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

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.

%B Nature Genetics %V 51 %P 237-244 %G eng %N 2 %R 10.1038/s41588-018-0307-5 %0 Journal Article %J Nature Genetics %D 2018 %T Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. %A Lee, James J %A Wedow, Robbee %A Okbay, Aysu %A Kong, Edward %A Maghzian, Omeed %A Zacher, Meghan %A Nguyen-Viet, Tuan Anh %A Bowers, Peter %A Sidorenko, Julia %A Richard Karlsson Linnér %A Mark Alan Fontana %A Kundu, Tushar %A Lee, Chanwook %A Hui Liu %A Li, Ruoxi %A Royer, Rebecca %A Pascal N Timshel %A Walters, Raymond K %A Willoughby, Emily A %A Yengo, Loic %A Alver, Maris %A Bao, Yanchun %A Clark, David W %A Day, Felix R %A Furlotte, Nicholas A %A Joshi, Peter K %A Kathryn E Kemper %A Kleinman, Aaron %A Langenberg, Claudia %A Mägi, Reedik %A Joey W Trampush %A Verma, Shefali Setia %A Wu, Yang %A Lam, Max %A Jing Hua Zhao %A Zheng, Zhili %A Jason D Boardman %A Campbell, Harry %A Freese, Jeremy %A Kathleen Mullan Harris %A Caroline Hayward %A Herd, Pamela %A Kumari, Meena %A Lencz, Todd %A Luan, Jian'an %A Anil K. Malhotra %A Andres Metspalu %A Lili Milani %A Ong, Ken K %A Perry, John R B %A David J Porteous %A Ritchie, Marylyn D %A Smart, Melissa C %A Smith, Blair H %A Tung, Joyce Y %A Wareham, Nicholas J %A James F Wilson %A Jonathan P. Beauchamp %A Dalton C Conley %A Tõnu Esko %A Lehrer, Steven F %A Patrik K E Magnusson %A Oskarsson, Sven %A Pers, Tune H %A Matthew R Robinson %A Thom, Kevin %A Watson, Chelsea %A Chabris, Christopher F %A Meyer, Michelle N %A David I Laibson %A Yang, Jian %A Johannesson, Magnus %A Philipp D Koellinger %A Turley, Patrick %A Peter M Visscher %A Daniel J. Benjamin %A Cesarini, David %K Adult %K Aged %K Aged, 80 and over %K Cohort Studies %K Educational Status %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Multifactorial Inheritance %K Phenotype %K Polymorphism, Single Nucleotide %X

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.

%B Nature Genetics %V 50 %P 1112-1121 %8 2018 07 23 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/30038396?dopt=Abstract %R 10.1038/s41588-018-0147-3