**Objective: **Alzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample.

**Methods: **In the US population-based Health and Retirement Study (waves 1995-2014), we evaluated the role of cumulative genetic risk of AD, with and without the alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry.

**Results: **In the European ancestry sample (n = 8,399), both AD polygenic score excluding the genetic region (odds ratio [OR] = 1.10; 95% confidence interval [CI]: 1.00-1.20) and the presence of any alleles (OR = 2.42; 95% CI: 1.99-2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any alleles was associated with 1.77 (95% CI: 1.20-2.61) times higher odds of dementia, whereas the AD polygenic score excluding the genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97-1.30).

**Conclusions: **Cumulative genetic risk of AD and are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

Although psychiatric phenotypes are hypothesized to organize into a two-factor internalizing-externalizing structure, few studies have evaluated the structure of psychopathology in older adults, nor explored whether genome-wide polygenic scores (PGSs) are associated with psychopathology in a domain-specific manner. We used data from 6003 individuals of European ancestry from the Health and Retirement Study, a large population-based sample of older adults in the United States. Confirmatory factor analyses were applied to validated measures of psychopathology and PGSs were derived from well-powered genome-wide association studies (GWAS). Genomic SEM was implemented to construct latent PGSs for internalizing, externalizing, and general psychopathology. Phenotypically, the data were best characterized by a single general factor of psychopathology, a factor structure that was replicated across genders and age groups. Although externalizing PGSs (cannabis use, antisocial behavior, alcohol dependence, attention deficit hyperactivity disorder) were not associated with any phenotypes, PGSs for major depressive disorder, neuroticism, and anxiety disorders were associated with both internalizing and externalizing phenotypes. Moreover, the variance explained in the general factor of psychopathology increased by twofold (from 1% to 2%) using the latent internalizing or latent one-factor PGSs, derived using weights from Genomic Structural Equation Modeling (SEM), compared with any of the individual PGSs. Collectively, results suggest that genetic risk factors for and phenotypic markers of psychiatric disorders are transdiagnostic in older adults of European ancestry. Alternative explanations are discussed, including methodological limitations of GWAS and phenotypic measurement of psychiatric outcome in large-scale population-based studies.

