Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

A Mesut ErzurumluogluMengzhen LiuVictoria E JacksonDaniel R BarnesGargi DattaCarl A MelbourneRobin YoungChiara BatiniPraveen SurendranTao JiangSheikh Daud AdnanSaima AfaqArpana AgrawalElisabeth AltmaierAntonis C AntoniouFolkert W AsselbergsClemens BaumbachLaura BierutSarah BertelsenMichael BoehnkeMichiel L BotsDavid M BrazelJohn C ChambersJenny Chang-ClaudeChu ChenJanie CorleyYi-Ling ChouSean P DavidRudolf A de BoerChristiaan A de LeeuwJoe G DennisAnna F DominiczakAlison M DunningDouglas F EastonCharles EatonPaul ElliottEvangelos EvangelouJessica D FaulTatiana ForoudAlison GoateJian GongHans J GrabeJeff HaesslerChristopher HaimanGöran HallmansAnke R HammerschlagSarah E HarrisAndrew HattersleyAndrew HeathChris HsuWilliam G IaconoStavroula KanoniManav KapoorJaakko KaprioSharon L KardiaFredrik KarpeJukka KonttoJaspal S KoonerCharles KooperbergKari KuulasmaaMarkku LaaksoDongbing LaiClaudia LangenbergNhung LeGuillaume LettreAnu LoukolaJian'an LuanPamela A F MaddenMassimo ManginoRiccardo E MarioniEirini MarouliJonathan MartenNicholas G MartinMatt McGueKyriaki MichailidouEvelin MihailovAlireza MoayyeriMarie MoitryMartina Müller-NurasyidAliya NaheedMatthias NauckMatthew J NevilleSune Fallgaard NielsenKari NorthMarkus PerolaPaul D P PharoahGiorgio PistisTinca J PoldermanDanielle PosthumaNeil PoulterBeenish QaiserAsif RasheedAlex ReinerFrida RenströmJohn RiceRebecca RohdeOlov RolandssonNilesh J SamaniMaria SamuelDavid SchlessingerSteven H ScholteRobert A ScottPeter SeverYaming ShaoNick ShrineJennifer A SmithJohn M StarrKathleen StirrupsDanielle StramHeather M StringhamIoanna TachmazidouJean-Claude TardifDeborah J ThompsonHilary A TindleVinicius TraganteStella TrompetValerie TurcotJessica TyrrellIlonca VaartjesAndries R van der LeijPeter van der MeerTibor V VargaNiek VerweijHenry VölzkeNicholas J WarehamHelen R WarrenDavid R WeirStefan WeissLeah WetherillHanieh YaghootkarErsin YavasYu JiangFang ChenXiaowei ZhanWeihua ZhangWei ZhaoWei ZhaoKaixin ZhouPhilippe AmouyelStefan BlankenbergMark J CaulfieldRajiv ChowdhuryFrancesco CuccaIan J DearyPanos DeloukasEmanuele Di AngelantonioMarco FerrarioJean FerrièresPaul W FranksTim M FraylingPhilippe FrossardIan P HallCaroline HaywardJan-Håkan JanssonJ Wouter JukemaFrank KeeSatu MännistöAndres MetspaluPatricia B MunroeBørge Grønne NordestgaardColin N A PalmerVeikko SalomaaNaveed SattarTimothy SpectorDavid Peter Strachannull nullPim van der HarstEleftheria ZegginiDanish SaleheenAdam S ButterworthLouise V WainGoncalo R AbecasisJohn DaneshMartin D TobinScott VriezeDajiang J LiuJoanna M M Howson

Published in: Molecular psychiatry (2019)

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

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