkage disequilib ium block despi e he significan ly disco dan e ec s o he p oxy sha ed a ian s be ween he e hnic g oups. The genome-wide anse hnic co ela ion o causal- a ian e ec -sizes is 0.898 and 0.851 o sys olic and dias olic BP, espec i ely. Some o he ances y-specific associa ion signals a e also influenced by a selec i e sweep. Ou esul s p o ide new e i- dence o he ole o common ances y-specific a ian s and na u al selec ion in e hnic di e ences in complex ai s such as BP. Fumihiko Takeuchi, Masa o Akiyama, Nana Ma oba, Tomohi o Ka suya, Masahi o Naka ochi, Yasuha u Taba a e al. # DOI: 10.1038/s41467-018-07345-0 OPEN Co espondence and eques s o ma e ials should be add essed o N.K. (email: [email p o ec ed]). # A ull lis o au ho s and hei a filia ions appea s a he end o he pape . NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.com/na u ecommunica ions 1 1234567890():,; High blood p essu e is a majo isk ac o o ca dio ascula diso de s such as co ona y hea disease and s oke. App oxima ely 10 million dea hs each yea can be a ibu ed o high blood p essu e globally1,2. An indi idual’s isk o high blood p essu e is de e mined by gene ic, en i onmen al and demog aphic ac o s and hei in e ac ion. Genome-wide associa ion s udies (GWASs) and/o la ge-scale analyses by gene- cen ic (o exome) a ia ion a ays ha e iden ified o e 200 gene ic loci influencing blood p essu e in p edominan ly Eu opean-descen popula ions (hence o h e e ed o as Eu - opeans)3–8. The p e alence o high blood p essu e is inc eased in people o Eas Asian ances y, con ibu ing o hei inc eased isk o s oke9. The easons o such e hnic di e ences emain o be cla ified om he iewpoin o gene ic suscep ibili y as well as li es yle. Al hough he ecen p og ession o GWAS in Eas Asians allows us o make a p elimina y compa ison o associa ion signals be ween he popula ions10,11, he sample sizes o GWAS in Eas Asians ha e been gene ally much smalle han hose in Eu opeans and unde -powe ed o he comp ehensi e in e e hnic compa ison a a genome-wide scale. The e o e, la ge-scale gen- ome-wide associa ion da a in bo h e hnic g oups a e equi ed o sys ema ic, genome-wide in e e hnic compa ison. He e, we pe o m a mul i-s age GWAS wi h a disco e y sample o 130,777 Eas Asian indi iduals and ollow-up me a-analyses in ol ing Eas Asians and Eu opeans (max N=289,038), o seek bo h anse hnic and ances y-specific gene ic e ec s o fi e blood p essu e pheno ypes: sys olic blood p essu e (SBP), dia- s olic blood p essu e (DBP), pulse p essu e (PP), mean a e ial p essu e (MAP), and hype ension. We hen seek in e e hnic gene ic he e ogenei y o GWAS esul s be ween Eas Asians and Eu opeans, ollowed by examina ion o na u al selec ion as a po en ial mechanism unde lying he e hnic di e ences in gene ic suscep ibili y o blood p essu e as well as o he complex ai s. We epo ances y-specific blood p essu e a ian s and selec ion signals in his s udy. Resul s Genome-wide associa ion analysis and lookup o eplica ion. Adop ing a join analysis s a egy12, we pe o med a GWAS, which consis ed o s age 1 (disco e y) and s age 2 ( ollow-up), and a eplica ion s udy (Supplemen a y Fig. 1). In s age 1 o GWAS, we used genome-wide associa ion da a om 130,777 indi iduals o Japanese ances y. Cha ac e is ics o pa icipan s, geno yping a ays, and impu a ion a e summa ized in Supple- men a y Tables 1, 2. Genomic con ol and in e cep s om linkage disequilib ium (LD) sco e eg ession13 we e calcula ed a each s udy le el (λ GC =0.89–1.24 and LD Sco e eg ession in e cep = 0.94–1.06), indica ing no esidual con ounding biases such as popula ion s a ifica ion (Supplemen a y Table 2). Since he LD Sco e eg ession in e cep can accoun o polygenic e ec s and infla ion due o la ge sample size13, we applied he LD Sco e eg ession in e cep as a co ec ion ac o o coho s wi h a sample size o >3000 indi iduals (BBJ in his s udy). Genomic con ol λ GC was used as a co ec ion ac o in he o he s udies. Quan ile−quan ile plo s o each o he fi e blood p essu e ai s a e p esen ed in Supplemen a y Fig. 2. Pheno ype-specific me a- analysis was ca ied ou in he wo-s age app oach o bo h he Eas Asian-specific and anse hnic me a-analyses (Supplemen- a y Figs. 1, 3). Genome-wide associa ion esul s in he s age-1 iden ified 13,003 SNPs wi h a P alue < 1.6×10–5agains any blood p essu e pheno ype in Eas Asians. This se o 13,003 SNPs (sen inel SNPs lis ed in Supplemen a y Da a 1) was ollowed up in 53,008 Eas Asian indi iduals (s age 2). Addi ionally, hese 13,003 SNPs we e examined in he anse hnic s age wi h pheno ype-specific esul s o Eu opeans (max N=105,253) om he In e na ional Conso ium on Blood P essu e (ICBP) GWAS (N=69,909)3and he In e na ional Genomics o Blood P essu e (iGEN-BP) Conso ium (N=35,344)10; he e was no o e lap in samples be ween he wo da a se s. Sen inel SNPs (smalles P alue agains any blood p essu e pheno ype) ha (i) eached P< 5×10–8in combined me a-analysis o s ages 1 and 2 and (ii) showed e idence o suppo (P< 0.05) in he s age 2 me a- analysis alone a e epo ed as no el loci in his s udy. We iden- ified 19 p e iously un epo ed loci; 15 loci in Eas Asian-specific analyses and 4 addi ional loci in he anse hnic me a-analysis (Table 1and Supplemen a y Da a 2). By lookup in an indepen- den eplica ion sample o Eu opeans om he UK Biobank (N= 422,771)14 plus Eas Asians om he China Kadoo ie Biobank (N =94,201)15, we examined associa ions a ou lis o 19 sen inel SNPs. Wi h he excep ion o ou SNPs, 15 sen inel SNPs showed significan (P< 0.00263 =0.05/19) blood p essu e associa ion wi h he conco dan di ec ion o allelic e ec s (Supplemen a y Da a 2), hus alida ing he loci. Regional associa ion plo s a e shown o he 19 newly iden ified loci in Supplemen a y Fig. 4. Associa ions o he 19 sen inel SNPs wi h o he blood p essu e pheno ypes a e demons a ed in Supplemen a y Da a 3. In he disco e y s age, we also eplica ed blood p essu e associa ions a p e iously epo ed loci, which included 36 loci a genome-wide significance and u he 179 loci a nominal significance (P< 0.05) (Supplemen a y Da a 4). Func ional anno a ions o new loci. To iden i y candida e genes a he newly iden ified blood p essu e loci, we examined whe he any o he associa ion signals (sen inel blood p essu e SNP and SNPs in Eas Asian LD 2> 0.80) we e coding o associa ed wi h gene exp ession and o he ai s. A h ee loci, he sen inel SNPs we e nonsynonymous, and 4 o 19 no el loci con ained SNPs (in LD o 2> 0.80 wi h he op eVa ian ) associa ed wi h exp ession quan i a i e ai loci (eQTLs) in a leas one issue in he Geno ype-Tissue Exp ession (GTEx) da abase (Supplemen a y Tables 3–5). A wo candida e gene loci, p oxy SNPs ( s760077 a MTX1 and s3825942 a LOXL1) we e nonsynonymous and associa ed wi h eQTLs. Fu he mo e, se en sen inel SNPs and/o hei p oxy SNPs ( 2≥0.95) we e p e iously epo ed o be sig- nifican ly associa ed wi h non-blood p essu e ai s (Supple- men a y Da a 5), including a sen inel SNP ( s11642015) a he FTO locus on 16q22, whose p oxies ( 2=0.97–0.99) ha e been epo ed o associa e wi h body mass index and ype 2 diabe es16. In ou s udy, s11642015 was significan ly associa ed wi h SBP, MAP, and PP (P=1.9×10–12–1.3×10–9) wi h consis en ep o- ducibili y in bo h s ages o Eas Asian analyses (Supplemen a y Da a 1, 3). In addi ion, s11642015 was ecen ly iden ified o be significan ly associa ed wi h SBP in mul i-ances y GWAS me a- analysis inco po a ing gene−smoking in e ac ion17. In e e hnic he e ogenei y o GWAS esul s. In he p esen s udy, he a ailabili y o genome-wide associa ion da a om >100,000 indi iduals o bo h Eas Asians and Eu opeans sepa- a ely mo i a ed us o pe o m addi ional analyses o sys ema ic, genome-wide in e e hnic compa ison. We used anse hnic associa ion summa y s a is ics a ailable o bo h Eas Asian (N= 158,645 om s age 1 and iGEN-BP) and Eu opean (max N= 105,253 om ICBP and iGEN-BP) GWAS esul s in he sub- sequen analysis o in e e hnic he e ogenei y. We defined in e - e hnic he e ogenei y as he e ogenei y o gene ic (o allelic) impac on SBP be ween he e hnic g oups. Using GWAS da a se s, we compa ed he gene ic impac a anse hnic SNPs and de ec ed a o al o eigh in e e hnic he e ogenei y loci— wo significan (P< 5×10–8) and six sugges i e (5×10–8≤P< 1×10–6) loci (Fig. 1a and Supplemen a y Da a 6). In his s udy we dis inguished he allelic ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 2NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions impac om allelic e ec -sizes as p e iously defined by B own e al.18; allelic impac is he geno ype−pheno ype co ela ion coe ficien , which is app oxima ely a p oduc o allelic e ec and mino allele equency (MAF). Se en o he eigh loci wi h in e e hnic he e ogenei y we e anno a ed o he p e iously epo ed blood p essu e loci; sen inel blood p essu e SNPs a hal o hem (i.e., ou loci nea he CACNB2,C10o 107,SH2B3 and DPEP1 genes3,5) we e ound o be in LD ( 2≥0.2) wi h he SNPs showing some e idence o in e e hnic he e ogenei y. The wo loci wi h significan in e e hnic he e ogenei y we e on 12q24 and 10q21 and bo h con ained mul iple associa ion signals (Fig. 1b). Fo he egion on 12q24 spanning 1.5 Mb, wo independen associa ion signals, each specific o Eu opeans (nea s3184504 a SH2B3) and Eas Asians (nea s671 a ALDH2), had been iden ified19. We ound ha bo h o he signals we e esponsible o he disco dan di ec ion o allelic e ec s on 12q24 (Fig. 1c and Supplemen a y Fig. 5a, b). Simila ly, we obse ed wo indepen- den associa ion signals nea he C10o 107 ansc ip on 10q21.2 (Fig. 1c and Supplemen a y Fig. 5c, d). The de i ed alleles o ances y-specific sen inel SNPs on 10q21 ( s4590817 and s145193831 specific o Eu opeans3and Eas Asians espec i ely) a ose om a haplo ype sha ed be ween e hnic g oups, con aining mul iple anse hnic SNPs. The disco dan di ec ion o e ec s o he sha ed haplo ypes could be explained by al e na ion o e ec s a ibu able o he de i ed alleles o s4590817 (dec easing in Eu opeans) and s145193831 (inc easing in Eas Asians) (Supplemen a y Fig. 6 and Supplemen a y Da a 7). Ances y-specific SNP loci. A o al o 750 p e iously epo ed SNPs (lis ed in Supplemen a y Da a 4) plus 19 newly iden ified SNPs could be classified in o 485 loci by ega ding wo SNPs a mos 500 kb apa o belong o he same locus. A e exclusion o 39 loci (MAF < 0.01 in bo h Eas Asians and Eu opeans, o no da a a ailable in GWAS da a se s o bo h popula ions), 446 loci we e e ained and ca ego ized in o wo g oups—g oup 1 and g oup 2. G oup 1 consis ed o 382 loci wi h MAF ≥0.01 in bo h popula ions and g oup 2 consis ed o 64 loci wi h po en ial e hnic specifici y, i.e., MAF < 0.01 in ei he Eas Asians o Eu opeans. G oup 2 was u he classified in o g oup 2a (46 loci wi h MAF < 0.01 in one popula ion and MAF ≥0.05 in he o he ) and g oup 2b (18 loci wi h MAF < 0.01 in one popula ion and 0.01 ≤MAF < 0.05 in he o he ) (Supplemen a y Fig. 7). Wi h ega ds o in e e hnic he e ogenei y o associa ion signals, we assumed wo dis inc scena ios: whe he he unde - lying causal a ian s a e sha ed be ween he e hnic g oups o no . Howe e , due o subs an ial in e e hnic di e ences in LD s uc u e, i is no always easible o dis inguish be ween he wo. Fi s , as an example o he po en ial nonsha ed causal a ian (o ances y specifici y), we examined in e e hnic compa abili y o gene ic impac on blood p essu e a 48 loci (46 loci in g oup 2a plus 2 a ge loci wi h po en ial ances y specifici y—C10o 107 and CACNB2—included in g oup 1; Supplemen a y Fig. 7), whe e sen inel common (MAF ≥0.05) blood p essu e SNPs o iginally epo ed in a gi en e hnic g oup we e monomo phic o MAF < 0.01 in he second e hnic g oup3–8,19. Then, we in es iga ed in e e hnic he e ogenei y a non- a e (MAF ≥0.01 in bo h e hnic g oups) blood p essu e loci (g oup 1 in Supplemen a y Fig. 7) ha migh be sha ed be ween he e hnic g oups as desc ibed la e . Conside ing he