TY - JOUR T1 - Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. JF - Nature Genetics Y1 - 2019 A1 - Liu, Mengzhen A1 - Jiang, Yu A1 - Wedow, Robbee A1 - Li, Yue A1 - Brazel, David M A1 - Chen, Fang A1 - Datta, Gargi A1 - Davila-Velderrain, Jose A1 - McGuire, Daniel A1 - Tian, Chao A1 - Zhan, Xiaowei A1 - Choquet, Hélène A1 - Docherty, Anna R A1 - Jessica Faul A1 - Foerster, Johanna R A1 - Fritsche, Lars G A1 - Gabrielsen, Maiken Elvestad A1 - Gordon, Scott D A1 - Jeffrey Haessler A1 - Jouke-Jan Hottenga A1 - Huang, Hongyan A1 - Jang, Seon-Kyeong A1 - Philip R Jansen A1 - Ling, Yueh A1 - Mägi, Reedik A1 - Matoba, Nana A1 - McMahon, George A1 - Mulas, Antonella A1 - Orrù, Valeria A1 - Palviainen, Teemu A1 - Anita Pandit A1 - Reginsson, Gunnar W A1 - Skogholt, Anne Heidi A1 - Smith, Jennifer A A1 - Taylor, Amy E A1 - Turman, Constance A1 - Gonneke Willemsen A1 - Young, Hannah A1 - Young, Kendra A A1 - Zajac, Gregory J M A1 - Zhao, Wei A1 - Zhou, Wei A1 - Bjornsdottir, Gyda A1 - Boardman, Jason D A1 - Boehnke, Michael A1 - Dorret I Boomsma A1 - Chen, Chu A1 - Francesco Cucca A1 - Davies, Gareth E A1 - Charles B Eaton A1 - Ehringer, Marissa A A1 - Tõnu Esko A1 - Fiorillo, Edoardo A1 - Gillespie, Nathan A A1 - Gudbjartsson, Daniel F A1 - Haller, Toomas A1 - Kathleen Mullan Harris A1 - Andrew C Heath A1 - Hewitt, John K A1 - Hickie, Ian B A1 - Hokanson, John E A1 - Hopfer, Christian J A1 - Hunter, David J A1 - Iacono, William G A1 - Johnson, Eric O A1 - Kamatani, Yoichiro A1 - Sharon L R Kardia A1 - Matthew C Keller A1 - Kellis, Manolis A1 - Charles Kooperberg A1 - Kraft, Peter A1 - Krauter, Kenneth S A1 - Laakso, Markku A1 - Penelope A Lind A1 - Loukola, Anu A1 - Lutz, Sharon M A1 - Pamela A F Madden A1 - Nicholas G Martin A1 - McGue, Matt A1 - Matthew B McQueen A1 - Sarah E Medland A1 - Andres Metspalu A1 - Mohlke, Karen L A1 - Nielsen, Jonas B A1 - Okada, Yukinori A1 - Peters, Ulrike A1 - Tinca J Polderman A1 - Posthuma, Danielle A1 - Reiner, Alexander P A1 - Rice, John P A1 - Rimm, Eric A1 - Rose, Richard J A1 - Runarsdottir, Valgerdur A1 - Stallings, Michael C A1 - Stančáková, Alena A1 - Stefansson, Hreinn A1 - Thai, Khanh K A1 - Hilary A Tindle A1 - Tyrfingsson, Thorarinn A1 - Wall, Tamara L A1 - David R Weir A1 - Weisner, Constance A1 - Whitfield, John B A1 - Winsvold, Bendik Slagsvold A1 - Yin, Jie A1 - Zuccolo, Luisa A1 - Laura Bierut A1 - Hveem, Kristian A1 - Lee, James J A1 - Munafò, Marcus R A1 - Saccone, Nancy L A1 - Willer, Cristen J A1 - Marilyn C Cornelis A1 - David, Sean P A1 - Hinds, David A A1 - Jorgenson, Eric A1 - Kaprio, Jaakko A1 - Stitzel, Jerry A A1 - Stefansson, Kari A1 - Thorgeirsson, Thorgeir E A1 - Gonçalo R Abecasis A1 - Liu, Dajiang J A1 - Scott Vrieze KW - Alcohol Drinking KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Risk KW - Smoking KW - Tobacco KW - Tobacco Use Disorder AB -

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.

VL - 51 IS - 2 ER - TY - JOUR T1 - Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. JF - Nature Genetics Y1 - 2018 A1 - Lee, James J A1 - Wedow, Robbee A1 - Okbay, Aysu A1 - Kong, Edward A1 - Maghzian, Omeed A1 - Zacher, Meghan A1 - Nguyen-Viet, Tuan Anh A1 - Bowers, Peter A1 - Sidorenko, Julia A1 - Richard Karlsson Linnér A1 - Mark Alan Fontana A1 - Kundu, Tushar A1 - Lee, Chanwook A1 - Hui Liu A1 - Li, Ruoxi A1 - Royer, Rebecca A1 - Pascal N Timshel A1 - Walters, Raymond K A1 - Willoughby, Emily A A1 - Yengo, Loic A1 - Alver, Maris A1 - Bao, Yanchun A1 - Clark, David W A1 - Day, Felix R A1 - Furlotte, Nicholas A A1 - Joshi, Peter K A1 - Kathryn E Kemper A1 - Kleinman, Aaron A1 - Langenberg, Claudia A1 - Mägi, Reedik A1 - Joey W Trampush A1 - Verma, Shefali Setia A1 - Wu, Yang A1 - Lam, Max A1 - Jing Hua Zhao A1 - Zheng, Zhili A1 - Jason D Boardman A1 - Campbell, Harry A1 - Freese, Jeremy A1 - Kathleen Mullan Harris A1 - Caroline Hayward A1 - Herd, Pamela A1 - Kumari, Meena A1 - Lencz, Todd A1 - Luan, Jian'an A1 - Anil K. Malhotra A1 - Andres Metspalu A1 - Lili Milani A1 - Ong, Ken K A1 - Perry, John R B A1 - David J Porteous A1 - Ritchie, Marylyn D A1 - Smart, Melissa C A1 - Smith, Blair H A1 - Tung, Joyce Y A1 - Wareham, Nicholas J A1 - James F Wilson A1 - Jonathan P. Beauchamp A1 - Dalton C Conley A1 - Tõnu Esko A1 - Lehrer, Steven F A1 - Patrik K E Magnusson A1 - Oskarsson, Sven A1 - Pers, Tune H A1 - Matthew R Robinson A1 - Thom, Kevin A1 - Watson, Chelsea A1 - Chabris, Christopher F A1 - Meyer, Michelle N A1 - David I Laibson A1 - Yang, Jian A1 - Johannesson, Magnus A1 - Philipp D Koellinger A1 - Turley, Patrick A1 - Peter M Visscher A1 - Daniel J. Benjamin A1 - Cesarini, David KW - Adult KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Educational Status KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Multifactorial Inheritance KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

VL - 50 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30038396?dopt=Abstract ER -