VL - 11 IS - 1 ER - TY - JOUR T1 - Validation of a hybrid approach to standardize immunophenotyping analysis in large population studies: The Health and Retirement Study JF - Scientific Reports Y1 - 2020 A1 - Hunter-Schlichting, DeVon A1 - Lane, John A1 - Cole, Benjamin A1 - Flaten, Zachary A1 - Barcelo, Helene A1 - Ramasubramanian, Ramya A1 - Cassidy, Erin A1 - Jessica D Faul A1 - Eileen M. Crimmins A1 - Pankratz, Nathan A1 - Bharat Thyagarajan KW - Bioinformatics KW - high-throughput screening AB - Traditional manual gating strategies are often time-intensive, place a high burden on the analyzer, and are susceptible to bias between analyzers. Several automated gating methods have shown to exceed performance of manual gating for a limited number of cell subsets. However, many of the automated algorithms still require significant manual interventions or have yet to demonstrate their utility in large datasets. Therefore, we developed an approach that utilizes a previously published automated algorithm (OpenCyto framework) with a manually created hierarchically cell gating template implemented, along with a custom developed visualization software (FlowAnnotator) to rapidly and efficiently analyze immunophenotyping data in large population studies. This approach allows pre-defining populations that can be analyzed solely by automated analysis and incorporating manual refinement for smaller downstream populations. We validated this method with traditional manual gating strategies for 24 subsets of T cells, B cells, NK cells, monocytes and dendritic cells in 931 participants from the Health and Retirement Study (HRS). Our results show a high degree of correlation (r ≥ 0.80) for 18 (78%) of the 24 cell subsets. For the remaining subsets, the correlation was low (<0.80) primarily because of the low numbers of events recorded in these subsets. The mean difference in the absolute counts between the hybrid method and manual gating strategy of these cell subsets showed results that were very similar to the traditional manual gating method. We describe a practical method for standardization of immunophenotyping methods in large scale population studies that provides a rapid, accurate and reproducible alternative to labor intensive manual gating strategies. VL - 10 SN - 2045-2322 IS - 1 JO - Scientific Reports ER - TY - JOUR T1 - The burden of health conditions across race and ethnicity for aging Americans: Disability-adjusted life years. JF - Medicine Y1 - 2019 A1 - Ryan P McGrath A1 - Soham Al Snih A1 - Kyriakos S Markides A1 - Jessica D Faul A1 - Brenda M Vincent A1 - Orman T Hall A1 - Mark D Peterson KW - Disability KW - health conditions KW - race AB -Despite evidence suggesting race and ethnicity are important factors in responses to environmental exposures, drug therapies, and disease risk, few studies focus on the health needs of racially- and ethnically-diverse aging adults.The objective of this study was to determine the burden of 10 health conditions across race and ethnicity for a nationally-representative sample of aging Americans.Data from the 1998 to 2014 waves of the Health and Retirement Study, an ongoing longitudinal-panel study, were analyzed.Those aged over 50 years who identified as Black, Hispanic, or White were included. There were 5510 Blacks, 3423 Hispanics, and 21,168 Whites in the study.At each wave, participants reported if they had cancer, chronic obstructive pulmonary disease, congestive heart failure, diabetes, back pain, hypertension, a fractured hip, myocardial infarction, rheumatism or arthritis, and a stroke. Disability-adjusted life years (DALYs) were calculated for each health condition by race and ethnicity. Ranked DALYs determined how race and ethnicity was differentially impacted by the burden of each health condition. Sample weights were utilized to make DALY estimates nationally-representative.Weighted DALY estimates (in thousands) ranged from 1405 to 55,631 for Blacks, 931 to 28,442 for Hispanics, and 15,313 to 295,623 for Whites. Although the health conditions affected each race and ethnicity differently, hypertension had the largest number of DALYs, and hip fractures had the fewest across race and ethnicity. In total, there were an estimated 198,621, 101,462, and 1,187,725 DALYs for older Black, Hispanic, and White aging adults.Our findings indicate that race and ethnicity may be influential on health and disease for aging adults in the United States. Monitoring DALYs may help guide the flow of health-related expenditures, improve the impact of health interventions, advance inclusive health care for diverse aging adult populations, and prepare healthcare providers for serving the health needs of aging adults.

VL - 98 IS - 46 ER - TY - RPRT T1 - Health and Retirement Study Imputation of Cognitive Functioning Measures: 1992-2016 Y1 - 2019 A1 - Ryan J McCammon A1 - Gwenith G Fisher A1 - Hassan, Halimah A1 - Jessica D Faul A1 - Rogers, Willard A1 - David R Weir KW - Health Conditions and Status KW - Methodology PB - Survey Research Center, University of Michigan CY - Ann Arbor, Michigan UR - http://hrsonline.isr.umich.edu/modules/meta/xyear/cogimp/desc/COGIMP9216_dd.pdf U4 - Cognition/HRS User Guide/methodology ER - TY - JOUR T1 - A meta-analysis of genome-wide association studies identifies multiple longevity genes. JF - Nature Communications Y1 - 2019 A1 - Deelen, Joris A1 - Daniel S Evans A1 - Dan E Arking A1 - Tesi, Niccolò A1 - Nygaard, Marianne A1 - Liu, Xiaomin A1 - Wojczynski, Mary K A1 - Biggs, Mary L A1 - van der Spek, Ashley A1 - Atzmon, Gil A1 - Erin B Ware A1 - Sarnowski, Chloé A1 - Albert Vernon Smith A1 - Seppälä, Ilkka A1 - Cordell, Heather J A1 - Dose, Janina A1 - Amin, Najaf A1 - Alice M. Arnold A1 - Kristin L. Ayers A1 - Barzilai, Nir A1 - Becker, Elizabeth J A1 - Beekman, Marian A1 - Blanché, Hélène A1 - Christensen, Kaare A1 - Christiansen, Lene A1 - Collerton, Joanna C A1 - Cubaynes, Sarah A1 - Steven R Cummings A1 - Davies, Karen A1 - Debrabant, Birgit A1 - Deleuze, Jean-François A1 - Duncan, Rachel A1 - Jessica D Faul A1 - Franceschi, Claudio A1 - Galan, Pilar A1 - Gudnason, Vilmundur A1 - Tamara B Harris A1 - Huisman, Martijn A1 - Hurme, Mikko A A1 - Jagger, Carol A1 - Jansen, Iris A1 - Jylhä, Marja A1 - Kähönen, Mika A1 - Karasik, David A1 - Sharon L R Kardia A1 - Kingston, Andrew A1 - Kirkwood, Thomas B L A1 - Lenore J Launer A1 - Lehtimäki, Terho A1 - Lieb, Wolfgang A1 - Lyytikäinen, Leo-Pekka A1 - Martin-Ruiz, Carmen A1 - Min, Junxia A1 - Nebel, Almut A1 - Anne B Newman A1 - Nie, Chao A1 - Nohr, Ellen A A1 - Orwoll, Eric S A1 - Thomas T Perls A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Olli T Raitakari A1 - Reinders, Marcel J T A1 - Robine, Jean-Marie A1 - Rotter, Jerome I A1 - Sebastiani, Paola A1 - Jennifer A Smith A1 - Sørensen, Thorkild I A A1 - Kent D Taylor A1 - André G Uitterlinden A1 - van der Flier, Wiesje A1 - Sven J van der Lee A1 - Cornelia M van Duijn A1 - van Heemst, Diana A1 - James W Vaupel A1 - David R Weir A1 - Ye, Kenny A1 - Zeng, Yi A1 - Zheng, Wanlin A1 - Holstege, Henne A1 - Douglas P Kiel A1 - Kathryn L Lunetta A1 - Eline P Slagboom A1 - Joanne M Murabito KW - genes KW - Genome-Wide Association Study KW - GWA KW - longevity genes KW - meta-analysis AB -Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

VL - 10 UR - https://www.ncbi.nlm.nih.gov/pubmed/31413261 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/31413261?dopt=Abstract ER - TY - JOUR T1 - Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. JF - Nat Genet Y1 - 2018 A1 - Turcot, Valérie A1 - Lu, Yingchang A1 - Highland, Heather M A1 - Schurmann, Claudia A1 - Justice, Anne E A1 - Fine, Rebecca S A1 - Bradfield, Jonathan P A1 - Tõnu Esko A1 - Giri, Ayush A1 - Graff, Mariaelisa A1 - Guo, Xiuqing A1 - Hendricks, Audrey E A1 - Karaderi, Tugce A1 - Lempradl, Adelheid A1 - Locke, Adam E A1 - Mahajan, Anubha A1 - Marouli, Eirini A1 - Sivapalaratnam, Suthesh A1 - Young, Kristin L A1 - Alfred, Tamuno A1 - Feitosa, Mary F A1 - Masca, Nicholas G D A1 - Manning, Alisa K A1 - Medina-Gomez, Carolina A1 - Mudgal, Poorva A1 - Ng, Maggie C Y A1 - Reiner, Alex P A1 - Vedantam, Sailaja A1 - Willems, Sara M A1 - Winkler, Thomas W A1 - Gonçalo R Abecasis A1 - Aben, Katja K A1 - Alam, Dewan S A1 - Alharthi, Sameer E A1 - Matthew A. Allison A1 - Amouyel, Philippe A1 - Asselbergs, Folkert W A1 - Auer, Paul L A1 - Balkau, Beverley A1 - Bang, Lia E A1 - Barroso, Inês A1 - Bastarache, Lisa A1 - Benn, Marianne A1 - Bergmann, Sven A1 - Bielak, Lawrence F A1 - Blüher, Matthias A1 - Boehnke, Michael A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Böger, Carsten A A1 - Bork-Jensen, Jette A1 - Bots, Michiel L A1 - Erwin P Bottinger A1 - Bowden, Donald W A1 - Brandslund, Ivan A1 - Breen, Gerome A1 - Brilliant, Murray H A1 - Broer, Linda A1 - Brumat, Marco A1 - Burt, Amber A A1 - Adam S Butterworth A1 - Campbell, Peter T A1 - Cappellani, Stefania A1 - Carey, David J A1 - Catamo, Eulalia A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Yii-Der I Chen A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Cook, James P A1 - Corley, Janie A1 - Jordi Corominas Galbany A1 - Cox, Amanda J A1 - Crosslin, David S A1 - Cuellar-Partida, Gabriel A1 - D'Eustacchio, Angela A1 - Danesh, John A1 - Gail Davies A1 - