@article {12124, title = {Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.}, journal = {Molecular Psychiatry}, volume = {25}, year = {2020}, pages = {2392-2409}, 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 {\texttimes} 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 {\texttimes} 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 {\texttimes} 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.

}, keywords = {Biological Specimen Banks, Databases, Factual, Europe, Exome, Female, Genetic Loci, Humans, Male, Polymorphism, Single Nucleotide, Smoking, United Kingdom}, issn = {1476-5578}, doi = {10.1038/s41380-018-0313-0}, author = {Erzurumluoglu, A Mesut and Liu, Mengzhen and Jackson, Victoria E and Barnes, Daniel R and Datta, Gargi and Melbourne, Carl A and Young, Robin and Batini, Chiara and Surendran, Praveen and Jiang, Tao and Adnan, Sheikh Daud and Afaq, Saima and Agrawal, Arpana and Altmaier, Elisabeth and Antoniou, Antonis C and Asselbergs, Folkert W and Baumbach, Clemens and Laura Bierut and Bertelsen, Sarah and Boehnke, Michael and Bots, Michiel L and Brazel, David M and Chambers, John C and Chang-Claude, Jenny and Chen, Chu and Corley, Janie and Chou, Yi-Ling and David, Sean P and de Boer, Rudolf A and Christiaan de Leeuw and Joe G Dennis and Dominiczak, Anna F and Dunning, Alison M and Easton, Douglas F and Charles B Eaton and Elliott, Paul and Evangelou, Evangelos and Jessica Faul and Tatiana Foroud and Goate, Alison and Gong, Jian and Hans-J{\"o}rgen Grabe and Jeffrey Haessler and Christopher A Haiman and Hallmans, G{\"o}ran and Anke R Hammerschlag and Sarah E Harris and Andrew T Hattersley and Andrew C Heath and Hsu, Chris and Iacono, William G and Kanoni, Stavroula and Kapoor, Manav and Kaprio, Jaakko and Sharon L R Kardia and Karpe, Fredrik and Kontto, Jukka and Kooner, Jaspal S and Charles Kooperberg and Kuulasmaa, Kari and Laakso, Markku and Lai, Dongbing and Langenberg, Claudia and Le, Nhung and Lettre, Guillaume and Loukola, Anu and Luan, Jian{\textquoteright}an and Pamela A F Madden and Mangino, Massimo and Riccardo E Marioni and Marouli, Eirini and Marten, Jonathan and Nicholas G Martin and McGue, Matt and Michailidou, Kyriaki and Mihailov, Evelin and Moayyeri, Alireza and Moitry, Marie and M{\"u}ller-Nurasyid, Martina and Naheed, Aliya and Nauck, Matthias and Neville, Matthew J and Sune Fallgaard Nielsen and Kari E North and Markus Perola and Pharoah, Paul D P and Pistis, Giorgio and Tinca J Polderman and Posthuma, Danielle and Neil Poulter and Qaiser, Beenish and Rasheed, Asif and Reiner, Alex and Renstrom, Frida and Rice, John and Rohde, Rebecca and Rolandsson, Olov and Nilesh J Samani and Samuel, Maria and Schlessinger, David and H Steven Scholte and Scott, Robert A and Peter Sever and Shao, Yaming and Shrine, Nick and Smith, Jennifer A and John M Starr and Kathleen E Stirrups and Stram, Danielle and Heather M Stringham and Tachmazidou, Ioanna and Tardif, Jean-Claude and Thompson, Deborah J and Hilary A Tindle and Tragante, Vinicius and Trompet, Stella and Turcot, Val{\'e}rie and Tyrrell, Jessica and Vaartjes, Ilonca and Van Der Leij, Andries R and van der Meer, Peter and Varga, Tibor V and Verweij, Niek and V{\"o}lzke, Henry and Wareham, Nicholas J and Warren, Helen R and David R Weir and Weiss, Stefan and Wetherill, Leah and Yaghootkar, Hanieh and Yavas, Ersin and Jiang, Yu and Chen, Fang and Zhan, Xiaowei and Zhang, Weihua and Zhao, Wei and Zhao, Wei and Zhou, Kaixin and Amouyel, Philippe and Blankenberg, Stefan and Caulfield, Mark J and Chowdhury, Rajiv and Francesco Cucca and Ian J Deary and Deloukas, Panos and Di Angelantonio, Emanuele and Marco M Ferrario and Ferri{\`e}res, Jean and Franks, Paul W and Timothy M Frayling and Frossard, Philippe and Hall, Ian P and Caroline Hayward and Jansson, Jan-H{\r a}kan and Jukema, J Wouter and Kee, Frank and M{\"a}nnist{\"o}, Satu and Andres Metspalu and Munroe, Patricia B and B{\o}rge G Nordestgaard and Palmer, Colin N A and Veikko Salomaa and Sattar, Naveed and Timothy Spector and David P Strachan and van der Harst, Pim and Zeggini, Eleftheria and Saleheen, Danish and Adam S Butterworth and Wain, Louise V and Gon{\c c}alo R Abecasis and Danesh, John and Tobin, Martin D and Scott Vrieze and Liu, Dajiang J and Howson, Joanna M M} } @article {12122, title = {Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.}, journal = {Nature Genetics}, volume = {51}, year = {2019}, pages = {237-244}, abstract = {

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

}, keywords = {Alcohol Drinking, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Risk, Smoking, Tobacco, Tobacco Use Disorder}, issn = {1546-1718}, doi = {10.1038/s41588-018-0307-5}, author = {Liu, Mengzhen and Jiang, Yu and Wedow, Robbee and Li, Yue and Brazel, David M and Chen, Fang and Datta, Gargi and Davila-Velderrain, Jose and McGuire, Daniel and Tian, Chao and Zhan, Xiaowei and Choquet, H{\'e}l{\`e}ne and Docherty, Anna R and Jessica Faul and Foerster, Johanna R and Fritsche, Lars G and Gabrielsen, Maiken Elvestad and Gordon, Scott D and Jeffrey Haessler and Jouke-Jan Hottenga and Huang, Hongyan and Jang, Seon-Kyeong and Philip R Jansen and Ling, Yueh and M{\"a}gi, Reedik and Matoba, Nana and McMahon, George and Mulas, Antonella and Orr{\`u}, Valeria and Palviainen, Teemu and Anita Pandit and Reginsson, Gunnar W and Skogholt, Anne Heidi and Smith, Jennifer A and Taylor, Amy E and Turman, Constance and Gonneke Willemsen and Young, Hannah and Young, Kendra A and Zajac, Gregory J M and Zhao, Wei and Zhou, Wei and Bjornsdottir, Gyda and Boardman, Jason D and Boehnke, Michael and Dorret I Boomsma and Chen, Chu and Francesco Cucca and Davies, Gareth E and Charles B Eaton and Ehringer, Marissa A and T{\~o}nu Esko and Fiorillo, Edoardo and Gillespie, Nathan A and Gudbjartsson, Daniel F and Haller, Toomas and Kathleen Mullan Harris and Andrew C Heath and Hewitt, John K and Hickie, Ian B and Hokanson, John E and Hopfer, Christian J and Hunter, David J and Iacono, William G and Johnson, Eric O and Kamatani, Yoichiro and Sharon L R Kardia and Matthew C Keller and Kellis, Manolis and Charles Kooperberg and Kraft, Peter and Krauter, Kenneth S and Laakso, Markku and Penelope A Lind and Loukola, Anu and Lutz, Sharon M and Pamela A F Madden and Nicholas G Martin and McGue, Matt and Matthew B McQueen and Sarah E Medland and Andres Metspalu and Mohlke, Karen L and Nielsen, Jonas B and Okada, Yukinori and Peters, Ulrike and Tinca J Polderman and Posthuma, Danielle and Reiner, Alexander P and Rice, John P and Rimm, Eric and Rose, Richard J and Runarsdottir, Valgerdur and Stallings, Michael C and Stan{\v c}{\'a}kov{\'a}, Alena and Stefansson, Hreinn and Thai, Khanh K and Hilary A Tindle and Tyrfingsson, Thorarinn and Wall, Tamara L and David R Weir and Weisner, Constance and Whitfield, John B and Winsvold, Bendik Slagsvold and Yin, Jie and Zuccolo, Luisa and Laura Bierut and Hveem, Kristian and Lee, James J and Munaf{\`o}, Marcus R and Saccone, Nancy L and Willer, Cristen J and Marilyn C Cornelis and David, Sean P and Hinds, David A and Jorgenson, Eric and Kaprio, Jaakko and Stitzel, Jerry A and Stefansson, Kari and Thorgeirsson, Thorgeir E and Gon{\c c}alo R Abecasis and Liu, Dajiang J and Scott Vrieze} } @article {12125, title = {Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol~Use.}, journal = {Biological Psychiatry}, volume = {85}, year = {2019}, pages = {946-955}, abstract = {

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.

METHODS: We analyzed \~{}250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.

RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1\% to 2.2\% of phenotypic variance, reflecting 11\% to 18\% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95\% credible intervals.

CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

}, keywords = {Alcohol Drinking, Databases, Genetic, Exome, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Smoking}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2018.11.024}, author = {Brazel, David M and Jiang, Yu and Hughey, Jordan M and Turcot, Val{\'e}rie and Zhan, Xiaowei and Gong, Jian and Batini, Chiara and Weissenkampen, J Dylan and Liu, Mengzhen and Barnes, Daniel R and Bertelsen, Sarah and Chou, Yi-Ling and Erzurumluoglu, A Mesut and Jessica Faul and Jeffrey Haessler and Anke R Hammerschlag and Hsu, Chris and Kapoor, Manav and Lai, Dongbing and Le, Nhung and Christiaan de Leeuw and Loukola, Anu and Mangino, Massimo and Melbourne, Carl A and Pistis, Giorgio and Qaiser, Beenish and Rohde, Rebecca and Shao, Yaming and Heather M Stringham and Wetherill, Leah and Zhao, Wei and Agrawal, Arpana and Laura Bierut and Chen, Chu and Charles B Eaton and Goate, Alison and Christopher A Haiman and Andrew C Heath and Iacono, William G and Nicholas G Martin and Tinca J Polderman and Reiner, Alex and Rice, John and Schlessinger, David and H Steven Scholte and Smith, Jennifer A and Tardif, Jean-Claude and Hilary A Tindle and Van Der Leij, Andries R and Boehnke, Michael and Chang-Claude, Jenny and Francesco Cucca and David, Sean P and Tatiana Foroud and Howson, Joanna M M and Sharon L R Kardia and Charles Kooperberg and Laakso, Markku and Lettre, Guillaume and Pamela A F Madden and McGue, Matt and Kari E North and Posthuma, Danielle and Timothy Spector and Stram, Daniel and Tobin, Martin D and David R Weir and Kaprio, Jaakko and Gon{\c c}alo R Abecasis and Liu, Dajiang J and Scott Vrieze} }