Title | Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | A Erzurumluoglu, M, Liu, M, Jackson, VE, Barnes, DR, Datta, G, Melbourne, CA, Young, R, Batini, C, Surendran, P, Jiang, T, Adnan, SDaud, 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, Y-L, David, SP, de Boer, RA, de Leeuw, C, Dennis, JG, Dominiczak, AF, Dunning, AM, Easton, DF, Eaton, CB, Elliott, P, Evangelou, E, Faul, J, Foroud, T, Goate, A, Gong, J, Grabe, H-J, Haessler, J, Haiman, CA, Hallmans, G, Hammerschlag, AR, Harris, SE, Hattersley, AT, Heath, AC, Hsu, C, Iacono, WG, Kanoni, S, Kapoor, M, Kaprio, J, Kardia, SLR, Karpe, F, Kontto, J, Kooner, JS, Kooperberg, C, Kuulasmaa, K, Laakso, M, Lai, D, Langenberg, C, Le, N, Lettre, G, Loukola, A, Luan, J'an, 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, SFallgaard, North, KE, Perola, M, Pharoah, PDP, Pistis, G, Polderman, TJ, Posthuma, D, Poulter, N, Qaiser, B, Rasheed, A, Reiner, A, Renstrom, F, Rice, J, Rohde, R, Rolandsson, O, Samani, NJ, Samuel, M, Schlessinger, D, H Scholte, S, Scott, RA, Sever, P, Shao, Y, Shrine, N, Smith, JA, Starr, JM, Stirrups, KE, Stram, D, Stringham, HM, Tachmazidou, I, Tardif, J-C, 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, MM, Ferrières, J, Franks, PW, Frayling, TM, Frossard, P, Hall, IP, Hayward, C, Jansson, J-H, J Jukema, W, Kee, F, Männistö, S, Metspalu, A, Munroe, PB, Nordestgaard, BG, Palmer, CNA, Salomaa, V, Sattar, N, Spector, T, Strachan, DP, van der Harst, P, Zeggini, E, Saleheen, D, Butterworth, AS, Wain, LV, Abecasis, GR, Danesh, J, Tobin, MD, Vrieze, S, Liu, DJ, Howson, JMM |
Corporate Authors | Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium |
Journal | Molecular Psychiatry |
Volume | 25 |
Issue | 10 |
Pagination | 2392-2409 |
ISSN Number | 1476-5578 |
Keywords | Biological Specimen Banks, Databases, Factual, Europe, Exome, Female, Genetic Loci, Humans, Male, Polymorphism, Single Nucleotide, Smoking, United Kingdom |
Abstract | 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 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) 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) 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. |
DOI | 10.1038/s41380-018-0313-0 |
Citation Key | 12124 |
PubMed ID | 30617275 |
PubMed Central ID | PMC7515840 |
Grant List | RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom 16/136/68 / DH_ / Department of Health / United Kingdom R21 DA040177 / DA / NIDA NIH HHS / United States MR/L01632X/1 / MRC_ / Medical Research Council / United Kingdom MR/L01341X/1 / MRC_ / Medical Research Council / United Kingdom G9521010D / MRC_ / Medical Research Council / United Kingdom MR/S003746/1 / MRC_ / Medical Research Council / United Kingdom RG/07/005/23633 / BHF_ / British Heart Foundation / United Kingdom MR/R023484/1 / MRC_ / Medical Research Council / United Kingdom 084723/Z/08/Z / WT_ / Wellcome Trust / United Kingdom MC_UU_00007/10 / MRC_ / Medical Research Council / United Kingdom 083948 / WT_ / Wellcome Trust / United Kingdom RP-PG-0407-10371 / DH_ / Department of Health / United Kingdom SP/09/002 / BHF_ / British Heart Foundation / United Kingdom G0601966 / MRC_ / Medical Research Council / United Kingdom 098381 / WT_ / Wellcome Trust / United Kingdom G1001799 / MRC_ / Medical Research Council / United Kingdom G0800270 / MRC_ / Medical Research Council / United Kingdom RE/13/5/30177 / BHF_ / British Heart Foundation / United Kingdom MR/N01104X/2 / MRC_ / Medical Research Council / United Kingdom RC4 AG039029 / AG / NIA NIH HHS / United States U01 AG009740 / AG / NIA NIH HHS / United States MC_U106179471 / MRC_ / Medical Research Council / United Kingdom 104036/Z/14/Z / WT_ / Wellcome Trust / United Kingdom SP/04/002 / BHF_ / British Heart Foundation / United Kingdom SP/08/005/25115 / BHF_ / British Heart Foundation / United Kingdom MC_QA137853 / MRC_ / Medical Research Council / United Kingdom MR/N011317/1 / MRC_ / Medical Research Council / United Kingdom MR/K023241/1 / MRC_ / Medical Research Council / United Kingdom R01 GM126479 / GM / NIGMS NIH HHS / United States CZD/16/6 / CSO_ / Chief Scientist Office / United Kingdom BTRU-2014-10024 / DH_ / Department of Health / United Kingdom G1000861 / MRC_ / Medical Research Council / United Kingdom PG/02/128 / BHF_ / British Heart Foundation / United Kingdom MC_PC_12010 / MRC_ / Medical Research Council / United Kingdom MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom C490/A16561 / CRUK_ / Cancer Research UK / United Kingdom MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom R01 HL119443 / HL / NHLBI NIH HHS / United States R01 DK062370 / DK / NIDDK NIH HHS / United States MR/N01104X/1 / MRC_ / Medical Research Council / United Kingdom R01 HG008983 / HG / NHGRI NIH HHS / United States RC2 AG036495 / AG / NIA NIH HHS / United States 268834 / ERC_ / European Research Council / International U01 DK062370 / DK / NIDDK NIH HHS / United States 090532 / WT_ / Wellcome Trust / United Kingdom MR/S003762/1 / MRC_ / Medical Research Council / United Kingdom 085475 / WT_ / Wellcome Trust / United Kingdom R01 HD057194 / HD / NICHD NIH HHS / United States 10119 / CRUK_ / Cancer Research UK / United Kingdom RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom HPRU-2012-10141 / DH_ / Department of Health / United Kingdom WT098051 / WT_ / Wellcome Trust / United Kingdom 10124 / CRUK_ / Cancer Research UK / United Kingdom G0700931 / MRC_ / Medical Research Council / United Kingdom |