obse a ions on 12q24 and 10q21, we explo ed common p oxy SNPs o ming a haplo ype sha ed be ween e hnic g oups a he locus (deno ed as haplo-SNPs), o which he mos significan in e e hnic he e ogenei y o gene ic impac was de ec ed (Supplemen a y Fig. 8a–c). A a o al o 11 loci (o 10 unique loci when he ALDH2 and SH2B3 loci on 12q24 we e combined) (Supplemen a y Figs. 6, 9 and Supplemen a y Da a 7), haplo-SNPs showed significan (P< 1.5×10–4unde egion-wise co ec ion) he e ogenei y be ween wo e hnic g oups. A 8 o 11 loci, we ound ha dis inc common ances y-specific a ian s colocalized wi hin he same LD block and ha he di ec ion o e ec s o he p oxy sha ed SNPs was disco dan be ween he e hnic g oups, simila o 12q24 and 10q21. On 5q14, o ins ance, a genome-wide significan associa ion o s112862634 wi h SBP, DBP, and MAP was de ec ed in Eas Asians o his s udy (Supplemen a y Da a 1), while SBP associa ion o s10059921 was p e iously epo ed in i s icini y (456 kb apa om Table 1 Gene ic loci newly iden ified o be associa ed wi h blood p essu e Sen inel SNP Ch Posi ion EA/NEA EAF T ai NE ec P Genome-wide significan and eplica ed s2990220 1 155,190,254 A/T 0.83 MAP 183,654a−0.41 (0.06) 2.2×10−12 s6772151 3 46,896,499 A/C 0.29 DBP 156,503a0.28 (0.05) 7.8×10−9 s17622152 3 183,520,112 A/G 0.47 MAP 183,759a−0.25 (0.04) 2.0×10−8 s12209106 6 1,621,042 T/G 0.68 DBP 160,436a0.28 (0.05) 6.4×10−9 s78399431 7 1,141,470 A/G 0.24 MAP 179,411a0.30 (0.05) 9.6×10−9 s2125067 10 48,434,420 C/G 0.12 SBP 179,003a0.60 (0.10) 4.8×10−9 s2305013 11 120,340,060 A/T 0.85 SBP 180,894a−0.59 (0.09) 5.6×10−10 s5006548 12 32,692,233 T/G 0.16 HT 71,847a0.09 (0.02) 2.2×10−8 s1535464 14 100,793,431 A/G 0.10 SBP 183,690a−0.61 (0.10) 3.5×10−9 s66978877 19 18,455,657 T/C 0.55 HT 68,850a0.07 (0.01) 4.5×10−9 s6021247 20 50,108,980 A/G 0.58 SBP 183,785a0.37 (0.06) 5.0×10−9 s3853476 5 141,817,754 A/G 0.58 MAP 244,831b−0.20 (0.03) 6.0×10−9 s10821808 10 62,390,646 A/G 0.58 SBP 288,917b−0.29 (0.05) 3.4×10−9 s4418728 10 94,839,724 T/G 0.62 DBP 256,118b−0.20 (0.03) 1.5×10−8 s1078967 15 74,222,987 T/C 0.15 SBP 265,280b0.42 (0.07) 5.6×10−9 Genome-wide significan bu no eplica ed s2076460 1 27,972,058 C/G 0.30 SBP 174,846a−0.42 (0.07) 3.6×10−9 s11642015 16 53,802,494 T/C 0.21 SBP 174,917a0.58 (0.08) 1.9×10−12 s9303509 17 64,530,887 A/C 0.40 SBP 183,769a0.37 (0.06) 3.9×10−9 s66658258 20 61,462,502 C/G 0.58 DBP 164,638a0.28 (0.05) 1.0×10−8 Posi ion is Build 37; EA: e ec allele; NEA: non-e ec allele; EAF: e ec allele equency; N: sample size (aEas Asians only; bwi h Eu opean ollow-up samples); E ec : as uni change in blood p essu e (SE) pe e ec allele copy (SBP, DBP, PP, MAP) o as log odds a io pe e ec allele (HT) NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 ARTICLE NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions 3 a –log10(P) 0.00 0.01 0.02 0.03 Gene ic impac in EUR 0.00 0.01 0.02 0.03 Gene ic impac in EUR 0.1 0.2 0.3 0.4 0.5 0.6 2 o 2 o s4590817 10q21 EUR s4590817 0.1 0.2 0.3 s3184504 12q24 EUR s3184504 b Gene ic impac in EAS 2 o 0.2 0.4 0.6 s145193831 s145193831 Posi ion on Ch 10 (Mb) 63.4 63.5 63.6 EAS –0.02 0.00 0.02 Gene ic impac in EAS Posi ion on Ch 12 (Mb) 2 o s671 s671 112.0 112.5 113.0 EAS –0.02 0.00 0.02 0.2 0.3 0.1 12q24 c H3 H4 H1 H2 H9 H6 H7 H8 H3 H4 H1 H2 H9 H6 H8H5 Ances al haplo ype Ances al haplo ype s3184504_T EAS EUR s671_A (ALDH2) H3 H2 H6 H7 H5 H4 H3 H2 H6 H8 H7 H4 Ances al haplo ype Ances al haplo ype s4590817_C s145193831_T EAS EUR 10q21 (SH2B3) 20 15 10 5 0 123456789 Ch omosome 11 13 15 18 22 Fig. 1 In e e hnic he e ogenei y o gene ic impac o SBP. aManha an plo showing esul s o genome-wide scan o gene ic impac he e ogenei y. The gene ic impac a anse hnic SNPs we e compa ed be ween wo popula ions o di e en ances ies using GWAS da a se s. bRegional plo s on 12q24 and 10q21, whe e he e we e mul iple SNPs wi h significan (P< 5×10–8) e idence o in e e hnic he e ogenei y (see Supplemen a y Da a 6). Bo de ed ci cles ep esen SNPs wi h significan in e e hnic he e ogenei y. T anse hnic SNPs we e plo ed in wo panels a each locus; gene ic impac s o each SNP a e deno ed sepa a ely o Eu opeans (EUR, op panel) and Eas Asians (EAS, bo om panel) on 12q24 (le ) and 10q21 ( igh ) such ha gene ic impac s in Eu opeans a e posi i e. In he indi idual egional plo s, he co ela ion o ances y-specific sen inel SNP o o he SNPs a he locus is shown on a scale om minimal (blue) o maximal ( ed); he sen inel SNPs hus benchma ked a e s3184504 (EUR specific) and s671 (EAS specific) on 12q24 and s4590817 (EUR specific) and s145193831 (EAS specific) on 10q21. The posi ion o ances y-specific sen inel SNP is indica ed by an a ow head. cPhylogene ic ela ionships o ances y-specific sen inel SNPs wi h anse hnic haplo ypes de ec able in Eu opeans ( op) and Eas Asians (bo om) on 12q24 (le ) and 10q21 ( igh ). Each node co esponds o a haplo ype and he SNPs appea on he edges. The edge wid h eflec s he haplo ype equency in he co esponding e hnic g oups. A each locus, blood p essu e inc easing and dec easing haplo ypes and de i ed, ances y-specific alleles a e colo ed in ed and blue, espec i ely ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 4NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions s112862634) in Eu opeans8. I u ned ou ha s112862634 was in s ong LD (Eas Asian LD 2=0.95) wi h a haplo-SNP ( s6882046) a his locus and dis inc common ances y-specific a ian s wi h mu ually in e ed gene ic e ec s—Eu opean- specific s10059921 (MAF =0.09 in EUR) and Eas Asian- specific s78245349 (MAF =0.46 in EAS)—did colocalize in his egion (Supplemen a y Fig. 8a and Supplemen a y Da a 7). A he emaining 3 (o 11) loci, al e na e a e ances y-specific SNPs we e likely o exis in he second e hnic g oup, al hough hey we e no de ec able in ou sea ch o public da abases. We designa ed hese as a common ances y-specific a ian associa ion model as discussed below. We hypo hesized ha he