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, 478 (7367), 103-9

Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk

International Consortium for Blood Pressure Genome-Wide Association StudiesGeorg B EhretPatricia B MunroeKenneth M RiceMurielle BochudAndrew D JohnsonDaniel I ChasmanAlbert V SmithMartin D TobinGermaine C VerwoertShih-Jen HwangVasyl PihurPeter VollenweiderPaul F O'ReillyNajaf AminJennifer L Bragg-GreshamAlexander TeumerNicole L GlazerLenore LaunerJing Hua ZhaoYurii AulchenkoSimon HeathSiim SõberAfshin ParsaJian'an LuanPankaj AroraAbbas DehghanFeng ZhangGavin LucasAndrew A HicksAnne U JacksonJohn F PedenToshiko TanakaSarah H WildIgor RudanWilmar IglYuri MilaneschiAlex N ParkerCristiano FavaJohn C ChambersErvin R FoxMeena KumariMin Jin GoPim van der HarstWen Hong Linda KaoMarketa SjögrenD G VinayMyriam AlexanderYasuharu TabaraSue Shaw-HawkinsPeter H WhincupYongmei LiuGang ShiJohanna KuusistoBamidele TayoMark SeielstadXueling SimKhanh-Dung Hoang NguyenTerho LehtimäkiGiuseppe MatulloYing WuTom R GauntN Charlotte Onland-MoretMatthew N CooperCarl G P PlatouElin OrgRebecca HardySantosh DahgamJutta PalmenVeronique VitartPeter S BraundTatiana KuznetsovaCuno S P M UiterwaalAdebowale AdeyemoWalter PalmasHarry CampbellBarbara LudwigMaciej TomaszewskiIoanna TzoulakiNicholette D PalmerCARDIoGRAM consortiumCKDGen ConsortiumKidneyGen ConsortiumEchoGen consortiumCHARGE-HF consortiumThor AspelundMelissa GarciaYen-Pei C ChangJeffrey R O'ConnellNanette I SteinleDiederick E GrobbeeDan E ArkingSharon L KardiaAlanna C MorrisonDena HernandezSamer NajjarWendy L McArdleDavid HadleyMorris J BrownJohn M ConnellAroon D HingoraniIan N M DayDebbie A LawlorJohn P BeilbyRobert W LawrenceRobert ClarkeJemma C HopewellHalit OngenAlbert W DreisbachYali LiJ Hunter YoungJoshua C BisMika KähönenJorma ViikariLinda S AdairNanette R LeeMing-Huei ChenMatthias OldenCristian PattaroJudith A Hoffman BoltonAnna KöttgenSven BergmannVincent MooserNish ChaturvediTimothy M FraylingMuhammad IslamTazeen H JafarJeanette ErdmannSmita R KulkarniStefan R BornsteinJürgen GrässlerLeif GroopBenjamin F VoightJohannes KettunenPhilip HowardAndrew TaylorSimonetta GuarreraFulvio RicceriValur EmilssonAndrew PlumpInês BarrosoKay-Tee KhawAlan B WederSteven C HuntYan V SunRichard N BergmanFrancis S CollinsLori L BonnycastleLaura J ScottHeather M StringhamLeena PeltonenMarkus PerolaErkki VartiainenStefan-Martin BrandJan A StaessenThomas J WangPaul R BurtonMaria Soler ArtigasYanbin DongHarold SniederXiaoling WangHaidong ZhuKurt K LohmanMegan E RudockSusan R HeckbertNicholas L SmithKerri L WigginsAyo DoumateyDaniel ShrinerGudrun VeldreMargus ViigimaaSanjay KinraDorairaj PrabhakaranVikal TripathyCarl D LangefeldAnnika RosengrenDag S ThelleAnna Maria CorsiAndrew SingletonTerrence ForresterGina HiltonColin A McKenzieTunde SalakoNaoharu IwaiYoshikuni KitaToshio OgiharaTakayoshi OhkuboTomonori OkamuraHirotsugu UeshimaSatoshi UmemuraSusana EyheramendyThomas MeitingerH-Erich WichmannYoon Shin ChoHyung-Lae KimJong-Young LeeJames ScottJoban S SehmiWeihua ZhangBo HedbladPeter NilssonGeorge Davey SmithAndrew WongNarisu NarisuAlena StančákováLeslie J RaffelJie YaoSekar KathiresanChristopher J O'DonnellStephen M SchwartzM Arfan IkramW T Longstreth JrThomas H MosleySudha SeshadriNick R G ShrineLouise V WainMario A MorkenAmy J SwiftJaana LaitinenInga ProkopenkoPaavo ZittingJackie A CooperSteve E HumphriesJohn DaneshAsif RasheedAnuj GoelAnders HamstenHugh WatkinsStephan J L BakkerWiek H van GilstCharles S JanipalliK Radha ManiChittaranjan S YajnikAlbert HofmanFrancesco U S Mattace-RasoBen A OostraAyse DemirkanAaron IsaacsFernando RivadeneiraEdward G LakattaMarco OrruAngelo ScuteriMika Ala-KorpelaAntti J KangasLeo-Pekka LyytikäinenPasi SoininenTaru TukiainenPeter WürtzRick Twee-Hee OngMarcus DörrHeyo K KroemerUwe VölkerHenry VölzkePilar GalanSerge HercbergMark LathropDiana ZelenikaPanos DeloukasMassimo ManginoTim D SpectorGuangju ZhaiJames F MeschiaMichael A NallsPankaj SharmaJanos TerzicM V Kranthi KumarMatthew DenniffEwa Zukowska-SzczechowskaLynne E WagenknechtF Gerald R FowkesFadi J CharcharPeter E H SchwarzCaroline HaywardXiuqing GuoCharles RotimiMichiel L BotsEva BrandNilesh J SamaniOzren PolasekPhilippa J TalmudFredrik NybergDiana KuhMaris LaanKristian HveemLyle J PalmerYvonne T van der SchouwJuan P CasasKaren L MohlkePaolo VineisOlli RaitakariSanthi K GaneshTien Y WongE Shyong TaiRichard S CooperMarkku LaaksoDabeeru C RaoTamara B HarrisRichard W MorrisAnna F DominiczakMika KivimakiMichael G MarmotTetsuro MikiDanish SaleheenGiriraj R ChandakJosef CoreshGerjan NavisVeikko SalomaaBok-Ghee HanXiaofeng ZhuJaspal S KoonerOlle MelanderPaul M RidkerStefania BandinelliUlf B GyllenstenAlan F WrightJames F WilsonLuigi FerrucciMartin FarrallJaakko TuomilehtoPeter P PramstallerRoberto ElosuaNicole SoranzoEric J G SijbrandsDavid AltshulerRuth J F LoosAlan R ShuldinerChristian GiegerPierre MenetonAndre G UitterlindenNicholas J WarehamVilmundur GudnasonJerome I RotterRainer RettigManuela UdaDavid P StrachanJacqueline C M WittemanAnna-Liisa HartikainenJacques S BeckmannEric BoerwinkleRamachandran S VasanMichael BoehnkeMartin G LarsonMarjo-Riitta JärvelinBruce M PsatyGonçalo R AbecasisAravinda ChakravartiPaul ElliottCornelia M van DuijnChristopher Newton-ChehDaniel LevyMark J CaulfieldToby Johnson
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Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk

International Consortium for Blood Pressure Genome-Wide Association Studies et al. Nature.

Abstract

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Figures

Fig. 1
Fig. 1
Genome-wide –log10 P-value plots and effects for significant loci. Genome-wide –log10 P-value plots are shown for systolic (SBP: panel a) and diastolic (DBP: panel b). SNPs within loci reaching genome-wide significance are labeled in red for SBP and blue for DBP (±2.5Mb of lowest P-value) and lowest P-values in the initial genome-wide analysis as well as the results of analysis including validation data are labeled separately. The lowest P-values in the initial GWAS are denoted as an X. The range of different sample sizes in the final meta-analysis including the validation data are indicated as: circle (96–140k), triangle (>140–180k), and diamond (>180–220k). SNPs near unconfirmed loci are in black. The horizontal dotted line is P=2.5 × 10−8. Panel c shows the effect size estimates and 95% confidence bars per BP-increasing allele of the 29 significant variants for SBP (red) and DBP (blue). Effect sizes are expressed in mmHg/allele. GUCY = GUCY1A3-GUCY1B3.

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