%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 Nat Genet %D 2016 %T Genome-wide analysis identifies 12 loci influencing human reproductive behavior. %A Nicola Barban %A Jansen, Rick %A de Vlaming, Ronald %A Vaez, Ahmad %A Mandemakers, Jornt J %A Felix C Tropf %A Shen, Xia %A James F Wilson %A Daniel I Chasman %A Ilja M Nolte %A Tragante, Vinicius %A van der Laan, Sander W %A Perry, John R B %A Kong, Augustine %A Ahluwalia, Tarunveer S %A Albrecht, Eva %A Laura M Yerges-Armstrong %A Atzmon, Gil %A Auro, Kirsi %A Kristin L. Ayers %A Bakshi, Andrew %A Ben-Avraham, Danny %A Klaus Berger %A Bergman, Aviv %A Bertram, Lars %A Bielak, Lawrence F %A Bjornsdottir, Gyda %A Bonder, Marc Jan %A Broer, Linda %A Bui, Minh %A Barbieri, Caterina %A Cavadino, Alana %A Chavarro, Jorge E %A Turman, Constance %A Maria Pina Concas %A Cordell, Heather J %A Gail Davies %A Eibich, Peter %A Eriksson, Nicholas %A Tõnu Esko %A Eriksson, Joel %A Falahi, Fahimeh %A Felix, Janine F %A Mark Alan Fontana %A Lude L Franke %A Gandin, Ilaria %A Gaskins, Audrey J %A Gieger, Christian %A Gunderson, Erica P %A Guo, Xiuqing %A Caroline Hayward %A He, Chunyan %A Edith Hofer %A Huang, Hongyan %A Joshi, Peter K %A Kanoni, Stavroula %A Karlsson, Robert %A Kiechl, Stefan %A Kifley, Annette %A Kluttig, Alexander %A Kraft, Peter %A Lagou, Vasiliki %A Lecoeur, Cecile %A Lahti, Jari %A Li-Gao, Ruifang %A Penelope A Lind %A Tian Liu %A Makalic, Enes %A Mamasoula, Crysovalanto %A Lindsay K Matteson %A Mbarek, Hamdi %A McArdle, Patrick F %A McMahon, George %A Meddens, S Fleur W %A Mihailov, Evelin %A Michael B Miller %A Missmer, Stacey A %A Monnereau, Claire %A van der Most, Peter J %A Myhre, Ronny %A Michael A Nalls %A Nutile, Teresa %A Ioanna Panagiota Kalafati %A Porcu, Eleonora %A Prokopenko, Inga %A Rajan, Kumar B %A Rich-Edwards, Janet %A Cornelius A Rietveld %A Robino, Antonietta %A Rose, Lynda M %A Rueedi, Rico %A Ryan, Kathleen A %A Saba, Yasaman %A Schmidt, Daniel %A Jennifer A Smith %A Stolk, Lisette %A Streeten, Elizabeth %A Tönjes, Anke %A Thorleifsson, Gudmar %A Ulivi, Sheila %A Wedenoja, Juho %A Jürgen Wellmann %A Willeit, Peter %A Yao, Jie %A Yengo, Loic %A Jing Hua Zhao %A Wei Zhao %A Zhernakova, Daria V %A Amin, Najaf %A Andrews, Howard %A Balkau, Beverley %A Barzilai, Nir %A Bergmann, Sven %A Biino, Ginevra %A Bisgaard, Hans %A Bønnelykke, Klaus %A Dorret I Boomsma %A Buring, Julie E %A Campbell, Harry %A Cappellani, Stefania %A Ciullo, Marina %A Cox, Simon R %A Francesco Cucca %A Toniolo, Daniela %A Davey-Smith, George %A Ian J Deary %A George Dedoussis %A Deloukas, Panos %A Cornelia M van Duijn %A Eco J. C. de Geus %A Johan G Eriksson %A Jessica Faul %A Cinzia Felicita Sala %A Froguel, Philippe %A Paolo P. Gasparini %A Giorgia G Girotto %A Hans-Jörgen Grabe %A Greiser, Karin Halina %A Groenen, Patrick J F %A de Haan, Hugoline G %A Haerting, Johannes %A Tamara B Harris %A Andrew C Heath %A Heikkilä, Kauko %A Hofman, Albert %A Homuth, Georg %A Holliday, Elizabeth G %A John L Hopper %A Hyppönen, Elina %A Jacobsson, Bo %A Vincent Jaddoe %A Johannesson, Magnus %A Jugessur, Astanand %A Kähönen, Mika %A Kajantie, Eero %A Sharon L R Kardia %A Keavney, Bernard %A Kolcic, Ivana %A Koponen, Päivikki %A Kovacs, Peter %A Kronenberg, Florian %A Kutalik, Zoltán %A La Bianca, Martina %A Lachance, Genevieve %A Iacono, William G %A Lai, Sandra %A Lehtimäki, Terho %A David C Liewald %A Lindgren, Cecilia M %A Yongmei Liu %A Luben, Robert %A Lucht, Michael %A Luoto, Riitta %A Magnus, Per %A Patrik K E Magnusson %A Nicholas G Martin %A McGue, Matt %A McQuillan, Ruth %A Sarah E Medland %A Meisinger, Christa %A Mellström, Dan %A Andres Metspalu %A Traglia, Michela %A Lili Milani %A Mitchell, Paul %A Grant W Montgomery %A Dennis O Mook-Kanamori %A de Mutsert, Renée %A Nohr, Ellen A %A Ohlsson, Claes %A Olsen, Jørn %A Ong, Ken K %A Paternoster, Lavinia %A Pattie, Alison %A Brenda W J H Penninx %A Markus Perola %A Peyser, Patricia A %A Pirastu, Mario %A Polasek, Ozren %A Power, Chris %A Kaprio, Jaakko %A Raffel, Leslie J %A Katri Räikkönen %A Olli T Raitakari %A Ridker, Paul M %A Ring, Susan M %A Roll, Kathryn %A Rudan, Igor %A Ruggiero, Daniela %A Rujescu, Dan %A Veikko Salomaa %A Schlessinger, David %A Schmidt, Helena %A Schmidt, Reinhold %A Schupf, Nicole %A Johannes H Smit %A Sorice, Rossella %A Timothy Spector %A John M Starr %A Stöckl, Doris %A Strauch, Konstantin %A Stumvoll, Michael %A Swertz, Morris A %A Thorsteinsdottir, Unnur %A A. Roy Thurik %A Nicholas J Timpson %A Tung, Joyce Y %A André G Uitterlinden %A Vaccargiu, Simona %A Viikari, Jorma %A Vitart, Veronique %A Völzke, Henry %A Vollenweider, Peter %A Vuckovic, Dragana %A Waage, Johannes %A Wagner, Gert G %A Wang, Jie Jin %A Wareham, Nicholas J %A David R Weir %A Gonneke Willemsen %A Willeit, Johann %A Alan F Wright %A Krina T Zondervan %A Stefansson, Kari %A Krueger, Robert F %A Lee, James J %A Daniel J. Benjamin %A Cesarini, David %A Philipp D Koellinger %A den Hoed, Marcel %A Snieder, Harold %A Melinda C Mills %X

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

%B Nat Genet %V 48 %P 1462-1472 %8 2016 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/27798627?dopt=Abstract %R 10.1038/ng.3698 %0 Journal Article %J Nature %D 2016 %T Genome-wide association study identifies 74 loci associated with educational attainment. %A Okbay, Aysu %A Jonathan P. Beauchamp %A Mark Alan Fontana %A Lee, James J %A Pers, Tune H %A Cornelius A Rietveld %A Turley, Patrick %A Chen, Guo-Bo %A Emilsson, Valur %A Meddens, S Fleur W %A Oskarsson, Sven %A Pickrell, Joseph K %A Thom, Kevin %A Pascal N Timshel %A de Vlaming, Ronald %A Abdel Abdellaoui %A Ahluwalia, Tarunveer S %A Bacelis, Jonas %A Baumbach, Clemens %A Bjornsdottir, Gyda %A Brandsma, Johannes H %A Maria Pina Concas %A Derringer, Jaime %A Furlotte, Nicholas A %A Galesloot, Tessel E %A Giorgia G Girotto %A Gupta, Richa %A Hall, Leanne M %A Sarah E Harris %A Edith Hofer %A Horikoshi, Momoko %A Huffman, Jennifer E %A Kaasik, Kadri %A Ioanna Panagiota Kalafati %A Karlsson, Robert %A Kong, Augustine %A Lahti, Jari %A Sven J van der Lee %A Christiaan de Leeuw %A Penelope A Lind %A Lindgren, Karl-Oskar %A Tian Liu %A Mangino, Massimo %A Marten, Jonathan %A Mihailov, Evelin %A Michael B Miller %A van der Most, Peter J %A Christopher J Oldmeadow %A Payton, Antony %A Pervjakova, Natalia %A Wouter J Peyrot %A Qian, Yong %A Olli T Raitakari %A Rueedi, Rico %A Salvi, Erika %A Schmidt, Börge %A Schraut, Katharina E %A Jianxin Shi %A Albert Vernon Smith %A Poot, Raymond A %A St Pourcain, Beate %A Teumer, Alexander %A Thorleifsson, Gudmar %A Verweij, Niek %A Vuckovic, Dragana %A Jürgen Wellmann %A Westra, Harm-Jan %A Yang, Jingyun %A Wei Zhao %A Zhihong Zhu %A Alizadeh, Behrooz Z %A Amin, Najaf %A Bakshi, Andrew %A Baumeister, Sebastian E %A Biino, Ginevra %A Bønnelykke, Klaus %A Patricia A. Boyle %A Campbell, Harry %A Cappuccio, Francesco P %A Gail Davies %A De Neve, Jan-Emmanuel %A Deloukas, Panos %A Demuth, Ilja %A Ding, Jun %A Eibich, Peter %A Eisele, Lewin %A Eklund, Niina %A Jessica Faul %A Feitosa, Mary F %A Andreas J Forstner %A Gandin, Ilaria %A Gunnarsson, Bjarni %A Halldórsson, Bjarni V %A Tamara B Harris %A Andrew C Heath %A Lynne J Hocking %A Holliday, Elizabeth G %A Homuth, Georg %A Horan, Michael A %A Jouke-Jan Hottenga %A Philip L de Jager %A Joshi, Peter K %A Jugessur, Astanand %A Marika A Kaakinen %A Kähönen, Mika %A Kanoni, Stavroula %A Keltigangas-Järvinen, Liisa %A Lambertus A Kiemeney %A Kolcic, Ivana %A Koskinen, Seppo %A Kraja, Aldi T %A Kroh, Martin %A Kutalik, Zoltán %A Latvala, Antti %A Lenore J Launer %A Lebreton, Maël P %A Douglas F Levinson %A Paul Lichtenstein %A Lichtner, Peter %A David C Liewald %A Loukola, Anu %A Pamela A F Madden %A Mägi, Reedik %A Mäki-Opas, Tomi %A Riccardo E Marioni %A Marques-Vidal, Pedro %A Meddens, Gerardus A %A McMahon, George %A Meisinger, Christa %A Meitinger, Thomas %A Milaneschi, Yusplitri %A Lili Milani %A Grant W Montgomery %A Myhre, Ronny %A Nelson, Christopher P %A Nyholt, Dale R %A William E R Ollier %A Aarno Palotie %A Paternoster, Lavinia %A Nancy L Pedersen %A Katja E Petrovic %A David J Porteous %A Katri Räikkönen %A Ring, Susan M %A Robino, Antonietta %A Rostapshova, Olga %A Rudan, Igor %A Rustichini, Aldo %A Veikko Salomaa %A Sanders, Alan R %A Sarin, Antti-Pekka %A Schmidt, Helena %A Rodney J Scott %A Smith, Blair H %A Jennifer A Smith %A Staessen, Jan A %A Steinhagen-Thiessen, Elisabeth %A Strauch, Konstantin %A Antonio Terracciano %A Tobin, Martin D %A Ulivi, Sheila %A Vaccargiu, Simona %A Quaye, Lydia %A van Rooij, Frank J A %A Venturini, Cristina %A Anna A E Vinkhuyzen %A Völker, Uwe %A Völzke, Henry %A Vonk, Judith M %A Vozzi, Diego %A Waage, Johannes %A Erin B Ware %A Gonneke Willemsen %A John R. Attia %A David A Bennett %A Klaus Berger %A Bertram, Lars %A Bisgaard, Hans %A Dorret I Boomsma %A Ingrid B Borecki %A Bültmann, Ute %A Chabris, Christopher F %A Francesco Cucca %A Cusi, Daniele %A Ian J Deary %A George Dedoussis %A Cornelia M van Duijn %A Johan G Eriksson %A Franke, Barbara %A Lude L Franke %A Paolo P. Gasparini %A Gejman, Pablo V %A Gieger, Christian %A Hans-Jörgen Grabe %A Gratten, Jacob %A Groenen, Patrick J F %A Gudnason, Vilmundur %A van der Harst, Pim %A Caroline Hayward %A Hinds, David A %A Hoffmann, Wolfgang %A Hyppönen, Elina %A Iacono, William G %A Jacobsson, Bo %A Järvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Kaprio, Jaakko %A Sharon L R Kardia %A Lehtimäki, Terho %A Lehrer, Steven F %A Patrik K E Magnusson %A Nicholas G Martin %A McGue, Matt %A Andres Metspalu %A Pendleton, Neil %A Brenda W J H Penninx %A Markus Perola %A Nicola Pirastu %A Pirastu, Mario %A Polasek, Ozren %A Posthuma, Danielle %A Power, Christine %A Province, Michael A %A Nilesh J Samani %A Schlessinger, David %A Schmidt, Reinhold %A Thorkild I. A. Sørensen %A Timothy Spector %A Stefansson, Kari %A Thorsteinsdottir, Unnur %A A. Roy Thurik %A Nicholas J Timpson %A Henning Tiemeier %A Tung, Joyce Y %A André G Uitterlinden %A Vitart, Veronique %A Vollenweider, Peter %A David R Weir %A James F Wilson %A Alan F Wright %A Dalton C Conley %A Krueger, Robert F %A George Davey Smith %A Hofman, Albert %A David I Laibson %A Sarah E Medland %A Meyer, Michelle N %A Yang, Jian %A Johannesson, Magnus %A Peter M Visscher %A Tõnu Esko %A Philipp D Koellinger %A Cesarini, David %A Daniel J. Benjamin %K Alzheimer's disease %K Bipolar Disorder %K Cognitive Ability %K Education %K Fetus %K Genome-Wide Association Study %K Humans %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Schizophrenia %K United Kingdom %X

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

%B Nature %V 533 %P 539-42 %8 2016 05 26 %G eng %N 7604 %1 http://www.ncbi.nlm.nih.gov/pubmed/27225129?dopt=Abstract %R 10.1038/nature17671