TY - JOUR

T1 - Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

AU - Erzurumluoglu, A Mesut

AU - Liu, Mengzhen

AU - Jackson, Victoria E

AU - Barnes, Daniel R

AU - Datta, Gargi

AU - Melbourne, Carl A

AU - Young, Robin

AU - Batini, Chiara

AU - Surendran, Praveen

AU - Jiang, Tao

AU - Adnan, Sheikh Daud

AU - Afaq, Saima

AU - Agrawal, Arpana

AU - Altmaier, Elisabeth

AU - Antoniou, Antonis C

AU - Asselbergs, Folkert W

AU - Baumbach, Clemens

AU - Bierut, Laura

AU - Bertelsen, Sarah

AU - Boehnke, Michael

AU - Bots, Michiel L

AU - Brazel, David M

AU - Chambers, John C

AU - Chang-Claude, Jenny

AU - Chen, Chu

AU - Corley, Janie

AU - Chou, Yi-Ling

AU - David, Sean P

AU - de Boer, Rudolf A

AU - de Leeuw, Christiaan A

AU - Dennis, Joe G

AU - Dominiczak, Anna F

AU - Dunning, Alison M

AU - Easton, Douglas F

AU - Eaton, Charles

AU - Elliott, Paul

AU - Evangelou, Evangelos

AU - Faul, Jessica D

AU - Foroud, Tatiana

AU - Goate, Alison

AU - Gong, Jian

AU - Grabe, Hans J

AU - Haessler, Jeff

AU - Haiman, Christopher

AU - Hallmans, Göran

AU - Karpe, Fredrik

AU - Nielsen, Sune Fallgaard

AU - Varga, Tibor V

AU - Chen, Fang

AU - Nordestgaard, Børge Grønne

AU - Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ consortium

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1038/s41380-018-0313-0

DO - 10.1038/s41380-018-0313-0

M3 - Review

C2 - 30617275

SP - 2392

EP - 2409

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -