Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Praveen SurendranElena Valeryevna FeofanovaNajim LahrouchiIoanna NtallaSavita KarthikeyanJames CookLingyan ChenBorbala MifsudChen YaoAldi T KrajaJames H CartwrightJacklyn N HellwegeAyush GiriVinicius TraganteGudmar ThorleifssonDajiang J LiuBram P PrinsIsobel D StewartClaudia P CabreraJames M EalesArtur AkbarovPaul L AuerLawrence F BielakJoshua C BisVickie S BraithwaiteJennifer A BrodyE Warwick DawHelen R WarrenFotios DrenosSune Fallgaard NielsenJessica D FaulEric B FaumanCristiano FavaTeresa FerreiraChristopher N FoleyNora FranceschiniHe GaoOlga GiannakopoulouFranco GiulianiniDaniel F GudbjartssonXiuqing GuoSarah E HarrisAki S HavulinnaAnna HelgadottirJennifer E HuffmanShih-Jen HwangStavroula KanoniJukka KonttoMartin G LarsonRuifang Li-GaoJaana LindströmLuca A LottaYingchang LuJian'an LuanAnubha MahajanGiovanni MalerbaNicholas G D MascaHao MeiCristina MenniDennis O Mook-KanamoriDavid Mosen-AnsorenaMartina Müller-NurasyidGuillaume ParéDirk S PaulMarkus PerolaAlaitz PovedaRainer RauramaaMelissa RichardTom G RichardsonNuno SepúlvedaXueling SimAlbert V SmithJennifer A SmithJames R StaleyAlena StanákováPatrick SulemSébastien ThériaultUnnur ThorsteinsdottirStella TrompetTibor V VargaDigna R Velez EdwardsGiovanni VeronesiStefan WeissSara M WillemsJie YaoRobin YoungBing YuWeihua ZhangJing-Hua ZhaoWei ZhaoWei ZhaoEvangelos EvangelouStefanie AeschbacherEralda AsllanajStefan BlankenbergLori L BonnycastleJette Bork-JensenIvan BrandslundPeter S BraundStephen BurgessKelly ChoCramer ChristensenJohn ConnellRenée de MutsertAnna F DominiczakMarcus DörrGudny EiriksdottirAliki-Eleni FarmakiJ Michael GazianoNiels GrarupMegan L GroveGöran HallmansTorben HansenChristian T HaveGerardo HeissMarit E JørgensenPekka JousilahtiEero KajantieMihir KamatAnneMari KäräjämäkiFredrik KarpeHeikki A KoistinenCsaba P KovesdyKari KuulasmaaTiina LaatikainenLars LannfeltI-Te LeeWen-Jane Leenull nullAllan LinnebergLisa W MartinMarie MoitryGirish NadkarniMatt J NevilleColin N A PalmerGeorge J PapanicolaouOluf PedersenJames PetersNeil PoulterAsif RasheedKatrine L RasmussenN William RaynerReedik MägiFrida RenströmRainer RettigJacques RossouwPamela J SchreinerPeter S SeverEmil L SigurdssonTea SkaabyYan V SunJohan SundstromGudmundur ThorgeirssonTõnu EskoElisabetta TrabettiPhilip S TsaoTiinamaija TuomiStephen T TurnerIoanna TzoulakiIlonca VaartjesAnne-Claire VergnaudCristen J WillerPeter W F WilsonDaniel R WitteEkaterina Yonova-DoingHe ZhangNaheed AliyaPeter AlmgrenPhilippe AmouyelFolkert W AsselbergsMichael R BarnesAlexandra I BlakemoreMichael BoehnkeMichiel L BotsErwin P BottingerJulie E BuringJohn C ChambersYii-Der Ida ChenRajiv ChowdhuryDavid ConenAdolfo CorreaGeorge Davey SmithRudolf A de BoerIan J DearyGeorge DedoussisPanos DeloukasEmanuele Di AngelantonioPaul Elliottnull nullnull nullStephan B FelixJean FerrièresIan FordMyriam FornagePaul W FranksStephen FranksPhilippe FrossardGiovanni GambaroTom R GauntLeif GroopVilmundur GudnasonTamara B HarrisCaroline HaywardBranwen J HennigKarl-Heinz HerzigErik IngelssonJaakko TuomilehtoMarjo-Riitta JärvelinJ Wouter JukemaSharon L R KardiaFrank KeeJaspal S KoonerCharles KooperbergLenore J LaunerLars LindRuth J F LoosAbdulla Al Shafi MajumderMarkku LaaksoMark I McCarthyOlle MelanderKaren L MohlkeAlison D MurrayBørge Grønne NordestgaardMarju Orho-MelanderChris J PackardSandosh PadmanabhanWalter PalmasOzren PolasekDavid J PorteousAndrew M PrenticeMichael A ProvinceCaroline L ReltonKenneth RicePaul M RidkerOlov RolandssonFrits R RosendaalJerome I RotterIgor RudanVeikko SalomaaNilesh J SamaniNaveed SattarWayne H-H SheuBlair H SmithNicole SoranzoTimothy D SpectorJohn M StarrSylvain SebertKent D TaylorTimo A LakkaNicholas J TimpsonMartin D Tobinnull nullPim van der HarstPeter van der MeerVasan S RamachandranNiek VerweijJarmo VirtamoUwe VölkerDavid R WeirEleftheria ZegginiFadi J Charcharnull nullNicholas J WarehamClaudia LangenbergMaciej TomaszewskiAdam S ButterworthMark J CaulfieldJohn DaneshTodd L EdwardsHilma HolmAdriana M HungCecilia M LindgrenChunyu LiuAlisa K ManningAndrew P MorrisAlanna C MorrisonChristopher J O'DonnellBruce M PsatyDanish SaleheenKari StefanssonEric BoerwinkleDaniel I ChasmanDaniel LevyChristopher Newton-ChehPatricia B Munroe Joanna M M Howson

Published in: Nature genetics (2020)

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.