Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

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 f...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Biological psychiatry (1969) Ročník 85; číslo 11; s. 946 - 955
Hlavní autoři:	Jiang, Yu, Hughey, Jordan M., Zhan, Xiaowei, Gong, Jian, Batini, Chiara, Liu, MengZhen, Surendran, Praveen, Young, Robin, Nielsen, Sune Fallgaard, Kontto, Jukka, Perola, Markus, Caslake, Muriel, Reily, Dermot F., Vogt, Thomas, Sattar, Naveed, Ford, Ian, Alam, Dewan S., Majumder, Abdulla al Shafi, Di Angelantonio, Emanuele, Chowdhury, Rajiv, Arveiler, Dominique, Blankenberg, Stefan, Veronesi, Giovanni, EPIC-CVD Consortium, Frossard, Philippe, Nordestgaard, Børge Grønne, Saleheen, Danish, Danesh, John, Butterworth, Adam S., Warren, Helen R., Tragante, Vinicius, Altmaier, Elisabeth, Luan, Jian’an, Scott, Robert A., Stirrups, Kathleen, Marouli, Eirini, Karpe, Fredrik, Poulter, Neil, Rolandsson, Olov, Chambers, John C., Kooner, Jaspal S., Wareham, Nicholas J., Renström, Frida, Hallmans, Göran, Marioni, Riccardo E., Corley, Janie, Starr, John M., van der Meer, Peter, Yavas, Ersin, Vaartjes, Ilonca, Asselbergs, Folkert W., Grabe, Hans J., Nauck, Matthias, Pharoah, Paul D.P., Dunning, Alison M., Dennis, Joe G., Tyrrell, Jessica, Mihailov, Evelin, Metspalu, Andres, Palmer, Colin N.A., Hall, Ian P., Strachan, David P., Understanding Society Scientific Group, Munroe, Patricia B., Jansson, Jan-Håkan, Franks, Paul W., Deloukas, Panos, Chou, Yi-Ling, Faul, Jessica D., Hammerschlag, Anke R., Hsu, Chris, Lai, Dongbing, Le, Nhung, Loukola, Anu, Mangino, Massimo, Melbourne, Carl A., Pistis, Giorgio, Qaiser, Beenish, Stringham, Heather, Wetherill, Leah, Bierut, Laura, Chen, Chu, Eaton, Charles B., Iacono, William G., Polderman, Tinca J., Schlessinger, David, Scholte, H. Steven, Smith, Jennifer A., Boehnke, Michael, Cucca, Francesco, David, Sean P., Foroud, Tatiana, Kardia, Sharon L.R., Madden, Pamela, McGue, Matt, Posthuma, Danielle, Spector, Timothy, Stram, Daniel, Kaprio, Jaakko, Vrieze, Scott
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 01.06.2019 Elsevier
Témata:	Alcohol Alcohol Drinking - genetics Alcohol Drinking - physiopathology Behavioral genetics Databases, Genetic Exome Genetic Predisposition to Disease - genetics Genetic Variation - physiology Genome-Wide Association Study - statistics & numerical data Genotype GWAS Heritability Humans Life Sciences Nicotine Oligonucleotide Array Sequence Analysis - statistics & numerical data Phenotype Polymorphism, Single Nucleotide - genetics Psychiatric/Mental Health Smoking - genetics Smoking - physiopathology Tobacco Alcohol Tobacco Heritability GWAS Behavioral genetics Nicotine
ISSN:	0006-3223, 1873-2402, 1873-2402
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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. 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. 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. 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC6534468 See acknowledgments for a list of authors associated with the replication consortia. These authors contributed equally to the work.
ISSN:	0006-3223 1873-2402 1873-2402
DOI:	10.1016/j.biopsych.2018.11.024