e we e h ee majo combina ions o Eas Asian-/Eu opean-specific SNPs and hei esul an di ec ion o e ec s o haplo-SNPs o ming a sha ed haplo ype a he locus, as schema ically shown in Supplemen a y Fig. 6b. In acco dance wi h his no ion, we de ec ed h ee ypes in his s udy (Supplemen a y Fig. 9), among which he fi s and majo ype (32 o 48 loci in g oup 2a) consis ed o he cases wi h mu ually in e ed gene ic e ec s as explained abo e. The second ype consis ed o hose wi h dis inc ances y-specific a ian s showing conco dan di ec ions o e ec such as he FGR locus (Supple- men a y Figs. 8b, 9). The hi d ype consis ed o hose wi h dis inc ances y-specific a ian s showing disco dan gene ic e ec s, one o which appea ed o be almos neu al such as he GNAS/EDN3 locus (Supplemen a y Fig. 8c). Howe e , wi hou using la ge sample sizes, i appea ed o be di ficul o show s a is ically significan in e e hnic he e ogenei y in pa icula , o hose in he second o hi d ype. A one locus (nea HSD17B1 on 17q21), a haplo-SNP could no be selec ed (Supplemen a y Fig. 8d and Supplemen a y Da a 7), p esumably because o he ances y-specific LD s uc u e and he modes s eng h o associa ion in he index e hnic g oup (Eu opeans a he locus) o his s udy. Fo loci wi h po en ial ances y specifici y (i.e., MAF < 0.01 in one popula ion and 0.01 ≤MAF < 0.05 in he o he ; 18 loci classified as g oup 2b in Supplemen a y Fig. 7), we did no in es iga e in e e hnic he e ogenei y o associa ion signals because o di ficul ies in he ele an es o a e (MAF < 0.01) and low- equency (0.01 ≤MAF < 0.05) gene ic a ian s by using impu ed GWAS esul s20. He e ogenei y a a ian s polymo phic in bo h ances ies.In addi ion o he ances y-specific loci, we in es iga ed in e e hnic he e ogenei y a non- a e (MAF ≥0.01 in bo h e hnic g oups) blood p essu e loci ha migh be sha ed be ween he e hnic g oups; 382 es ed loci we e ei he p e iously epo ed o newly iden ified in he p esen s udy (deno ed as g oup 1 in Supple- men a y Fig. 7a). Since ICBP and iGEN-BP (Eu opean) da a we e impu ed wi h HapMap SNPs, app oxima ely one- hi d o g oup-1 SNPs we e una ailable in ou Eu opean GWAS da a se s. Thus, 242 (ou o 382) loci in g oup 1 we e subjec ed o in e e hnic compa ison o gene ic impac on a lead blood p essu e ai (Supplemen a y Da a 8). Al hough majo i y o hem appea ed o show conco dan e ec s (co ela ion coe ficien =0.754), nine sen inel SNPs (3.7%) showed significan (P he e o < 2.1×10–4) in e e hnic he e ogenei y (Supplemen a y Fig. 10). Gene ic impac s we e mo e p ominen in Eu opeans han in Eas Asians a eigh o nine loci apa om s1451538 in SLC28A1, a which gene ic impac s we e p ominen in Eas Asians bu no in Eu - opeans (Supplemen a y Da a 8). The e we e no p oxy SNPs nea each o he eigh loci in he same LD block (Supplemen a y Fig. 11), which could ha e shown s onge associa ion signals in Eas Asians han he sen inel SNPs o iginally epo ed in Eu - opeans due o po en ial in e e hnic di e ences in LD s uc u e, i any. O no e is he finding on 10q23 nea PLCE1, he e was ano he SBP associa ion signal a s7080472 in Eas Asians (P= 3.9×10–8in he combined samples; Supplemen a y Da a 1) despi e he absence o p ominen associa ion a s932764, whose associa ion was p e iously epo ed4and p ominen in Eu opeans (Supplemen a y Fig. 11). s7080472 was loca ed in he LD block nex o he one o s932764 (Eas Asian LD 2=0.003 be ween s7080472 and s932764). On 10q21 nea C10o 107, a DBP associa ion signal was p e iously epo ed a s153044021, which we ound o be in LD (Eu opean LD 2=0.48) wi h an ances y- specific SNP a he locus, s4590817, a o emen ioned (Supple- men a y Da a 7). Also, on 10p12 nea CACNB2, a DBP associa- ion signal was p e iously epo ed a s18133533, which we ound o be in LD (Eu opean LD 2=0.56) wi h an ances y- specific SNP a he locus, s12258967. These indica ed ha in e e hnic he e ogenei ies iden ified o non- a e anse hnic a ian s on 10q21 and 10p12 we e he cases o which common ances y-specific a ian s we e ac ually esponsible. By calib a ing he p opo ion in he g oup-1 subse , in which blood p essu e GWAS esul s o in e e hnic compa ison we e a ailable o 242 (o 382) loci, we es ima ed he p opo ion o loci showing significan in e e hnic he e ogenei y wi hin he o al blood p essu e loci es ed (N=446). The es ima ed p opo ion was 2.5% each in g oup 1 and g oup 2a, whe e he C10o 107 and CACNB2 loci we e coun ed in g oup 2a (Supplemen a y Fig. 7b). Gene ic co ela ion and powe o GWAS. As an app oach o quan i a i ely e alua ing he in e e hnic di e ences in blood p essu e GWAS esul s, we es ima ed he gene ic co ela ion using summa y s a is ics o he en i e spec um o GWAS asso- cia ions18.Wefi s es ima ed he SNP-based he i abili y (h2)o SBP and DBP (Fig. 2). Fo SBP, h2es ima es in ou s udy we e 0.107 (SE 0.007) o Eas Asians and 0.086 (SE 0.009) o Eu - opeans and lowe han a p e iously epo ed UK Biobank es i- ma e o 0.156 (SE 0.004)22 calcula ed by he momen -ma ching me hod in Eu opeans. This disc epancy was likely due o he me hodological di e ences in SNP-based he i abili y analyses be ween he s udies bu does no appea o a ec gene ic- co ela ion es ima es hemsel es23. Also, he h2o DBP was almos compa able be ween he e hnic g oups in his s udy. Then, we ound ha he gene ic co ela ions in SBP and DBP we e 0.898 (SE 0.040) and 0.851 (SE 0.046) espec i ely, and significan ly di e en om 1 (P=0.005 o SBP and P=0.0007 o DBP). This indica ed ha he allele-subs i u ion e ec -sizes di e ed significan ly be ween he wo e hnic g oups despi e he epo edly subs an ial gene ic o e lap in blood p essu e ai s (Supplemen- a y Da a 4). To es ima e he deg ee o in e e hnic o e lap and nono e lap o blood p essu e loci, we u he calcula ed he powe o GWAS o di e en sample sizes (i.e., 100K, 200K, and 500K) based on he i abili y pa ame e s (see de ails in Supplemen a y Me hods) ia modeling, compu ing and andom sampling (Fig. 3and Supplemen a y Figs. 12, 13). Simila