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

Erzurumluoglu, A. M. et al. (2020) Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Molecular Psychiatry, 25(10), pp. 2392-2409. (doi: 10.1038/s41380-018-0313-0) (PMID:30617275) (PMCID:PMC7515840)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Dominiczak, Professor Anna and Young, Dr Robin and Sattar, Professor Naveed
Authors: Erzurumluoglu, A. M., Liu, M., Jackson, V. E., Barnes, D. R., Datta, G., Melbourne, C. A., Young, R., Batini, C., Surendran, P., Jiang, T., Adnan, S. D., Afaq, S., Agrawal, A., Altmaier, E., Antoniou, A. C., Asselbergs, F. W., Baumbach, C., Bierut, L., Bertelsen, S., Boehnke, M., Bots, M. L., Brazel, D. M., Chambers, J. C., Chang-Claude, J., Chen, C., Corley, J., Chou, Y.-L., David, S. P., de Boer, R. A., de Leeuw, C. A., Dennis, J. G., Dominiczak, A. F., Dunning, A. M., Easton, D. F., Eaton, C., Elliott, P., Evangelou, E., Faul, J. D., Foroud, T., Goate, A., Gong, J., Grabe, H. J., Haessler, J., Haiman, C., Hallmans, G., Hammerschlag, A. R., Harris, S. E., Hattersley, A., Heath, A., Hsu, C., Iacono, W. G., Kanoni, S., Kapoor, M., Kaprio, J., Kardia, S. L., Karpe, F., Kontto, J., Kooner, J. S., Kooperberg, C., Kuulasmaa, K., Laakso, M., Lai, D., Langenberg, C., Le, N., Lettre, G., Loukola, A., Luan, J.'a., Madden, P. A. F., Mangino, M., Marioni, R. E., Marouli, E., Marten, J., Martin, N. G., McGue, M., Michailidou, K., Mihailov, E., Moayyeri, A., Moitry, M., Müller-Nurasyid, M., Naheed, A., Nauck, M., Neville, M. J., Nielsen, S. F., North, K., Perola, M., Pharoah, P. D. P., Pistis, G., Polderman, T. J., Posthuma, D., Poulter, N., Qaiser, B., Rasheed, A., Reiner, A., Renström, F., Rice, J., Rohde, R., Rolandsson, O., Samani, N. J., Samuel, M., Schlessinger, D., Scholte, S. H., Scott, R. A., Sever, P., Shao, Y., Shrine, N., Smith, J. A., Starr, J. M., Stirrups, K., Stram, D., Stringham, H. M., Tachmazidou, I., Tardif, J.-C., Thompson, D. J., Tindle, H. A., Tragante, V., Trompet, S., Turcot, V., Tyrrell, J., Vaartjes, I., van der Leij, A. R., van der Meer, P., Varga, T. V., Verweij, N., Völzke, H., Wareham, N. J., Warren, H. R., Weir, D. R., 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, M. J., Chowdhury, R., Cucca, F., Deary, I. J., Deloukas, P., Di Angelantonio, E., Ferrario, M., Ferrières, J., Franks, P. W., Frayling, T. M., Frossard, P., Hall, I. P., Hayward, C., Jansson, J.-H., Jukema, J. W., Kee, F., Männistö, S., Metspalu, A., Munroe, P. B., Nordestgaard, B. G., Palmer, C. N. A., Salomaa, V., Sattar, N., Spector, T., Strachan, D. P., van der Harst, P., Zeggini, E., Saleheen, D., Butterworth, A. S., Wain, L. V., Abecasis, G. R., Danesh, J., Tobin, M. D., Vrieze, S., Liu, D. J., and Howson, J. M. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
Journal Name:Molecular Psychiatry
Publisher:Springer Nature
ISSN (Online):1476-5578
Published Online:07 January 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Molecular Psychiatry 25(10): 2392-2409
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
483571Collaborative strategy for a definitive genome scan in essential hypertension: high fidelity phenotyping and "hypercontrols"Anna DominiczakBritish Heart Foundation (BHF)SP/08/005/25115RI CARDIOVASCULAR & MEDICAL SCIENCES
421221InGenious HyperCare - Integrating Genomics, Clinical Research and Care in HypertensionAnna DominiczakEuropean Commission (EC)LSHM-CT-2006-037093RI CARDIOVASCULAR & MEDICAL SCIENCES
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES