Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

VL - 48 IS - 6 ER - TY - JOUR T1 - Genome-wide analysis identifies 12 loci influencing human reproductive behavior. JF - Nat Genet Y1 - 2016 A1 - Nicola Barban A1 - Jansen, Rick A1 - de Vlaming, Ronald A1 - Vaez, Ahmad A1 - Mandemakers, Jornt J A1 - Felix C Tropf A1 - Shen, Xia A1 - Wilson, James F A1 - Chasman, Daniel I A1 - Nolte, Ilja M A1 - Tragante, Vinicius A1 - van der Laan, Sander W A1 - Perry, John R B A1 - Kong, Augustine A1 - Ahluwalia, Tarunveer S A1 - Albrecht, Eva A1 - Laura Yerges-Armstrong A1 - Atzmon, Gil A1 - Auro, Kirsi A1 - Ayers, Kristin A1 - Bakshi, Andrew A1 - Ben-Avraham, Danny A1 - Berger, Klaus A1 - Bergman, Aviv A1 - Bertram, Lars A1 - Bielak, Lawrence F A1 - Bjornsdottir, Gyda A1 - Bonder, Marc Jan A1 - Broer, Linda A1 - Bui, Minh A1 - Barbieri, Caterina A1 - Cavadino, Alana A1 - Chavarro, Jorge E A1 - Turman, Constance A1 - Maria Pina Concas A1 - Cordell, Heather J A1 - Gail Davies A1 - Eibich, Peter A1 - Eriksson, Nicholas A1 - Tõnu Esko A1 - Eriksson, Joel A1 - Falahi, Fahimeh A1 - Felix, Janine F A1 - Mark A Fontana A1 - Lude L. Franke A1 - Gandin, Ilaria A1 - Gaskins, Audrey J A1 - Gieger, Christian A1 - Gunderson, Erica P A1 - Guo, Xiuqing A1 - Hayward, Caroline A1 - He, Chunyan A1 - Hofer, Edith A1 - Huang, Hongyan A1 - Joshi, Peter K A1 - Kanoni, Stavroula A1 - Karlsson, Robert A1 - Kiechl, Stefan A1 - Kifley, Annette A1 - Kluttig, Alexander A1 - Kraft, Peter A1 - Lagou, Vasiliki A1 - Lecoeur, Cecile A1 - Lahti, Jari A1 - Li-Gao, Ruifang A1 - Penelope A. Lind A1 - Liu, Tian A1 - Makalic, Enes A1 - Mamasoula, Crysovalanto A1 - Lindsay Matteson A1 - Mbarek, Hamdi A1 - McArdle, Patrick F A1 - McMahon, George A1 - Meddens, S Fleur W A1 - Mihailov, Evelin A1 - Mike Miller A1 - Missmer, Stacey A A1 - Monnereau, Claire A1 - van der Most, Peter J A1 - Myhre, Ronny A1 - Mike A Nalls A1 - Nutile, Teresa A1 - Ioanna Panagiota Kalafati A1 - Porcu, Eleonora A1 - Prokopenko, Inga A1 - Rajan, Kumar B A1 - Rich-Edwards, Janet A1 - Cornelius A Rietveld A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rueedi, Rico A1 - Ryan, Kathleen A A1 - Saba, Yasaman A1 - Schmidt, Daniel A1 - Jennifer A. Smith A1 - Stolk, Lisette A1 - Streeten, Elizabeth A1 - Tönjes, Anke A1 - Thorleifsson, Gudmar A1 - Ulivi, Sheila A1 - Wedenoja, Juho A1 - Wellmann, Juergen A1 - Willeit, Peter A1 - Yao, Jie A1 - Yengo, Loic A1 - Jing Hua Zhao A1 - Wei Zhao A1 - Zhernakova, Daria V A1 - Amin, Najaf A1 - Andrews, Howard A1 - Balkau, Beverley A1 - Barzilai, Nir A1 - Bergmann, Sven A1 - Biino, Ginevra A1 - Bisgaard, Hans A1 - Bønnelykke, Klaus A1 - Dorret I. Boomsma A1 - Buring, Julie E A1 - Campbell, Harry A1 - Cappellani, Stefania A1 - Ciullo, Marina A1 - Cox, Simon R A1 - Francesco Cucca A1 - Toniolo, Daniela A1 - Davey-Smith, George A1 - Ian J Deary A1 - George Dedoussis A1 - Deloukas, Panos A1 - Cornelia M van Duijn A1 - Eco J C de Geus A1 - Johan G Eriksson A1 - Jessica D. Faul A1 - Cinzia Sala A1 - Froguel, Philippe A1 - Paolo Gasparini A1 - Giorgia Girotto A1 - Grabe, Hans-Jörgen A1 - Greiser, Karin Halina A1 - Groenen, Patrick J F A1 - de Haan, Hugoline G A1 - Haerting, Johannes A1 - Tamara B Harris A1 - Heath, Andrew C A1 - Heikkilä, Kauko A1 - Hofman, Albert A1 - Homuth, Georg A1 - Holliday, Elizabeth G A1 - John L Hopper A1 - Hyppönen, Elina A1 - Jacobsson, Bo A1 - Jaddoe, Vincent W V A1 - Johannesson, Magnus A1 - Jugessur, Astanand A1 - Kähönen, Mika A1 - Kajantie, Eero A1 - Sharon L. R. Kardia A1 - Keavney, Bernard A1 - Kolcic, Ivana A1 - Koponen, Päivikki A1 - Kovacs, Peter A1 - Kronenberg, Florian A1 - Kutalik, Zoltán A1 - La Bianca, Martina A1 - Lachance, Genevieve A1 - Iacono, William G A1 - Lai, Sandra A1 - Lehtimäki, Terho A1 - David C Liewald A1 - Lindgren, Cecilia M A1 - Liu, Yongmei A1 - Luben, Robert A1 - Lucht, Michael A1 - Luoto, Riitta A1 - Magnus, Per A1 - Patrik K E Magnusson A1 - Nicholas G Martin A1 - McGue, Matt A1 - McQuillan, Ruth A1 - Sarah E. Medland A1 - Meisinger, Christa A1 - Mellström, Dan A1 - Andres Metspalu A1 - Traglia, Michela A1 - Lili Milani A1 - Mitchell, Paul A1 - Grant W. Montgomery A1 - Dennis O Mook-Kanamori A1 - de Mutsert, Renée A1 - Nohr, Ellen A A1 - Ohlsson, Claes A1 - Olsen, Jørn A1 - Ong, Ken K A1 - Paternoster, Lavinia A1 - Pattie, Alison A1 - Brenda W Penninx A1 - Markus Perola A1 - Peyser, Patricia A A1 - Pirastu, Mario A1 - Polasek, Ozren A1 - Power, Chris A1 - Kaprio, Jaakko A1 - Raffel, Leslie J A1 - Katri Räikkönen A1 - Olli T Raitakari A1 - Ridker, Paul M A1 - Ring, Susan M A1 - Roll, Kathryn A1 - Rudan, Igor A1 - Ruggiero, Daniela A1 - Rujescu, Dan A1 - Veikko Salomaa A1 - Schlessinger, David A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Schupf, Nicole A1 - Johannes Smit A1 - Sorice, Rossella A1 - Tim D Spector A1 - John M Starr A1 - Stöckl, Doris A1 - Strauch, Konstantin A1 - Stumvoll, Michael A1 - Swertz, Morris A A1 - Thorsteinsdottir, Unnur A1 - Thurik, A Roy A1 - Nicholas J. Timpson A1 - Tung, Joyce Y A1 - André G Uitterlinden A1 - Vaccargiu, Simona A1 - Viikari, Jorma A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Waage, Johannes A1 - Wagner, Gert G A1 - Wang, Jie Jin A1 - Wareham, Nicholas J A1 - David R. Weir A1 - Gonneke Willemsen A1 - Willeit, Johann A1 - Wright, Alan F A1 - Krina T Zondervan A1 - Stefansson, Kari A1 - Krueger, Robert F A1 - Lee, James J A1 - Daniel J. Benjamin A1 - Cesarini, David A1 - Philipp Koellinger A1 - den Hoed, Marcel A1 - Snieder, Harold A1 - Melinda C Mills AB -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.

VL - 48 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27798627?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies 74 loci associated with educational attainment. JF - Nature Y1 - 2016 A1 - Okbay, Aysu A1 - Jonathan P. Beauchamp A1 - Mark A Fontana A1 - Lee, James J A1 - Pers, Tune H A1 - Cornelius A Rietveld A1 - Turley, Patrick A1 - Chen, Guo-Bo A1 - Emilsson, Valur A1 - Meddens, S Fleur W A1 - Oskarsson, Sven A1 - Pickrell, Joseph K A1 - Thom, Kevin A1 - Timshel, Pascal A1 - de Vlaming, Ronald A1 - Abdel Abdellaoui A1 - Ahluwalia, Tarunveer S A1 - Bacelis, Jonas A1 - Baumbach, Clemens A1 - Bjornsdottir, Gyda A1 - Brandsma, Johannes H A1 - Maria Pina Concas A1 - Derringer, Jaime A1 - Furlotte, Nicholas A A1 - Galesloot, Tessel E A1 - Giorgia Girotto A1 - Gupta, Richa A1 - Hall, Leanne M A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Horikoshi, Momoko A1 - Huffman, Jennifer E A1 - Kaasik, Kadri A1 - Ioanna Panagiota Kalafati A1 - Karlsson, Robert A1 - Kong, Augustine A1 - Lahti, Jari A1 - van der Lee, Sven J A1 - Christiaan de Leeuw A1 - Penelope A. Lind A1 - Lindgren, Karl-Oskar A1 - Liu, Tian A1 - Mangino, Massimo A1 - Marten, Jonathan A1 - Mihailov, Evelin A1 - Michael B Miller A1 - van der Most, Peter J A1 - Christopher Oldmeadow A1 - Payton, Antony A1 - Pervjakova, Natalia A1 - Wouter J Peyrot A1 - Qian, Yong A1 - Olli T Raitakari A1 - Rueedi, Rico A1 - Salvi, Erika A1 - Schmidt, Börge A1 - Schraut, Katharina E A1 - Shi, Jianxin A1 - Albert Vernon Smith A1 - Poot, Raymond A A1 - St Pourcain, Beate A1 - Teumer, Alexander A1 - Thorleifsson, Gudmar A1 - Verweij, Niek A1 - Vuckovic, Dragana A1 - Wellmann, Juergen A1 - Westra, Harm-Jan A1 - Yang, Jingyun A1 - Wei Zhao A1 - Zhu, Zhihong A1 - Alizadeh, Behrooz Z A1 - Amin, Najaf A1 - Bakshi, Andrew A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bønnelykke, Klaus A1 - Patricia A. Boyle A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Gail Davies A1 - De Neve, Jan-Emmanuel A1 - Deloukas, Panos A1 - Demuth, Ilja A1 - Ding, Jun A1 - Eibich, Peter A1 - Eisele, Lewin A1 - Eklund, Niina A1 - Jessica D. Faul A1 - Feitosa, Mary F A1 - Andreas Forstner A1 - Gandin, Ilaria A1 - Gunnarsson, Bjarni A1 - Halldórsson, Bjarni V A1 - Tamara B Harris A1 - Heath, Andrew C A1 - Hocking, Lynne J A1 - Holliday, Elizabeth G A1 - Homuth, Georg A1 - Horan, Michael A A1 - Jouke-Jan Hottenga A1 - Philip L. De Jager A1 - Joshi, Peter K A1 - Jugessur, Astanand A1 - Marika A Kaakinen A1 - Kähönen, Mika A1 - Kanoni, Stavroula A1 - Keltigangas-Järvinen, Liisa A1 - Lambertus A Kiemeney A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kraja, Aldi T A1 - Kroh, Martin A1 - Kutalik, Zoltán A1 - Latvala, Antti A1 - Lenore J Launer A1 - Lebreton, Maël P A1 - Douglas F Levinson A1 - Paul Lichtenstein A1 - Lichtner, Peter A1 - David C Liewald A1 - Loukola, Anu A1 - Pamela A Madden A1 - Mägi, Reedik A1 - Mäki-Opas, Tomi A1 - Riccardo E Marioni A1 - Marques-Vidal, Pedro A1 - Meddens, Gerardus A A1 - McMahon, George A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Milaneschi, Yusplitri A1 - Lili Milani A1 - Grant W. Montgomery A1 - Myhre, Ronny A1 - Nelson, Christopher P A1 - Nyholt, Dale R A1 - Ollier, William E R A1 - Aarno Palotie A1 - Paternoster, Lavinia A1 - Nancy L. Pedersen A1 - Petrovic, Katja E A1 - David Porteous A1 - Katri Räikkönen A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rostapshova, Olga A1 - Rudan, Igor A1 - Rustichini, Aldo A1 - Veikko Salomaa A1 - Sanders, Alan R A1 - Sarin, Antti-Pekka A1 - Schmidt, Helena A1 - Scott, Rodney J A1 - Smith, Blair H A1 - Jennifer A. Smith A1 - Staessen, Jan A A1 - Steinhagen-Thiessen, Elisabeth A1 - Strauch, Konstantin A1 - Antonio Terracciano A1 - Tobin, Martin D A1 - Ulivi, Sheila A1 - Vaccargiu, Simona A1 - Quaye, Lydia A1 - van Rooij, Frank J A A1 - Venturini, Cristina A1 - Anna E Vinkhuyzen A1 - Völker, Uwe A1 - Völzke, Henry A1 - Vonk, Judith M A1 - Vozzi, Diego A1 - Waage, Johannes A1 - Erin B Ware A1 - Gonneke Willemsen A1 - John R. Attia A1 - David A. Bennett A1 - Berger, Klaus A1 - Bertram, Lars A1 - Bisgaard, Hans A1 - Dorret I. Boomsma A1 - Ingrid B. Borecki A1 - Bültmann, Ute A1 - Chabris, Christopher F A1 - Francesco Cucca A1 - Cusi, Daniele A1 - Ian J Deary A1 - George Dedoussis A1 - Cornelia M van Duijn A1 - Johan G Eriksson A1 - Franke, Barbara A1 - Lude L. Franke A1 - Paolo Gasparini A1 - Gejman, Pablo V A1 - Gieger, Christian A1 - Grabe, Hans-Jörgen A1 - Gratten, Jacob A1 - Groenen, Patrick J F A1 - Gudnason, Vilmundur A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - Hinds, David A A1 - Hoffmann, Wolfgang A1 - Hyppönen, Elina A1 - Iacono, William G A1 - Jacobsson, Bo A1 - Järvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Kaprio, Jaakko A1 - Sharon L. R. Kardia A1 - Lehtimäki, Terho A1 - Lehrer, Steven F A1 - Patrik K E Magnusson A1 - Nicholas G Martin A1 - McGue, Matt A1 - Andres Metspalu A1 - Pendleton, Neil A1 - Brenda W Penninx A1 - Markus Perola A1 - Nicola N Pirastu A1 - Pirastu, Mario A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Power, Christine A1 - Province, Michael A A1 - Nilesh Samani A1 - Schlessinger, David A1 - Schmidt, Reinhold A1 - Thorkild I. A. Sørensen A1 - Tim D Spector A1 - Stefansson, Kari A1 - Thorsteinsdottir, Unnur A1 - Thurik, A Roy A1 - Nicholas J. Timpson A1 - Henning Tiemeier A1 - Tung, Joyce Y A1 - André G Uitterlinden A1 - Vitart, Veronique A1 - Vollenweider, Peter A1 - David R. Weir A1 - Wilson, James F A1 - Wright, Alan F A1 - Dalton C. Conley A1 - Krueger, Robert F A1 - George Davey Smith A1 - Hofman, Albert A1 - David I Laibson A1 - Sarah E. Medland A1 - Meyer, Michelle N A1 - Yang, Jian A1 - Johannesson, Magnus A1 - Peter M Visscher A1 - Tõnu Esko A1 - Philipp Koellinger A1 - Cesarini, David A1 - Daniel J. Benjamin KW - Alzheimer's disease KW - Bipolar Disorder KW - Cognitive Ability KW - Education KW - Fetus KW - Genome-Wide Association Study KW - Humans KW - Molecular Sequence Annotation KW - Polymorphism, Single Nucleotide KW - Schizophrenia KW - United Kingdom AB -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.