o Eu opeans, he ecen p og esses o GWAS in Eas Asians p omp ed us o in es iga e di e en sample sizes in p epa a ion o much-la ge anse hnic me a-analysis. When GWASs o he same size we e ca ied ou o SBP and DBP, i was expec ed ha an almos equi alen numbe o genome-wide significan loci could be iden ified in bo h Eas Asians and Eu opeans bu he numbe o o e lap was less han hal . We ex ended he in e e hnic analyses o o he complex ai s such as plasma lipid le el, an h opome ic measu emen , and ype 2 diabe es using published GWAS summa y s a is ics o ela i ely la ge numbe o samples (Supplemen a y Table 6). Al hough gene ic co ela ion appea ed o be a ied among he NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 ARTICLE NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions 5 complex ai s examined (Fig. 2), we ound ha he p opo ion o nono e lap [(nono e lap) / (o e lap +nono e lap)] was ela- i ely consis en ac oss he ai s o he same sample size; 0.71–0.82 o 100K, 0.65–0.78 o 200K and 0.46–0.70 o 500K (Fig. 3and Supplemen a y Fig. 12). As he sample sizes in bo h e hnic g oups become la ge , we can expec a highe p opo ion o in e e hnic o e lap; ne e heless, mo e han o nea ly hal o he genome-wide significan loci may no o e lap be ween he e hnic g oups o GWAS o he same sample size. Selec i e sweeps a ances y-specific loci. Subsequen ly, we c e- a ed a lis o ances y-specific loci o SBP, DBP and o he complex ai s in which an SNP- ai associa ion was genome- wide significan in one e hnic g oup (e.g., Eas Asians) bu no significan associa ion signal was de ec able in ano he (e.g., Eu opeans) due o low allele equency (MAF < 0.05) (Supple- men a y Da a 9). Fo he loci wi h he same SNPs being mono- mo phic in he second e hnic g oup, ou selec ion c i e ia o ances y-specific loci could be ega ded s ingen in ha he absence o locus-wide significan associa ion signals in he icini y (≤500 kb) o he es ed SNPs was equi ed. A la ge numbe o significan loci had been epo ed in Eu opeans compa ed o Eas Asians, eflec ing he di e ences in sample size o GWAS conduc ed o da e (mean o fi e ai s was 81,991 in Eas Asians s. 202,390 in Eu opeans) (Fig. 4and Supplemen a y Fig. 14). Thus, he o al numbe o ances y- specific loci ac oss he examined ai s was smalle in Eas Asians (10 loci) han in Eu opeans (63 loci). While i was mos p ominen o heigh , he sen inel SNPs a he ances y-specific loci ended o ha e bo h lowe MAF (0.20 ± 0.04 in Eas Asians, 0.16 ± 0.01 in Eu opeans) and gene ic impac (0.020 ± 0.002 in Eas Asians, 0.014 ± 0.0004 in Eu opeans) ac oss he ai s. Among a lis o ances y-specific loci o mul iple ai s, we iden ified e idence o a posi i e selec ion a fi e unique loci using a highly sensi i e algo i hm, haploPS24 (Fig. 5and Supplemen a y Da a 9). Fo blood p essu e, a sen inel SNP s56174355 on 17q23 p e iously epo ed o be associa ed wi h DBP only in Eu opeans8 was localized o a egion wi h e idence o posi i e selec ion in Eas Asians (Fig. 5d). In his egion, we obse ed he long haplo ypes a high equencies (i.e., 70–80%) o be selec ed exclusi ely in Eas Asians, on which he p esen -day majo allele (G o s56174355) could eside, whe eas he mino allele (T o s56174355) was associa ed wi h lowe DBP in Eu opeans. Thus, a selec i e sweep in he egion is conside ed o ha e e ained he majo allele ha was likely beneficial in he popula ions o Eas Asian ances y; con e sely, his has educed MAF in Eas Asians (T allele: 0.03 in Eas Asians s. 0.10 in Eu opeans). We ound simila examples o he ai s o he han blood p essu e in ou egions: s12748152 o LDL-C and iglyce ides, s17031005 o T2D, s11862222 o heigh and s4253772 o o al choles e ol (Fig. 5a−c, e). The e was a significan (P Binomial =4.2 × 10–5) inc ease in he incidence o ecen selec ion signals a he ances y-specific loci, gi en ha a o al o 405 dis inc genomic egions we e iden ified o show e idence o posi i e selec ion ac oss 14 popula ions wo ldwide24. Discussion Ou GWAS in 183,785 Eas Asian indi iduals iden ified 15 new gene ic loci influencing blood p essu e pheno ypes and 4 addi- ional loci when combined wi h Eu opean indi iduals (max N= 289,038) (Table 1). O he 19 newly iden ified loci, 15 loci we e eplica ed in an independen sample o Eu opeans (N=422,771) plus Eas Asians (N=94,201) (Supplemen a y Da a 2). A no able ea u e o his s udy is he use o a ela i ely la ge disco e y-s age sample size in popula ions o non-Eu opean descen , he eby enabling us o iden i y a numbe o gene ic loci ha ha e no been epo ed by GWAS me a-analysis in Eu opeans (Fig. 3). By combining he Eas Asian da a wi h Eu opean da a, we we e also able o seek in e e hnic gene ic he e ogenei y o GWAS esul s o blood p essu e be ween he wo ances ies (Fig. 1) as well as o he complex ai s. In pa icula , he p esen s udy p o ides examples o in e e hnic gene ic he e ogenei y, al hough he incidence may no be high, disco e ing wo ema kable phenomena: (1) he colocaliza ion o dis inc ances y-specific a ian s ha a e no a e and can exe mu ually in e ed gene ic e ec s be ween he e hnic g oups and (2) he po en ial in ol emen o na u al selec ion in he occu ence o ances y-specific associa ion signals. Among gene ic loci iden ified in Eas Asians, o no e is he finding ha a wo loci on 1p35 and 3p21, he la e o which esides nea he associa ion signal p e iously epo ed in Chi- nese25, sen inel SNPs ( s2076460 and s3774447) appea o be specific o Eas Asians; i.e., in Eu opeans he co esponding SNPs we e monomo phic and no significan associa ion signals we e de ec able in he icini y (Supplemen a y Da a 7). These suppo he possible p esence o mul iple Eas Asian-specific associa ions as well as Eu opean-specific ones. 0.00 0.25 0.50 0.75 1.00 T ans-ances y gene ic co ela ion (95% CI) EAS s. EUR SBP DBP HDL LDL TC TG T2D BMI Heigh He i abili y (95% CI) 0.00 0.25 0.50 0.75 1.00 EAS SBP DBP HDL LDL TC TG T2D BMI Heigh He i abili y (95% CI) 0.00 0.25 0.50 0.75 1.00 EUR SBP DBP HDL LDL TC TG T2D BMI Heigh Fig. 2 T anse hnic gene ic co ela ion and SNP-based he i abili y. SNP-based he i abili y o SBP, DBP and o he complex disease and pheno ype ai s is shown sepa a ely o Eas Asians (EAS) and Eu opeans (EUR) by using he published GWAS summa y s a is ics (Supplemen a y Table 6). The whiske s a e 95% confidence in e als o each alue ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 6NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions I has been sugges ed ha GWAS signals a e p oduced by causal a ian s ha a e common and sha ed be ween ances y g oups26, wi h e idence o al e na i e a e a ian associa ion models (e.g., syn he ic associa ion27) ha a e assumed o be es ic ed o a limi ed numbe o loci. Apa om hese models, we ha e disco e ed a new model in which gene ic e ec s o anse hnic SNPs ha o m a sha ed haplo ype a a locus a e d i en by causal a ian s ha a e ances y-specific bu a e no a e, which can be called a common ances y-specific a ian associa ion model. We p e iously epo ed on 12q24 he Eas Asian-specific associa ion signal a ALDH2 wi h blood p essu e, which was loca ed nea he associa ion signal a SH2B3 iden ified –0.02 0.00 0.02 –0.02 0.00 0.02 = 0.12 Signi ican in NEUR = 105,253 Signi ican in NEAS= 158,645 DBP a S anda dized e ec -size in EUR S anda dized e ec -size in EAS –0.2 –0.1 0.0 0.1 0.2 –0.15 –0.10 –0.05 0.00 0.05 0.10 0.15 = 0.05 Signi ican in NEUR = 173,082 Signi ican in NEAS= 31,732 LDL-C S anda dized e ec -size in EUR S anda dized e ec -size in EAS –0.04 0.00 0.04 –0.04 –0.02 0.00 0.02 0.04 Signi ican in NEUR = 158,186 Signi ican in NEAS= 25,066 = 0.07 T2D S anda dized e ec -size in EUR S anda dized e ec -size in EAS –0.050 –0.025 0.000 0.025 0.050 –0.050 –0.025 0.000 0.025 0.050 Signi ican in NEUR = 322,154 Signi ican in NEAS= 158,284 = 0.26 BMI S anda dized e ec -size in EUR S anda dized e ec -size in EAS Numbe o SNPs in bin 110 3106 –0.050 –0.025 0.000 0.025 0.050 –0.06 –0.03 0.00 0.03 0.06 Signi ican in NEUR = 253,279 Signi ican in NEAS= 36,227 = 0.20 Heigh S anda dized e ec -size in EUR S anda dized e ec -size in EAS 100K 200K 500K 21 59 224 22 8 13 18 62 13 25 45 234 18 43 110 100K200K 500K Numbe o loci de ec able in a single EUR GWAS, NEUR= Numbe o loci de ec able in a single EAS GWAS, NEAS = b 28 66 198 59 17 28 43 137 21 41 78 383 26 55 135 100K200K 500K Numbe o loci de ec able in a single EUR GWAS, NEUR= 100K 200K 500K Numbe o loci de ec able in a single EAS GWAS, NEAS = 17 56 233 9579 32 9 17 27 144143787 100K 200K 500K Numbe o loci de ec able in a single EAS GWAS, NEAS = 100K200K 500K Numbe o loci de ec able in a single EUR GWAS, NEUR= 26 94 403 13 6 9 12 51 13 26 43 249 21 61 155 100K 200K 500K 100K 200K 500K Numbe o loci de ec able in a single EAS GWAS, NEAS = 100K200K 500K Numbe o loci de ec able in a single EUR GWAS, NEUR= 93 239 656 153 56 95 136 370 76 157 286 836 90 220 525 Numbe o loci de ec able in a single EAS GWAS, NEAS = 100K200K 500K Numbe o loci de ec able in a single EUR GWAS, NEUR= NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 ARTICLE NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions 7 in Eu opeans19. We also epo ed ha hese wo associa ion signals we e phylogene ically independen , al hough a dis ance be ween he sen inel SNPs ( s671 and s3184504) was ela i ely close (357 kb apa ). Mo eo e , in he p esen s udy we ha e de ec ed a numbe o anse hnic SNPs in he 12q24 egion o show highly significan he e ogenei y o gene ic impac on SBP be ween he e hnic g oups (e.g., β EAS =−0.73 and β EUR =0.37, P he =9.74×10–21 a s4766566), whe e in e ed gene ic e ec s a e a ibu able o each o he ances y-specific sen inel SNPs; a simila si ua ion was also obse ed on 10q21 o ep oduce his phenomenon (Fig. 1and Supplemen a y Da a 6). Using ances y- specific SNPs ha a e epo ed o each genome-wide significance in ei he o he e hnic g oups, we ha e ound u he e idence suppo ing he common ances y-specific a ian associa ion model a 11 o 48 loci (23%) examined (Supplemen a y Da a 7). This co esponds o 2.5% o o al non- a e genome-wide sig- nifican blood p essu e loci epo ed o da e in popula ions o Eu opean and/o Eas Asian descen 3–8,19 (Supplemen a y Fig. 7). Al hough i is beyond he scope o his s udy, pa o he low- equency a ian s a g oup-2b loci (which cons i u e 4.0% o he es ed blood p essu e loci) may also be ances y-specific20. These findings a e impo an and should be kep in mind in he wo well-known applica ions o anse hnic GWAS, i.e., me a-analyses o inc ease he powe o de ec ing new suscep ibili y loci and fine mapping. Wi h he inc ease in sample size used o GWAS me a-analysis, i is expec ed ha a la ge numbe o gene ic loci will be de ec ed, and he dis ibu ion o such loci in he genome will become dense . Associa ion signals anno a ed o he same locus a e empi ically defined such ha a se o SNPs a e bounded by pai wise co ela ion wi h he index SNP o 2≥0.1−0.3 wi hin ±250–500 kb o he index SNP26,28. This is usually discussed in he con ex o locus he e ogenei y a he han allelic he e o- genei y. Apa om ex eme cases in which an index SNP is monomo phic in he second e hnic g oup as abo e-men ioned, he cases in which a common a ian in ques ion is less common o e en a e in he second e hnic g oup necessi a e a g ea e sample size o achie e compa able s a is ical powe o de ec ing a significan associa ion. We should be ca e ul in se ing app o- p ia e significance h esholds o main ain a balance be ween gene a ing spu ious associa ions and missing ue modes asso- cia ions in he second e hnic g oup. Hence, we chose ances y- specific loci based on he P alue h esholds adjus ed o he numbe o SNPs loca ed ≤500 kb om he sen inel SNP. This se o loci may no exclude some cases wi h insu ficien s a is ical powe bu can include he cases in which gene ic impac a he locus is la gely ega ded as specific o he o iginal e hnic g oup. E idence o posi i e selec ion was obse ed a fi e unique