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

Erzurumluoglu, AM; Liu, M; Jackson, VE; Barnes, DR; Datta, G; Melbourne, CA; Young, R; Batini, C; Surendran, P; Jiang, T; et al. 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; Beirut, 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, 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, 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, M; Ferrières, J; Franks, PW; Frayling, TM; Frossard, P; Hall, IP; Hayward, C; Jansson, J-H; 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 (2019) Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. MOLECULAR PSYCHIATRY. ISSN 1359-4184 https://doi.org/10.1038/s41380-018-0313-0
SGUL Authors: Strachan, David Peter

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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 × 10−8 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.

Item Type: Article
Additional Information: © The Author(s) 2019. This article is published with open access Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: 11 Medical And Health Sciences, 06 Biological Sciences, 17 Psychology And Cognitive Sciences, Psychiatry
SGUL Research Institute / Research Centre: Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: MOLECULAR PSYCHIATRY
ISSN: 1359-4184
Dates:
DateEvent
9 January 2019Published Online
14 November 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/L01632X/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/L01341X/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
ES/H029745/1Economic and Social Research Councilhttp://dx.doi.org/10.13039/501100000269
WT098051Wellcome Trusthttp://dx.doi.org/10.13039/100004440
C490/A16561Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
MC_U106179471Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_12015/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G9521010DMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
PG/02/128British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
083948Wellcome Trusthttp://dx.doi.org/10.13039/100004440
085475Wellcome Trusthttp://dx.doi.org/10.13039/100004440
RG/07/005/23633British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
SP/08/005/25115British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/14/5/30893British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
SP/04/002British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
G0601966Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0700931Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
084723/Z/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
090532Wellcome Trusthttp://dx.doi.org/10.13039/100004440
098381Wellcome Trusthttp://dx.doi.org/10.13039/100004440
G0800270Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
SP/09/002British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MR/L003120/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
RG/13/13/30194British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
URI: http://openaccess.sgul.ac.uk/id/eprint/110459
Publisher's version: https://doi.org/10.1038/s41380-018-0313-0

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