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

TitleMeta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.
Publication TypeJournal Article
Year of Publication2020
AuthorsA 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 AuthorsUnderstanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium
JournalMolecular Psychiatry
Volume25
Issue10
Pagination2392-2409
ISSN Number1476-5578
KeywordsBiological 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.

DOI10.1038/s41380-018-0313-0
Citation Key12124
PubMed ID30617275
PubMed Central IDPMC7515840
Grant ListRG/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