loci among he lis o ances y-specific loci (Fig. 5and Supplemen a y Da a 9). In addi ion o ances y-specific loci, al hough he p opo ion appea s o be ela i ely modes (app oxima ely 2.5%), we ha e ound significan in e e hnic he e ogenei y o gene ic impac a a numbe o blood p essu e loci ha a e non- a e in bo h ances ies, wi h mos o hem o iginally epo ed in Eu opeans o da e. I is assumed ha he po en ial p esence o modifie genes and/o gene−en i onmen in e ac ions can con ibu e o such in e e hnic he e ogenei y bu he o e all influences and unde - lying mechanisms emain o be in es iga ed. When combined wi h ances y-specific a ian associa ions (a g oup-2a o g oup- 2b loci in Supplemen a y Fig. 7), >5% o blood p essu e loci a e likely o show significan in e e hnic he e ogenei y be ween Eas Asians and Eu opeans. Acco ding o ou SNP-based he i abili y analysis, he genome- wide co ela ion o causal- a ian e ec -sizes a SNPs common in bo h ances y g oups is 0.898 and 0.851 o SBP and DBP, espec i ely (Fig. 2). Pa o he educed in e e hnic co ela ion is a ibu able o anse hnic a ian s ha a e common ac oss popula ions bu show subs an ial in e e hnic he e ogenei y, al hough he p opo ion o such a ian s may no be high (e.g., 9 loci wi h in e e hnic he e ogenei y de ec ed in g oup-1; Supple- men a y Fig. 7). E en hough hey a e no included in he SNP- based he i abili y analysis, ances y-specific a ian s (a g oup-2a loci in Supplemen a y Fig. 7) can influence he pe -allele e ec - sizes o a numbe o anse hnic SNPs a he co esponding loci ia LD, e.g., a he C10o 107 and CACNB2 loci. In summa y, we iden i y a o al o 19 gene ic loci ha ha e no been epo ed p e iously by GWAS me a-analysis, using ela- i ely la ge disco e y-s age sample size in Eas Asian popula ions. By compa ing GWAS da a o wo e hnic g oups, we ha e newly defined, so o speak, a common ances y-specific a ian asso- cia ion model, which should be b ough o a en ion in he applica ions o anse hnic GWAS. Me hods Popula ions and geno yping. Desc ip ion o he s udy design and pheno ype measu emen o each Eas Asian s udy (o coho ) pa icipa ing in GWAS me a- analysis is p o ided in he Supplemen a y Me hods. Desc ip i e s a is ics o he indi iduals, geno yping a ays, quali y con ol fil e s, and geno ype impu a ion applied o he indi idual s udies a e p o ided in Supplemen a y Tables 1, 2; 1000 Genomes Phase 3 e e ence panel was used o impu a ion in all s udies excep BBJ (1000 Genomes Phase 1) and TMM CommCoho S udy (ToMMo 2KJPN panel plus 1000 Genomes Phase 3). SNP alleles we e o ien ed o he o wa d s and o he GRCh37/hg19 e e ence sequence o he human genome. Collec ion o da a and samples by he coho s pa icipa ing in he s udy was app o ed by espec i e esea ch e hics commi ees, and w i en consen o pa icipa ion was p o ided by all esea ch pa icipan s. Pheno ype modeling and SNP associa ion analysis. Fo indi iduals aking an ihype ensi e he apies, blood p essu e was impu ed by adding 15 mmHg and 10 mmHg o SBP and DBP alues, espec i ely. MAP and PP we e calcula ed as MAP =(2 DBP +SBP)/3 and PP =SBP –DBP. In each s udy, he associa ion o blood p essu e (SBP, DBP, MAP o PP) wi h SNP allele dose was es ed using linea eg ession adjus ed o age, sex, and any s udy-specific co a ia es. Hype - ensi e cases we e defined as ollows: (i) SBP ≥160 mmHg and/o DBP ≥100 mmHg and/o on an ihype ensi e ea men and (ii) age o onse ≤65 yea s. No mo ensi e con ols we e defined as ollows: (i) SBP < 130 mmHg and DBP < 85 mmHg and no on an ihype ensi e ea men and (ii) age ≥50 yea s. In each s udy, he associa ion o a dicho omous ai o hype ension s a us wi h SNP allele dose was es ed using logis ic eg ession adjus ed o sex and any s udy-specific co - a ia es. The e ec -sizes and s anda d e o s es ima ed in linea and logis ic eg essions we e used in subsequen me a-analysis. Fig. 3 Dis ibu ion o SNP e ec -size in GWAS and powe o GWAS. They a e compa ed be ween Eas Asians and Eu opeans o DBP, low-densi y lipop o ein choles e ol (LDL-C), ype 2 diabe es (T2D), body mass index (BMI) and heigh . aDis ibu ion o SNP e ec -size in ac ual GWAS conduc ed in Eas Asians (x-axis) and Eu opeans (y-axis). The e ec -size o an SNP was s anda dized such ha each o he ai and allele has a uni a iance. The s anda dized e ec -size equals he gene ic impac . A posi i e e ec -size indica es a highe ai alue o he ALT allele compa ed o he REF allele o he 1000 Genomes (1000G) phase-3 da a se . The ho izon al and e ical ba s o he bo om and igh o he plo s indica e he ange o e ec -sizes, in which genome-wide significan SNPs a e localized. bThe expec ed numbe s o genome-wide significan loci de ec able in a single GWAS and hei in e e hnic o e lap. The numbe o SNPs was scaled o 1000G SNPs e en o GWAS in which HapMap-de i ed SNPs we e assayed. SNPs loca ed ≤500 kb we e ega ded o be a he same suscep ibili y locus. The numbe s o loci we e in e ed om he he i abili y model shown in Supplemen a y Fig. 13, whe e ue obse able e ec -sizes we e compu ed based on 100 ials o andom sampling unde he assumed he i abili y pa ame e s (see Me hods) ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 8NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions DBP Sen inel SNPs o loci associa ed in EAS Speci ic o EAS (1) No speci ic (39) 0.00 0.01 0.02 0.03 0.04 S anda dized e ec -size in EAS (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EAS LDL-C Speci ic o EAS (0) No speci ic (11) 0.00 0.05 0.10 0.15 0.20 S anda dized e ec -size in EAS (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EAS T2D Speci ic o EAS (2) No speci ic (22) 0.000 0.025 0.050 0.075 S anda dized e ec -size in EAS (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EAS BMI Speci ic o EAS (6) No speci ic (61) 0.00 0.01 0.02 0.03 0.04 0.05 S anda dized e ec -size in EAS (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EAS Heigh Speci ic o EAS (0) No speci ic (70) 0.00 0.02 0.04 0.06 S anda dized e ec -size in EAS (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EAS Sen inel SNPs o loci associa ed in EUR Speci ic o EUR (8) No speci ic (47) 0.00 0.01 0.02 0.03 0.04 S anda dized e ec -size in EUR (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EUR Speci ic o EUR (7) No speci ic (65) 0.00 0.05 0.10 0.15 0.20 S anda dized e ec -size in EUR (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EUR 0.000 0.025 0.050 0.075 Speci ic o EUR (3) No speci ic (36) S anda dized e ec -size in EUR (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EUR Speci ic o EUR (6) No speci ic (68) 0.00 0.01 0.02 0.03 0.04 0.05 S anda dized e ec -size in EUR (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EUR 0.00 0.02 0.04 0.06 Speci ic o EUR (21) No speci ic (459) S anda dized e ec -size in EUR (absolu e alue) 0.0 0.1 0.2 0.3 0.4 0.5 Mino allele equency in EUR Fig. 4 In e e hnic compa ibili y o GWAS esul s o DBP, LDL-C, T2D, BMI, and heigh . Each poin in he plo s ep esen s a sen inel SNP wi h genome-wide significance in he GWAS summa y s a is ics (Supplemen a y Table 6), plo ed wi h i s s anda dized e ec -size (in y-axis) agains mino allele equency (in x-axis) o Eas Asians (EAS in he le column) and Eu opeans (EUR in he igh column). SNPs specific o ei he o he e hnic g oups a e colo ed in ed; ances y-specific associa ion was defined such ha he sen inel SNPs a he co esponding loci eached genome-wide significance (P< 5×10–8) in one e hnic g oup bu we e non-polymo phic o a e (MAF < 0.05) in ano he e hnic g oup NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 ARTICLE NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions 9 Uni e si y Medical Cen e G oningen, Uni e si y o G oningen, Hanzeplein 1, 9713 GZ G oningen, Ne he lands. 113 Depa men o Obs e ics and Gynecology, Uni e si y Hospi al o Oulu, Uni e si y o Oulu, Oulu FI-90014, Finland. 114 Depa men o Clinical Sciences/Obs e ics and Gynecology, Uni e si y o Oulu, Oulu FI-90014, Finland. 115 Cen e o Ca dio ascula Diagnos ics and P e en ion, Cle eland Clinic, Cle eland, OH 44195, USA. 116 Depa men o Cellula and Molecula Medicine, Le ne Resea ch Ins i u e, Cle eland Clinic, Cle eland, OH 44195, USA. 117 Keck School o Medicine, Uni e si y o Sou he n Cali o nia, Los Angeles, CA 90089, USA. 118 Resea ch Cen e o P e en ion and Heal h, Glos up Uni e si y Hospi al, 2600 Glos up, Denma k. 119 Depa men o Epidemiology and Public Heal h, UCL, London WC1E 6BT, UK. 120 Hea Cen e, Depa men o Ca diology, Tampe e Uni e si y Hospi al, and Uni e si y o Tampe e School o Medicine, FI-33521 Tampe e, Finland. 121 Depa men o Public Heal h & Clinical Medicine, Sec ion o Family Medicine, Umeå uni e si e , SE-901 85 Umeå, Sweden. 122 Depa men o Epidemiology, Uni e si y Medical Cen e G oningen, Uni e si y o G oningen, Hanzeplein 1, 9713 GZ G oningen, Ne he lands. 123 Depa men o Vascula Medicine, Uni e si y Medical Cen e U ech , 3508 GA U ech , Ne he lands. 124 Alzheime Sco land Demen ia Resea ch Cen e, Uni e si y o Edinbu gh, 7 Geo ge Squa e, Edinbu gh EH8 9JZ, UK. 125 Academic Sec ion o Ge ia ic Medicine, Ins i u e o Ca dio ascula and Medical Sciences, Facul y o Medicine, Uni e si y o Glasgow, Glasgow G4 0SF, UK. 126 Ins i u e o Clinical Molecula Biology, Ch is ian-Alb ech s-Uni e si y o Kiel, Kiel 24105, Ge many. 127 Depa men o Ca diology, Leiden Uni e si y Medical Cen e , 2300 RC Leiden, Ne he lands. 128 Depa men o Clinical Physiology, Tampe e Uni e si y Hospi al, FI-33521 Tampe e, Finland. 129 Depa men o Clinical Physiology, Uni e si y o Tampe e School o Medicine, FI-33014 Tampe e, Finland. 130 Depa men o Obs e ics and Gynecology, Oulu Uni e si y Hospi al, PO Box 23FI-90029 Oulu, Finland. 131 Depa men o Medicine, Tu ku Uni e si y Hospi al, FI-20521 Tu ku, Finland. 132 Depa men o Medicine, Uni e si y o Tu ku, FI-20014 Tu ku, Finland. 133 Du e Cen e o Ca diogene ic Resea ch, ICIN-Ne he lands Hea Ins i u e, 3511 GC U ech , Ne he lands. 134 Ins i u e o Ca dio ascula Science, Facul y o Popula ion Heal h Sciences, Uni e si y College London, London WC1E 6BT, UK. 135 Depa men o Nu i ion, Ha a d School o Public Heal h, Bos on, MA 02115, USA. 136 Ins i u e o Rep oduc i e and De elopmen al Biology, Impe ial College London, Hamme smi h Hospi al, London W12 0HS, UK. 137 School o Medicine, Uni e si y o Minneso a, Minneapolis, MN 55455, USA. 138 Biocen e Oulu, Uni e si y o Oulu, P.O. Box 5000Aapis ie 5A, FI-90014 Oulu, Finland. 139 Uni o P ima y Ca e, Oulu Uni e si y Hospi al, Kajaanin ie 50P.O.Box 20FI-90220 Oulu, Finland. 140 Depa men o Child en and Young People and Families, Na ional Ins i u e o Heal h and Wel a e, Aapis ie 1, Box 310, FI-90101 Oulu, Finland. 141 In e uni e si y Ca diology Ins i u e o he Ne he lands, U ech 3511 EP, Ne he lands. 142 Depa men o Ca dio ascula Sciences, Uni e si y o Leices e , Glenfield Hospi al, Leices e LE3 9QP, UK. 143 Na ional Ins i u e o Heal h Resea ch Leices e Ca dio ascula Biomedical Resea ch Uni , Glenfield Hospi al, Leices e LE3 9QP, UK. 144 Ins i u e o Molecula Gene icsCNR, 27100 Pa ia, I aly. 145 Clinical Ins i u e o Medical and Chemical Labo a o y Diagnos ics, Medical Uni e si y o G az, Auenb ugge pla z 15, 8036 G az, Aus ia. 146 Synlab Academy, Synlab Se ices GmbH, Go lieb- Daimle -S aße 25, 68165 Mannheim, Ge many. 147 Depa men o Endoc inology, Uni e si y Medical Cen e G oningen, Uni e si y o G oningen, Hanzeplein 1, 9713 GZ G oningen, Ne he lands. 148 Na ional Hellenic Resea ch Founda ion, Ins i u e o Biological Resea ch and Bio echnology, A hens 116 35, G eece. 149 Depa men o Toxicogenomics, Maas ich Uni e si y, Uni e si ei ssingel 50, 6229ER Maas ich , Ne he lands. 150 Ox o d Cen e o Diabe es Endoc inology and Me abolism, Uni e si y o Ox o d, Ox o d OX3 7LE, UK ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-07345-0 16 NATURE COMMUNICATIONS | (2018) 9:5052 | DOI: 10.1038/s41467-018-07345-0 | www.na u e.c om/na u ecommunica ions