Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.
Lisa de Las FuentesYun Ju SungRaymond NoordamThomas WinklerMary F FeitosaKaren SchwanderAmy R BentleyMichael R BrownXiuqing GuoAlisa ManningDaniel I ChasmanHugues AschardTraci M BartzLawrence F BielakArchie I CampbellChing-Yu ChengRajkumar DorajooFernando Pires HartwigA R V R HorimotoChangwei LiRuifang Li-GaoYongmei LiuJonathan MartenSolomon K MusaniIoanna NtallaTuomo RankinenMelissa A RichardXueling S SimAlbert V SmithSalman M TajuddinBamidele O TayoDina VojinovicHelen R WarrenDeng XuanMaris AlverMathilde BoisselJin-Fang ChaiXu ChenKaare ChristensenJasmin DiversEvangelos EvangelouChuan GaoGiorgia GirottoSarah E HarrisMeian HeFang-Chi HsuBrigitte KühnelFederica LaguzziXiaoyin LiLeo-Pekka LyytikäinenIlja Maria NolteAlaitz PovedaRainer RauramaaMuhammad RiazRico RueediXiao-Ou ShuHarold SniederTamar SoferFumihiko TakeuchiNiek VerweijErin B WareStefan WeissLisa R YanekNajaf AminDan E ArkingDonna K ArnettSven BergmannEric BoerwinkleJennifer A BrodyUlrich BroeckelMarco BrumatGregory BurkeClaudia P CabreraMickaël CanouilMiao Li CheeYii-Der Ida ChenMassimiliano CoccaJohn ConnellH Janaka de SilvaPaul S de VriesGudny EiriksdottirJessica D FaulVirginia FisherTerrence ForresterErvin F FoxYechiel FriedlanderHe GaoBruna GiganteFranco GiulianiniChi Charles GuDongfeng GuTamara B HarrisJiang HeSami HeikkinenChew-Kiat HengSteven HuntMohammad Arfan IkramMarguerite R IrvinMika KähönenMaryam KavousiChiea Chuen KhorTuomas O KilpeläinenWoon-Puay KohPirjo KomulainenAldi T KrajaJ E KriegerCarl D LangefeldYize LiJingjing LiangDavid C M LiewaldChing-Ti LiuJian-Jun LiuKurt K LohmanReedik MägiColin A McKenzieThomas MeitingerAndres MetspaluYuri MilaneschiLili A MilaniDennis O Mook-KanamoriMike A NallsChristopher P NelsonJill M NorrisJeff O'ConnellAdesola OgunniyiSandosh PadmanabhanNicholette D D AllredNancy L PedersenThomas PerlsAnnette PetersAstrid PetersmannPatricia A PeyserOzren PolasekDavid J PorteousLeslie J RaffelTreva K RiceJerome I RotterIgor RudanOscar-Leonel Rueda-OchoaCharumathi SabanayagamBabatunde L SalakoPamela J SchreinerJames M ShikanyStephen S SidneyMario SimsColleen M SitlaniJennifer A SmithJohn M StarrKonstantin StrauchMorris A SwertzAlexander TeumerYih Chung ThamAndre G UitterlindenDhananjay VaidyaM Yldau van der EndeMelanie WaldenbergerLihua WangYa-Xing WangWen-Bin WeiDavid R WeirWanqing WenJie YaoBing YuCaizheng YuJian-Min YuanWei ZhaoAlan B ZondermanDiane M BeckerDonald W BowdenIan J DearyMarcus DörrTõnu EskoBarry I FreedmanPhillippe FroguelPaolo GaspariniChristian GiegerJost Bruno JonasCandace M KammererNorihiro KatoTimo A LakkaKarin LeanderTerho Lehtimäkinull nullPatrik K E MagnussonPedro-Manuel Marques-VidalBrenda W J H PenninxNilesh J SamaniPim van der HarstLynne E WagenknechtTangchun WuWei ZhengXiaofeng ZhuClaude BouchardRichard S CooperAdolfo CorreaMichele K EvansVilmundur G GudnasonCaroline HaywardBernardo Lessa HortaTanika N KellyStephen B KritchevskyDaniel LevyWalter R PalmasA C PereiraMichael M ProvinceBruce M PsatyPaul M RidkerCharles N RotimiE Shyong TaiRob M van DamCornelia M van DuijnTien Yin WongKenneth RiceW James GaudermanAlanna C MorrisonKari E NorthSharon L R KardiaMark J CaulfieldPaul ElliottPatricia B MunroePaul W FranksDabeeru C RaoMyriam FornagePublished in: Molecular psychiatry (2020)
Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.