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

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Title: Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
Authors: Erzurumluoglu, AM
Chambers, JC
Elliott, P
Evangelou, E
Kooner, JS
Poulter, N
Sever, P
Zhang, W
Howson, JMM
Wells, J
Item Type: Journal Article
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.
Issue Date: 7-Jan-2019
Date of Acceptance: 14-Nov-2018
URI: http://hdl.handle.net/10044/1/66414
DOI: https://dx.doi.org/10.1038/s41380-018-0313-0
ISSN: 1359-4184
Publisher: Springer Nature [academic journals on nature.com]
Journal / Book Title: Molecular Psychiatry
Copyright Statement: © The Author(s) 2019. his article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, aslong as you give appropriate credit to the original author(s) and thesource, provide a link to the Creative Commons license, and indicate ifchanges were made. The images or other third party material in thisarticle are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is notincluded in the article’s Creative Commons license and your intendeduse is not permitted by statutory regulation or exceeds the permitteduse, you will need to obtain permission directly from the copyrightholder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Home Office
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
UK DRI Ltd
Funder's Grant Number: PG0484
MR/L01632X/1
MR/L01632X/1
MR/L01341X/1
RTJ6219303-1
RDF03
N/A
Keywords: Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium
11 Medical And Health Sciences
06 Biological Sciences
17 Psychology And Cognitive Sciences
Psychiatry
Publication Status: Published online
Online Publication Date: 2019-01-07
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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