VL - 533 IS - 7604 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27225129?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. JF - Nat Genet Y1 - 2016 A1 - Liu, Chunyu A1 - Kraja, Aldi T A1 - Jennifer A. Smith A1 - Brody, Jennifer A A1 - Franceschini, Nora A1 - Joshua C. Bis A1 - Rice, Kenneth A1 - Alanna Morrison A1 - Lu, Yingchang A1 - Weiss, Stefan A1 - Guo, Xiuqing A1 - Walter Palmas A1 - Martin, Lisa W A1 - Yii-Der I Chen A1 - Surendran, Praveen A1 - Drenos, Fotios A1 - Cook, James P A1 - Auer, Paul L A1 - Chu, Audrey Y A1 - Giri, Ayush A1 - Wei Zhao A1 - Jakobsdottir, Johanna A1 - Lin, Li-An A1 - Stafford, Jeanette M A1 - Amin, Najaf A1 - Mei, Hao A1 - Yao, Jie A1 - Voorman, Arend A1 - Larson, Martin G A1 - Grove, Megan L A1 - Albert Vernon Smith A1 - Hwang, Shih-Jen A1 - Chen, Han A1 - Huan, Tianxiao A1 - Kosova, Gulum A1 - Stitziel, Nathan O A1 - Kathiresan, Sekar A1 - Nilesh Samani A1 - Schunkert, Heribert A1 - Deloukas, Panos A1 - Li, Man A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Gorski, Mathias A1 - Kooperberg, Charles A1 - George J. Papanicolaou A1 - Rossouw, Jacques E A1 - Jessica D. Faul A1 - Sharon L. R. Kardia A1 - Bouchard, Claude A1 - Raffel, Leslie J A1 - André G Uitterlinden A1 - Franco, Oscar H A1 - Ramachandran S. Vasan A1 - O'Donnell, Christopher J A1 - Kent Taylor A1 - Liu, Kiang A1 - Erwin P. Bottinger A1 - Gottesman, Omri A1 - Daw, E Warwick A1 - Giulianini, Franco A1 - Ganesh, Santhi A1 - Salfati, Elias A1 - Tamara B Harris A1 - Lenore J Launer A1 - Dörr, Marcus A1 - Felix, Stephan B A1 - Rettig, Rainer A1 - Völzke, Henry A1 - Eric S. Kim A1 - Lee, Wen-Jane A1 - Lee, I-Te A1 - Sheu, Wayne H-H A1 - Tsosie, Krystal S A1 - Digna R Velez Edwards A1 - Liu, Yongmei A1 - Correa, Adolfo A1 - David R. Weir A1 - Völker, Uwe A1 - Ridker, Paul M A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Reiner, Alexander P A1 - Cornelia M van Duijn A1 - Ingrid B. Borecki A1 - Edwards, Todd L A1 - Chakravarti, Aravinda A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Ruth J F Loos A1 - Myriam Fornage A1 - Georg Ehret A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Chasman, Daniel I AB -Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

VL - 48 IS - 10 ER - TY - JOUR T1 - Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies. JF - Psychological Medicine Y1 - 2016 A1 - Demirkan, A A1 - J. Lahti A1 - Nese Direk A1 - Viktorin, A. A1 - Kathryn L. Lunetta A1 - Antonio Terracciano A1 - Mike A Nalls A1 - Toshiko Tanaka A1 - Karin Hek A1 - Myriam Fornage A1 - Jürgen Wellmann A1 - Marilyn Cornelis A1 - Ollila, H. M. A1 - Lei Yu A1 - Luke C. Pilling A1 - Isaacs, A A1 - Aarno Palotie A1 - W V Zhuang A1 - Alan B. Zonderman A1 - Jessica D. Faul A1 - Angelina R. Sutin A1 - Osorio Meirelles A1 - Mulas, A A1 - Hofman, A A1 - André G Uitterlinden A1 - Fernando Rivadeneira A1 - Markus Perola A1 - Wei Zhao A1 - Veikko Salomaa A1 - Kristine Yaffe A1 - Luik, A I A1 - Liu, Y A1 - Ding, J A1 - Paul Lichtenstein A1 - Landén, M A1 - Elisabeth Widen A1 - David R. Weir A1 - David J. Llewellyn A1 - Murray, A A1 - Sharon L. R. Kardia A1 - Johan G Eriksson A1 - Karestan C. Koenen A1 - Patrik K E Magnusson A1 - Luigi Ferrucci A1 - Thomas H. Mosley A1 - Francesco Cucca A1 - Ben A Oostra A1 - David A. Bennett A1 - Paunio, T. A1 - Berger, K. A1 - Tamara B Harris A1 - Nancy L. Pedersen A1 - Joanne M Murabito A1 - Henning Tiemeier A1 - Cornelia M van Duijn A1 - Katri Räikkönen KW - CHARGE KW - Depressive symptoms KW - Older Adults AB -**BACKGROUND: **Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.

**METHOD: **We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).

**RESULTS: **One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity.

**CONCLUSIONS: **Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

VL - 523 IS - 7561 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract ER - TY - JOUR T1 - Genetic studies of body mass index yield new insights for obesity biology. JF - Nature Y1 - 2015 A1 - Locke, Adam E A1 - Kahali, Bratati A1 - Berndt, Sonja I A1 - Justice, Anne E A1 - Pers, Tune H A1 - Day, Felix R A1 - Powell, Corey A1 - Vedantam, Sailaja A1 - Buchkovich, Martin L A1 - Yang, Jian A1 - Croteau-Chonka, Damien C A1 - Tõnu Esko A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gustafsson, Stefan A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Andrew R Wood A1 - Workalemahu, Tsegaselassie A1 - Jessica D. Faul A1 - Jennifer A. Smith A1 - Jing Hua Zhao A1 - Wei Zhao A1 - Chen, Jin A1 - Fehrmann, Rudolf A1 - Hedman, Åsa K A1 - Karjalainen, Juha A1 - Schmidt, Ellen M A1 - Absher, Devin A1 - Amin, Najaf A1 - Anderson, Denise A1 - Beekman, Marian A1 - Bolton, Jennifer L A1 - Bragg-Gresham, Jennifer L A1 - Buyske, Steven A1 - Demirkan, Ayse A1 - Deng, Guohong A1 - Georg Ehret A1 - Feenstra, Bjarke A1 - Feitosa, Mary F A1 - Fischer, Krista A1 - Goel, Anuj A1 - Gong, Jian A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - Kristiansson, Kati A1 - Lim, Unhee A1 - Lotay, Vaneet A1 - Mangino, Massimo A1 - Mateo Leach, Irene A1 - Medina-Gomez, Carolina A1 - Sarah E. Medland A1 - Mike A Nalls A1 - Palmer, Cameron D A1 - Pasko, Dorota A1 - Pechlivanis, Sonali A1 - Peters, Marjolein J A1 - Prokopenko, Inga A1 - Shungin, Dmitry A1 - Stančáková, Alena A1 - Strawbridge, Rona J A1 - Yun Ju Sung A1 - Toshiko Tanaka A1 - Teumer, Alexander A1 - Trompet, Stella A1 - van der Laan, Sander W A1 - van Setten, Jessica A1 - Van Vliet-Ostaptchouk, Jana V A1 - Wang, Zhaoming A1 - Yengo, Loic A1 - Zhang, Weihua A1 - Isaacs, Aaron A1 - Albrecht, Eva A1 - Ärnlöv, Johan A1 - Arscott, Gillian M A1 - Attwood, Antony P A1 - Bandinelli, Stefania A1 - Barrett, Amy A1 - Bas, Isabelita N A1 - Bellis, Claire A1 - Bennett, Amanda J A1 - Berne, Christian A1 - Blagieva, Roza A1 - Blüher, Matthias A1 - Böhringer, Stefan A1 - Bonnycastle, Lori L A1 - Böttcher, Yvonne A1 - Boyd, Heather A A1 - Bruinenberg, Marcel A1 - Caspersen, Ida H A1 - Yii-Der I Chen A1 - Robert Clark A1 - Daw, E Warwick A1 - de Craen, Anton J M A1 - Delgado, Graciela A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Eklund, Niina A1 - Estrada, Karol A1 - Eury, Elodie A1 - Folkersen, Lasse A1 - Fraser, Ross M A1 - Melissa E Garcia A1 - Geller, Frank A1 - Giedraitis, Vilmantas A1 - Gigante, Bruna A1 - Alan S Go A1 - Golay, Alain A1 - Goodall, Alison H A1 - Gordon, Scott D A1 - Gorski, Mathias A1 - Grabe, Hans-Jörgen A1 - Grallert, Harald A1 - Grammer, Tanja B A1 - Gräßler, Jürgen A1 - Grönberg, Henrik A1 - Groves, Christopher J A1 - Gusto, Gaëlle A1 - Haessler, Jeffrey A1 - Hall, Per A1 - Haller, Toomas A1 - Hallmans, Göran A1 - Hartman, Catharina A A1 - Hassinen, Maija A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Helmer, Quinta A1 - Hengstenberg, Christian A1 - Oddgeir Holmen A1 - Jouke-Jan Hottenga A1 - James, Alan L A1 - Jeff, Janina M A1 - Johansson, Åsa A1 - Jolley, Jennifer A1 - Juliusdottir, Thorhildur A1 - Kinnunen, Leena A1 - Koenig, Wolfgang A1 - Koskenvuo, Markku A1 - Kratzer, Wolfgang A1 - Laitinen, Jaana A1 - Lamina, Claudia A1 - Leander, Karin A1 - Lee, Nanette R A1 - Lichtner, Peter A1 - Lars Lind A1 - Lindström, Jaana A1 - Ken S Lo A1 - Lobbens, Stéphane A1 - Lorbeer, Roberto A1 - Lu, Yingchang A1 - Mach, François A1 - Patrik K E Magnusson A1 - Mahajan, Anubha A1 - McArdle, Wendy L A1 - McLachlan, Stela A1 - Menni, Cristina A1 - Merger, Sigrun A1 - Mihailov, Evelin A1 - Lili Milani A1 - Moayyeri, Alireza A1 - Monda, Keri L A1 - Morken, Mario A A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Musk, Arthur W A1 - Nagaraja, Ramaiah A1 - Nöthen, Markus M A1 - Nolte, Ilja M A1 - Pilz, Stefan A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Ripke, Stephan A1 - Neil Robertson A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scharnagl, Hubert A1 - Scholtens, Salome A1 - Schumacher, Fredrick R A1 - Scott, William R A1 - Seufferlein, Thomas A1 - Shi, Jianxin A1 - Albert Vernon Smith A1 - Smolonska, Joanna A1 - Stanton, Alice V A1 - Steinthorsdottir, Valgerdur A1 - Kathleen Stirrups A1 - Stringham, Heather M A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Syvänen, Ann-Christine A1 - Tan, Sian-Tsung A1 - Bamidele Tayo A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tyrer, Jonathan P A1 - Uh, Hae-Won A1 - Vandenput, Liesbeth A1 - Verhulst, Frank C A1 - Vermeulen, Sita H A1 - Verweij, Niek A1 - Vonk, Judith M A1 - Waite, Lindsay L A1 - Warren, Helen R A1 - Dawn Waterworth A1 - Michael N Weedon A1 - Wilkens, Lynne R A1 - Willenborg, Christina A1 - Wilsgaard, Tom A1 - Wojczynski, Mary K A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zhang, Qunyuan A1 - Brennan, Eoin P A1 - Murim Choi A1 - Dastani, Zari A1 - Alexander Drong A1 - Eriksson, Per A1 - Franco-Cereceda, Anders A1 - Gådin, Jesper R A1 - Gharavi, Ali G A1 - Goddard, Michael E A1 - Handsaker, Robert E A1 - Huang, Jinyan A1 - Karpe, Fredrik A1 - Kathiresan, Sekar A1 - Keildson, Sarah A1 - Kiryluk, Krzysztof A1 - Kubo, Michiaki A1 - Lee, Jong-Young A1 - Liang, Liming A1 - Lifton, Richard P A1 - Ma, Baoshan A1 - McCarroll, Steven A A1 - McKnight, Amy J A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Grant W. Montgomery A1 - Joanne M Murabito A1 - Nicholson, George A1 - Nyholt, Dale R A1 - Okada, Yukinori A1 - Perry, John R B A1 - Dorajoo, Rajkumar A1 - Reinmaa, Eva A1 - Salem, Rany M A1 - Sandholm, Niina A1 - Scott, Robert A A1 - Stolk, Lisette A1 - Takahashi, Atsushi A1 - Tanaka, Toshihiro A1 - Van't Hooft, Ferdinand M A1 - Anna E Vinkhuyzen A1 - Westra, Harm-Jan A1 - Wei Zhang A1 - Krina T Zondervan A1 - Heath, Andrew C A1 - Arveiler, Dominique A1 - Bakker, Stephan J L A1 - Beilby, John A1 - Bergman, Richard N A1 - Blangero, John A1 - Bovet, Pascal A1 - Campbell, Harry A1 - Caulfield, Mark J A1 - Cesana, Giancarlo A1 - Chakravarti, Aravinda A1 - Chasman, Daniel I A1 - Chines, Peter S A1 - Collins, Francis S A1 - Crawford, Dana C A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Danesh, John A1 - de Faire, Ulf A1 - Hester M Ruijter A1 - Dominiczak, Anna F A1 - Erbel, Raimund A1 - Erdmann, Jeanette A1 - Johan G Eriksson A1 - Farrall, Martin A1 - Felix, Stephan B A1 - Ferrannini, Ele A1 - Ferrières, Jean A1 - Ford, Ian A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Gansevoort, Ron T A1 - Gejman, Pablo V A1 - Gieger, Christian A1 - Gottesman, Omri A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hall, Alistair S A1 - Tamara B Harris A1 - Hattersley, Andrew T A1 - Hicks, Andrew A A1 - Hindorff, Lucia A A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hovingh, G Kees A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hyppönen, Elina A1 - Illig, Thomas A1 - Jacobs, Kevin B A1 - Järvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Johansen, Berit A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti M A1 - Kaprio, Jaakko A1 - Kastelein, John J P A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Lambertus A Kiemeney A1 - Knekt, Paul A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Le Marchand, Loic A1 - Lehtimäki, Terho A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Marette, André A1 - Matise, Tara C A1 - McKenzie, Colin A A1 - McKnight, Barbara A1 - Moll, Frans L A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Murray, Jeffrey C A1 - Nelis, Mari A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Pamela A Madden A1 - Pasterkamp, Gerard A1 - Peden, John F A1 - Peters, Annette A1 - Postma, Dirkje S A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Qi, Lu A1 - Olli T Raitakari A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Rioux, John D A1 - Ritchie, Marylyn D A1 - Rudan, Igor A1 - Veikko Salomaa A1 - Nilesh Samani A1 - Saramies, Jouko A1 - Sarzynski, Mark A A1 - Schunkert, Heribert A1 - Schwarz, Peter E H A1 - Sever, Peter A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tönjes, Anke A1 - Trégouët, David-Alexandre A1 - Tremblay, Angelo A1 - Tremoli, Elena A1 - Virtamo, Jarmo A1 - Vohl, Marie-Claude A1 - Völker, Uwe A1 - Waeber, Gérard A1 - Gonneke Willemsen A1 - Witteman, Jacqueline C A1 - Zillikens, M Carola A1 - Adair, Linda S A1 - Amouyel, Philippe A1 - Asselbergs, Folkert W A1 - Assimes, Themistocles L A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Bornstein, Stefan R A1 - Erwin P. Bottinger A1 - Bouchard, Claude A1 - Cauchi, Stéphane A1 - Chambers, John C A1 - Chanock, Stephen J A1 - Cooper, Richard S A1 - de Bakker, Paul I W A1 - George Dedoussis A1 - Luigi Ferrucci A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Groop, Leif C A1 - Haiman, Christopher A A1 - Hamsten, Anders A1 - Hui, Jennie A1 - Hunter, David J A1 - Hveem, Kristian A1 - Kaplan, Robert C A1 - Mika Kivimaki A1 - Kuh, Diana A1 - Laakso, Markku A1 - Liu, Yongmei A1 - Nicholas G Martin A1 - März, Winfried A1 - Melbye, Mads A1 - Andres Metspalu A1 - Moebus, Susanne A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Ben A Oostra A1 - Palmer, Colin N A A1 - Nancy L. Pedersen A1 - Markus Perola A1 - Pérusse, Louis A1 - Peters, Ulrike A1 - Power, Chris A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Fernando Rivadeneira A1 - Saaristo, Timo E A1 - Saleheen, Danish A1 - Sattar, Naveed A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Eline P. Slagboom A1 - Snieder, Harold A1 - Tim D Spector A1 - Thorsteinsdottir, Unnur A1 - Stumvoll, Michael A1 - Tuomilehto, Jaakko A1 - André G Uitterlinden A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Walker, Mark A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - David R. Weir A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Zanen, Pieter A1 - Ingrid B. Borecki A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Heid, Iris M A1 - O'Connell, Jeffrey R A1 - Strachan, David P A1 - Stefansson, Kari A1 - Cornelia M van Duijn A1 - Gonçalo Abecasis A1 - Lude L. Franke A1 - Timothy M. Frayling A1 - McCarthy, Mark I A1 - Peter M Visscher A1 - Scherag, Andre A1 - Willer, Cristen J A1 - Boehnke, Michael A1 - Mohlke, Karen L A1 - Lindgren, Cecilia M A1 - Beckmann, Jacques S A1 - Barroso, Inês A1 - North, Kari E A1 - Ingelsson, Erik A1 - Joel Hirschhorn A1 - Ruth J F Loos A1 - Speliotes, Elizabeth K KW - Age Factors KW - BMI KW - Continental Population Groups KW - Energy Metabolism KW - Europe KW - Female KW - Genome-Wide Association Study KW - Glutamic Acid KW - Humans KW - Insulin KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Synapses AB -Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

VL - 518 IS - 7538 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25673413?dopt=Abstract ER - TY - JOUR T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. JF - Journals of Gerontology Series A: Biological Sciences and Medical Sciences Y1 - 2015 A1 - Broer, Linda A1 - Aron S. Buchman A1 - Deelen, Joris A1 - Daniel S. Evans A1 - Jessica D. Faul A1 - Kathryn L. Lunetta A1 - Sebastiani, Paola A1 - Jennifer A. Smith A1 - Albert Vernon Smith A1 - Toshiko Tanaka A1 - Lei Yu A1 - Alice M. Arnold A1 - Aspelund, Thor A1 - Emelia J. Benjamin A1 - Philip L. De Jager A1 - Guðny Eiríksdóttir A1 - Melissa E Garcia A1 - Hofman, Albert A1 - Kaplan, Robert C A1 - Sharon L. R. Kardia A1 - Douglas P. Kiel A1 - Ben A Oostra A1 - Orwoll, Eric S A1 - Parimi, Neeta A1 - Psaty, Bruce M A1 - Fernando Rivadeneira A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Andrew B. Singleton A1 - Henning Tiemeier A1 - André G Uitterlinden A1 - Wei Zhao A1 - Bandinelli, Stefania A1 - David A. Bennett A1 - Luigi Ferrucci A1 - Gudnason, Vilmundur A1 - Tamara B Harris A1 - Karasik, David A1 - Lenore J Launer A1 - Thomas Perls A1 - Eline P. Slagboom A1 - Tranah, Gregory J A1 - David R. Weir A1 - Anne B Newman A1 - Cornelia M van Duijn A1 - Joanne M Murabito KW - CHARGE KW - Genetics KW - Longevity KW - Mortality KW - Older Adults AB -**BACKGROUND: **The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

**METHODS: **We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

**RESULTS: **In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

**CONCLUSIONS: **We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract ER - TY - JOUR T1 - Cohort Profile: the Health and Retirement Study (HRS) JF - International Journal of Epidemiology Y1 - 2014 A1 - Amanda Sonnega A1 - Jessica D. Faul A1 - Mary Beth Ofstedal A1 - Kenneth M. Langa A1 - John W. R. Phillips A1 - David R. Weir KW - Methodology AB - The Health and Retirement Study (HRS) is a nationally representative longitudinal survey of more than 37 000 individuals over age 50 in 23 000 households in the USA. The survey, which has been fielded every 2 years since 1992, was established to provide a national resource for data on the changing health and economic circumstances associated with ageing at both individual and population levels. Its multidisciplinary approach is focused on four broad topics income and wealth; health, cognition and use of healthcare services; work and retirement; and family connections. HRS data are also linked at the individual level to administrative records from Social Security and Medicare, Veteran s Administration, the National Death Index and employer-provided pension plan information. Since 2006, data collection has expanded to include biomarkers and genetics as well as much greater depth in psychology and social context. This blend of economic, health and psychosocial information provides unprecedented potential to study increasingly complex questions about ageing and retirement. The HRS has been a leading force for rapid release of data while simultaneously protecting the confidentiality of respondents. Three categories of data public, sensitive and restricted can be accessed through procedures described on the HRS website (hrsonline.isr.umich.edu). PB - 43 VL - 43 IS - 2 U4 - administrative data/Restricted data ER - TY - JOUR T1 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genetics Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Albert Vernon Smith A1 - Kathryn L. Lunetta A1 - Mike A Nalls A1 - Jennifer A. Smith A1 - Toshiko Tanaka A1 - Gail Davies A1 - Lei Yu A1 - Saira S Mirza A1 - Teumer, Alexander A1 - Coresh, Josef A1 - Pankow, James S A1 - Franceschini, Nora A1 - Scaria, Anish A1 - Oshima, Junko A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Guðny Eiríksdóttir A1 - Tamara B Harris A1 - Li, Hanyue A1 - Karasik, David A1 - Douglas P. Kiel A1 - Melissa E Garcia A1 - Liu, Yongmei A1 - Jessica D. Faul A1 - Sharon L. R. Kardia A1 - Wei Zhao A1 - Luigi Ferrucci A1 - Allerhand, Michael A1 - David C Liewald A1 - Redmond, Paul A1 - John M Starr A1 - Philip L. De Jager A1 - Nese Direk A1 - M Arfan Ikram A1 - André G Uitterlinden A1 - Homuth, Georg A1 - Lorbeer, Roberto A1 - Grabe, Hans J A1 - Lenore J Launer A1 - Joanne M Murabito A1 - Andrew B. Singleton A1 - David R. Weir A1 - Bandinelli, Stefania A1 - Ian J Deary A1 - David A. Bennett A1 - Henning Tiemeier A1 - Kocher, Thomas A1 - Lumley, Thomas A1 - Dan E Arking KW - CHARGE KW - Diversity KW - Genetics KW - Mortality KW - Older Adults KW - Risk Assessment AB -**BACKGROUND: **It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

**RESULTS: **We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

**CONCLUSIONS: **This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

VL - 93 IS - 3 ER - TY - JOUR T1 - GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. JF - Science Y1 - 2013 A1 - Cornelius A Rietveld A1 - Sarah E. Medland A1 - Derringer, Jaime A1 - Yang, Jian A1 - Tõnu Esko A1 - Martin, Nicolas W A1 - Westra, Harm-Jan A1 - Shakhbazov, Konstantin A1 - Abdel Abdellaoui A1 - Agrawal, Arpana A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Amin, Najaf A1 - Barnard, John A1 - Baumeister, Sebastian E A1 - Benke, Kelly S A1 - Bielak, Lawrence F A1 - Boatman, Jeffrey A A1 - Patricia A. Boyle A1 - Gail Davies A1 - Christiaan de Leeuw A1 - Eklund, Niina A1 - Daniel S. Evans A1 - Ferhmann, Rudolf A1 - Fischer, Krista A1 - Gieger, Christian A1 - Gjessing, Håkon K A1 - Hägg, Sara A1 - Harris, Jennifer R A1 - Hayward, Caroline A1 - Holzapfel, Christina A1 - Carla A. Ibrahim-Verbaas A1 - Ingelsson, Erik A1 - Jacobsson, Bo A1 - Joshi, Peter K A1 - Jugessur, Astanand A1 - Marika A Kaakinen A1 - Kanoni, Stavroula A1 - Karjalainen, Juha A1 - Kolcic, Ivana A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - J. Lahti A1 - Lee, Sang H A1 - Lin, Peng A1 - Penelope A. Lind A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Loitfelder, Marisa A1 - McMahon, George A1 - Vidal, Pedro Marques A1 - Osorio Meirelles A1 - Lili Milani A1 - Myhre, Ronny A1 - Nuotio, Marja-Liisa A1 - Christopher Oldmeadow A1 - Petrovic, Katja E A1 - Wouter J Peyrot A1 - Polasek, Ozren A1 - Quaye, Lydia A1 - Reinmaa, Eva A1 - Rice, John P A1 - Rizzi, Thais S A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Albert Vernon Smith A1 - Jennifer A. Smith A1 - Toshiko Tanaka A1 - Antonio Terracciano A1 - van der Loos, Matthijs J H M A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Jürgen Wellmann A1 - Lei Yu A1 - Wei Zhao A1 - Allik, Jüri A1 - John R. Attia A1 - Bandinelli, Stefania A1 - Bastardot, François A1 - Jonathan P. Beauchamp A1 - David A. Bennett A1 - Berger, Klaus A1 - Bierut, Laura J A1 - Dorret I. Boomsma A1 - Bültmann, Ute A1 - Campbell, Harry A1 - Chabris, Christopher F A1 - Cherkas, Lynn A1 - Chung, Mina K A1 - Francesco Cucca A1 - de Andrade, Mariza A1 - Philip L. De Jager A1 - De Neve, Jan-Emmanuel A1 - Ian J Deary A1 - George Dedoussis A1 - Deloukas, Panos A1 - Dimitriou, Maria A1 - Guðny Eiríksdóttir A1 - Elderson, Martin F A1 - Johan G Eriksson A1 - Jessica D. Faul A1 - Luigi Ferrucci A1 - Melissa E Garcia A1 - Grönberg, Henrik A1 - Guðnason, Vilmundur A1 - Hall, Per A1 - Harris, Juliette M A1 - Tamara B Harris A1 - Hastie, Nicholas D A1 - Heath, Andrew C A1 - Dena Hernandez A1 - Hoffmann, Wolfgang A1 - Hofman, Adriaan A1 - Holle, Rolf A1 - Holliday, Elizabeth G A1 - Jouke-Jan Hottenga A1 - Iacono, William G A1 - Illig, Thomas A1 - Järvelin, Marjo-Riitta A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kirkpatrick, Robert M A1 - Kowgier, Matthew A1 - Latvala, Antti A1 - Lenore J Launer A1 - Lawlor, Debbie A A1 - Lehtimäki, Terho A1 - Li, Jingmei A1 - Paul Lichtenstein A1 - Lichtner, Peter A1 - David C Liewald A1 - Pamela A Madden A1 - Patrik K E Magnusson A1 - Mäkinen, Tomi E A1 - Masala, Marco A1 - McGue, Matt A1 - Andres Metspalu A1 - Mielck, Andreas A1 - Michael B Miller A1 - Grant W. Montgomery A1 - Mukherjee, Sutapa A1 - Nyholt, Dale R A1 - Ben A Oostra A1 - Palmer, Lyle J A1 - Aarno Palotie A1 - Brenda W Penninx A1 - Markus Perola A1 - Peyser, Patricia A A1 - Preisig, Martin A1 - Katri Räikkönen A1 - Olli T Raitakari A1 - Realo, Anu A1 - Ring, Susan M A1 - Ripatti, Samuli A1 - Fernando Rivadeneira A1 - Rudan, Igor A1 - Rustichini, Aldo A1 - Veikko Salomaa A1 - Sarin, Antti-Pekka A1 - Schlessinger, David A1 - Scott, Rodney J A1 - Snieder, Harold A1 - St Pourcain, Beate A1 - John M Starr A1 - Sul, Jae Hoon A1 - Surakka, Ida A1 - Svento, Rauli A1 - Teumer, Alexander A1 - Henning Tiemeier A1 - van Rooij, Frank J A A1 - Van Wagoner, David R A1 - Vartiainen, Erkki A1 - Viikari, Jorma A1 - Vollenweider, Peter A1 - Vonk, Judith M A1 - Waeber, Gérard A1 - David R. Weir A1 - Wichmann, H-Erich A1 - Elisabeth Widen A1 - Gonneke Willemsen A1 - Wilson, James F A1 - Wright, Alan F A1 - Dalton C. Conley A1 - Davey-Smith, George A1 - Lude L. Franke A1 - Groenen, Patrick J F A1 - Hofman, Albert A1 - Johannesson, Magnus A1 - Sharon L. R. Kardia A1 - Krueger, Robert F A1 - David I Laibson A1 - Nicholas G Martin A1 - Meyer, Michelle N A1 - Posthuma, Danielle A1 - A. Roy Thurik A1 - Nicholas J. Timpson A1 - André G Uitterlinden A1 - Cornelia M van Duijn A1 - Peter M Visscher A1 - Daniel J. Benjamin A1 - Cesarini, David A1 - Philipp Koellinger KW - CHARGE KW - Cognitive Ability KW - Education KW - Genetics KW - Women and Minorities AB -A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

VL - 340 IS - 6139 ER - TY - JOUR T1 - Linking Survey and Administrative Records: Mechanisms of Consent JF - Sociological Methods & Research Y1 - 2012 A1 - Joseph W. Sakshaug A1 - Mick P. Couper A1 - Mary Beth Ofstedal A1 - David R. Weir KW - Consent KW - Meta-analyses KW - Survey Methodology AB -Survey records are increasingly being linked to administrative databases to enhance the survey data and increase research opportunities for data users. A necessary prerequisite to linking survey and administrative records is obtaining informed consent from respondents. Obtaining consent from all respondents is a difficult challenge and one that faces significant resistance. Consequently, data linkage consent rates vary widely from study-to-study. Several studies have found significant differences between consenters and non-consenters on socio-demographic variables, but no study has investigated the underlying mechanisms of consent from a theory-driven perspective. In this study, we describe and test several hypotheses related to respondents' willingness to consent to an earnings and benefit data linkage request based on mechanisms related to financial uncertainty, privacy concerns, resistance towards the survey interview, level of attentiveness during the interview, the respondents' preexisting relationship with the administrative data agency, and matching respondents and interviewers on observable characteristics. The results point to several implications for survey practice and suggestions for future research.

VL - 41 IS - 4 ER - TY - RPRT T1 - Updates to HRS Sample Weights Y1 - 2011 A1 - Mary Beth Ofstedal A1 - David R. Weir A1 - Chen, K.T. A1 - James Wagner KW - Methodology PB - Institute for Social Research, University of Michigan CY - Ann Arbor, Michigan U4 - Survey Methods/Sample Design ER - TY - RPRT T1 - Aging, Demographics and Memory Study (ADAMS): Sample Design, Weighting and Analysis for ADAMS Y1 - 2009 A1 - Steven G. Heeringa A1 - Gwenith G. Fisher A1 - Michael D. Hurd A1 - Kenneth M. Langa A1 - Mary Beth Ofstedal A1 - Brenda L. Plassman A1 - Rogers, Willard A1 - David R. Weir KW - Health Conditions and Status KW - Methodology AB - This technical report describes the sample design, design-based weighting and analysis procedures for the Aging, Demographics and Memory Study (ADAMS), a national study that recruited Health and Retirement Study (HRS) panel members to undergo a psychometric evaluation and clinical assessment visit. Langa et al. (2005) describe the general design and methods for the ADAMS including relevant background on the HRS longitudinal sample. This document provides additional detail on the sample design for the ADAMS including a description of survey sample selection, sample attrition and nonresponse, population weights, design-based variance estimation and related topics of importance to analysts of the ADAMS data. PB - Institute for Social Research, University of Michigan CY - Ann Arbor, Michigan U4 - survey Methods/Sample Design/Cognition ER - TY - RPRT T1 - Documentation of Health Behaviors and Risk Factors Measured in the Health and Retirement Study (HRS/AHEAD) Y1 - 2008 A1 - Kristi Rahrig Jenkins A1 - Mary Beth Ofstedal A1 - David R. Weir KW - Health Conditions and Status KW - Methodology AB - The two most important negative behaviors for population health are smoking, which is declining over time, and obesity, which is on the rise. Recognizing the important role of health behaviors and risk factors with respect to issues of key importance to the HRS (health, employment, wealth, timing of retirement), the original designers of the HRS incorporated a set of core measures of health behaviors at the outset. These measures have been expanded over time. The health behaviors and risk factors that are covered in the HRS include: Cigarette smoking (current and past behavior); Alcohol consumption (current behavior and past drinking problems); Body mass index (derived from self-reports of height and weight); Exercise (current level); Preventive health screenings. This report is organized as follows. Section II provides an inventory of the measures of health behaviors and risk factors that are covered in HRS, noting additions and changes that have occurred across waves. Special methodological issues that must be considered when using these data are covered in Section III. Section IV (and corresponding Tables 2-28) presents prevalence estimates and frequency counts for each of the health behavior and risk factor measures over time. Lastly, Section V addresses data quality by comparing HRS prevalence estimates with those from other surveys, reviewing results from some of the studies that have used HRS data to study health behaviors and risk factors, and investigating the level of missing data for these measures. PB - Institute for Social Research, University of Michigan CY - Ann Arbor, Michigan U4 - survey measurement/methodology/health Behavior/alcohol consumption/Body Mass Index ER - TY - RPRT T1 - Documentation of Physical Measures, Anthropometrics and Blood Pressure in the Health and Retirement Study Y1 - 2008 A1 - Eileen M. Crimmins A1 - Heidi Guyer A1 - Kenneth M. Langa A1 - Mary Beth Ofstedal A1 - Robert B. Wallace A1 - David R. Weir KW - Health Conditions and Status KW - Healthcare KW - Methodology AB - The assessment of physical performance is an important component of the evaluation of functioning of older persons. The HRS has employed a set of standardized assessments of lung function, grip strength, balance, and walking speed. In addition, HRS collected measures of blood pressure, height, weight, and waist circumference. In 2006, HRS included the following measurements, administered in this order: Blood pressure; Lung function; Hand grip strength; Balance tests; Timed walk; Height; Weight; Waist circumference. This report describes the following for each of the measures listed above: Rationale and key citations; Sample description; Measure description; Equipment; Protocol description; Special instructions PB - Institute for Social Research, University of Michigan CY - Ann Arbor, Michigan U4 - health measures/survey Methods/Physical Activity ER - TY - JOUR T1 - The Aging, Demographics and Memory Study: Study Design and Methods JF - Neuroepidemiology Y1 - 2005 A1 - Kenneth M. Langa A1 - Brenda L. Plassman A1 - Robert B. Wallace A1 - A. Regula Herzog A1 - Steven G. Heeringa A1 - Mary Beth Ofstedal A1 - James F. Burke A1 - Gwenith G. Fisher A1 - Fultz, Nancy H. A1 - Michael D. Hurd A1 - Guy G. Potter A1 - Willard L. Rodgers A1 - David C. Steffens A1 - David R. Weir KW - Health Conditions and Status KW - Healthcare AB - Objective: We describe the design and methods of the Aging, Demographics, and Memory Study (ADAMS), a new national study that will provide data on the antecedents, prevalence, outcomes, and costs of dementia and cognitive impairment, not demented (CIND) using a unique study design based on the nationally representative Health and Retirement Study (HRS). We also illustrate potential uses of the ADAMS data and provide information to interested researchers on obtaining ADAMS and HRS data. Methods: The ADAMS is the first population-based study of dementia in the United States to include subjects from all regions of the country, while at the same time using a single standardized diagnostic protocol in a community-based sample. A sample of 856 individuals aged 70 or older who were participants in the on-going HRS received an extensive in-home clinical and neuropsychological assessment to determine a diagnosis of normal, CIND, or dementia. Within the CIND and dementia categories, subcategories (e.g., Alzheimer disease, vascular dementia) were assigned to denote the etiology of cognitive impairment. Conclusion: Linking the ADAMS dementia clinical assessment data to the wealth of available longitudinal HRS data on health, health care utilization, informal care, and economic resources and behavior, will provide a unique opportunity to study the onset of CIND and dementia in a nationally-representative population-based sample, as well as the risk factors, prevalence, outcomes, and costs of CIND and dementia. PB - 25 VL - 25 U4 - Aging/Dementia/Epidemiology ER -