Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.
Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.
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DOI：
10.1038/s41380-018-0313-0
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发表时间：
2020-10
影响因子：
11
通讯作者：
Howson JMM
中科院分区：
文献类型：
--
作者：
Erzurumluoglu AM;Liu M;Jackson VE;Barnes DR;Datta G;Melbourne CA;Young R;Batini C;Surendran P;Jiang T;Adnan SD;Afaq S;Agrawal A;Altmaier E;Antoniou AC;Asselbergs FW;Baumbach C;Bierut L;Bertelsen S;Boehnke M;Bots ML;Brazel DM;Chambers JC;Chang-Claude J;Chen C;Corley J;Chou YL;David SP;de Boer RA;de Leeuw CA;Dennis JG;Dominiczak AF;Dunning AM;Easton DF;Eaton C;Elliott P;Evangelou E;Faul JD;Foroud T;Goate A;Gong J;Grabe HJ;Haessler J;Haiman C;Hallmans G;Hammerschlag AR;Harris SE;Hattersley A;Heath A;Hsu C;Iacono WG;Kanoni S;Kapoor M;Kaprio J;Kardia SL;Karpe F;Kontto J;Kooner JS;Kooperberg C;Kuulasmaa K;Laakso M;Lai D;Langenberg C;Le N;Lettre G;Loukola A;Luan J;Madden PAF;Mangino M;Marioni RE;Marouli E;Marten J;Martin NG;McGue M;Michailidou K;Mihailov E;Moayyeri A;Moitry M;Müller-Nurasyid M;Naheed A;Nauck M;Neville MJ;Nielsen SF;North K;Perola M;Pharoah PDP;Pistis G;Polderman TJ;Posthuma D;Poulter N;Qaiser B;Rasheed A;Reiner A;Renström F;Rice J;Rohde R;Rolandsson O;Samani NJ;Samuel M;Schlessinger D;Scholte SH;Scott RA;Sever P;Shao Y;Shrine N;Smith JA;Starr JM;Stirrups K;Stram D;Stringham HM;Tachmazidou I;Tardif JC;Thompson DJ;Tindle HA;Tragante V;Trompet S;Turcot V;Tyrrell J;Vaartjes I;van der Leij AR;van der Meer P;Varga TV;Verweij N;Völzke H;Wareham NJ;Warren HR;Weir DR;Weiss S;Wetherill L;Yaghootkar H;Yavas E;Jiang Y;Chen F;Zhan X;Zhang W;Zhao W;Zhao W;Zhou K;Amouyel P;Blankenberg S;Caulfield MJ;Chowdhury R;Cucca F;Deary IJ;Deloukas P;Di Angelantonio E;Ferrario M;Ferrières J;Franks PW;Frayling TM;Frossard P;Hall IP;Hayward C;Jansson JH;Jukema JW;Kee F;Männistö S;Metspalu A;Munroe PB;Nordestgaard BG;Palmer CNA;Salomaa V;Sattar N;Spector T;Strachan DP;Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium;van der Harst P;Zeggini E;Saleheen D;Butterworth AS;Wain LV;Abecasis GR;Danesh J;Tobin MD;Vrieze S;Liu DJ;Howson JMM
吸烟是许多疾病的主要遗传和可改变的风险因素，包括癌症、常见呼吸系统疾病和心血管疾病。14个基因位点以前与吸烟行为相关的特征有关。我们在多达61项研究（多达346，813名参与者）的固定效应荟萃分析中测试了外显子组阵列上多达235，116个单核苷酸变异（SNV）与吸烟开始，每天吸烟，包年和戒烟的相关性。在112，811名参与者的子集中，还对另外100万个SNV进行了基因分型，并测试了与四种吸烟行为特征的相关性。两种分析中P < 5 × 10−8的SNV-性状关联在来自英国生物库的多达275，596名独立参与者中进行复制。最后，对发现和复制研究进行了荟萃分析。在发现样本中，16个SNV与至少一种吸烟行为特征相关（P < 5 × 10−8）。对10个新的SNV进行了随访，其中包括TMEM 182附近的rs 12616219，（REV 3L中的rs 462779，CNNM 2中的rs 12780116，GPR 101中的rs 1190736，PJA 1中的rs 11539157，和rs 12616219接近TMEM 182）在Bonferroni显著性阈值（P < 4.5 × 10−3）复制，具有一致的作用方向。在发现加复制荟萃分析中，另外35个SNV与吸烟行为性状相关（多达622，409名参与者），包括CCDC 141中的罕见SNV rs 150493199和CEP 350和HDGFRP 2中的两个低频SNV。功能随访提示REV 3L表达降低可能会降低吸烟开始的概率。新的基因座将有助于理解吸烟行为的遗传病因，并可能导致识别潜在的药物靶点，用于预防吸烟和/或戒烟。
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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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
158.5
作者：
CARMELLI, D;SWAN, GE;FABSITZ, R
通讯作者：
FABSITZ, R