Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.
paper
Primary
Public
- Authors
- Erzurumluoglu, A Mesut; Liu, Mengzhen; Jackson, Victoria E; Barnes, Daniel R; Datta, Gargi; Melbourne, Carl A; Young, Robin; Batini, Chiara; Surendran, Praveen; Jiang, Tao; Adnan, Sheikh Daud; Afaq, Saima; Agrawal, Arpana; Altmaier, Elisabeth; Antoniou, Antonis C; Asselbergs, Folkert W; Baumbach, Clemens; Bierut, Laura; Bertelsen, Sarah; Boehnke, Michael; Bots, Michiel L; Brazel, David M; Chambers, John C; Chang-Claude, Jenny; Chen, Chu; Corley, Janie; Chou, Yi-Ling; David, Sean P; de Boer, Rudolf A; de Leeuw, Christiaan A; Dennis, Joe G; Dominiczak, Anna F; Dunning, Alison M; Easton, Douglas F; Eaton, Charles; Elliott, Paul; Evangelou, Evangelos; Faul, Jessica D; Foroud, Tatiana; Goate, Alison; Gong, Jian; Grabe, Hans J; Haessler, Jeff; Haiman, Christopher; Hallmans, Göran; Hammerschlag, Anke R; Harris, Sarah E; Hattersley, Andrew; Heath, Andrew; Hsu, Chris; Iacono, William G; Kanoni, Stavroula; Kapoor, Manav; Kaprio, Jaakko; Kardia, Sharon L; Karpe, Fredrik; Kontto, Jukka; Kooner, Jaspal S; Kooperberg, Charles; Kuulasmaa, Kari; Laakso, Markku; Lai, Dongbing; Langenberg, Claudia; Le, Nhung; Lettre, Guillaume; Loukola, Anu; Luan, Jian'an; Madden, Pamela A F; Mangino, Massimo; Marioni, Riccardo E; Marouli, Eirini; Marten, Jonathan; Martin, Nicholas G; McGue, Matt; Michailidou, Kyriaki; Mihailov, Evelin; Moayyeri, Alireza; Moitry, Marie; Müller-Nurasyid, Martina; Naheed, Aliya; Nauck, Matthias; Neville, Matthew J; Nielsen, Sune Fallgaard; North, Kari; Perola, Markus; Pharoah, Paul D P; Pistis, Giorgio; Polderman, Tinca J; Posthuma, Danielle; Poulter, Neil; Qaiser, Beenish; Rasheed, Asif; Reiner, Alex; Renström, Frida; Rice, John; Rohde, Rebecca; Rolandsson, Olov; Samani, Nilesh J; Samuel, Maria; Schlessinger, David; Scholte, Steven H; Scott, Robert A; Sever, Peter; Shao, Yaming; Shrine, Nick; Smith, Jennifer A; Starr, John M; Stirrups, Kathleen; Stram, Danielle; Stringham, Heather M; Tachmazidou, Ioanna; Tardif, Jean-Claude; Thompson, Deborah J; Tindle, Hilary A; Tragante, Vinicius; Trompet, Stella; Turcot, Valerie; Tyrrell, Jessica; Vaartjes, Ilonca; van der Leij, Andries R; van der Meer, Peter; Varga, Tibor V; Verweij, Niek; Völzke, Henry; Wareham, Nicholas J; Warren, Helen R; Weir, David R; Weiss, Stefan; Wetherill, Leah; Yaghootkar, Hanieh; Yavas, Ersin; Jiang, Yu; Chen, Fang; Zhan, Xiaowei; Zhang, Weihua; Zhao, Wei; Zhao, Wei; Zhou, Kaixin; Amouyel, Philippe; Blankenberg, Stefan; Caulfield, Mark J; Chowdhury, Rajiv; Cucca, Francesco; Deary, Ian J; Deloukas, Panos; Di Angelantonio, Emanuele; Ferrario, Marco; Ferrières, Jean; Franks, Paul W; Frayling, Tim M; Frossard, Philippe; Hall, Ian P; Hayward, Caroline; Jansson, Jan-Håkan; Jukema, J Wouter; Kee, Frank; Männistö, Satu; Metspalu, Andres; Munroe, Patricia B; Nordestgaard, Børge Grønne; Palmer, Colin N A; Salomaa, Veikko; Sattar, Naveed; Spector, Timothy; Strachan, David Peter; Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium; van der Harst, Pim; Zeggini, Eleftheria; Saleheen, Danish; Butterworth, Adam S; Wain, Louise V; Abecasis, Goncalo R; Danesh, John; Tobin, Martin D; Vrieze, Scott; Liu, Dajiang J; Howson, Joanna M M
- Year
- 2020
- Journal
- Molecular psychiatry
- PMID
- 30617275
- DOI
- 10.1038/s41380-018-0313-0
- PMCID
- PMC7515840
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.
Study design including the discovery and replication stages. NB: Gene-based studies, conditional analyses, and replication in African American ancestry samples not shown here for clarity. *GFG and NAGOZALC studies contributed additional custom content
A concentric Circos plot of the association results for smoking initiation (SI; outer ring), cigarettes per day (CPD) and smoking cessation (SC; inner ring) for chromosomes 1–22 (Pack-years results, which can be found in Supp. Figure 1, are omitted for clarity). Each dot represents a SNV, with the X and Y axes corresponding to genomic location in Mb and -log10P-values, respectively. Labels show the nearest gene to the novel sentinel variants identified in the discovery stage and taken forward to replication. The top signals were truncated at 10−10 for clarity. Novel and previously reported signals are highlighted in red and dark blue, respectively. Grey rings on the y-axis increase by increments of 2 (initial ring corresponding to P = 0.001, then 0.00001 etc.); and the outer and inner red rings correspond to the genome-wide significance level (P = 5 × 10−8) and P = 5 × 10−7, respectively. Image was created using Circos (v0.65)
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