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

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.

Expanding the Genetic Architecture of Nicotine Dependence and its Shared Genetics with Multiple Traits: Findings from the Nicotine Dependence GenOmics (iNDiGO) Consortium

“…Beyond our discovery of rs1862416 with ND, SNPs across the TENM2 gene have been identified at genome-wide significance, as presented in the GWAS catalog 57 , for educational attainment, 38 smoking initiation (ever vs. never smoking), 5,[58][59][60] age of smoking initiation, 5 smoking cessation (current vs. former smoking), 5 cigarette pack-years, 61 alcohol consumption (drinks per week), 5 lung function, 60,62 height, 60 number of sexual partners, 58 depression, 63,64 risk taking tendency, 58 body mass index, 60 menarche (age at onset) 65 , and regular attendance at a religious group 66 . Our pairwise comparisons supported pleiotropic associations in the TENM2 region.…”

The Older Finnish Twin Cohort — 45 Years of Follow-up

“…We have also contributed to multiple other meta-analyses of GWAS data on various smoking and alcohol phenotypes, notably the GSCAN consortium GWAS and exome analyses (Brazel et al, 2018;Erzurumluoglu et al, 2019;Liu et al, 2019), for nicotine dependence (Hancock et al, 2018) and alcohol dependence (Walters et al, 2018). These analyses have been based on alcohol and smoking behavior data from the surveys, as well as from the structured psychiatric interviews conducted as part of the NAG study.…”

Genome-wide association study of smoking trajectory and meta-analysis of smoking status in 842,000 individuals

“…igarette smoking has an estimated heritability of 40-70% 1,2 , and is a leading cause of morbidity and mortality worldwide. In the past two decades, over 25 genome-wide association studies (GWAS) of smoking and smoking-related phenotypes have been reported [3][4][5][6][7][8][9] . Among several hundred reported loci, the established loci are predominantly in a few genomic regions, such as 15q25 (CHRNA5-A3-B4) and 8p11 (CHRNB3-CHRNA6) 3,4,10,11 .…”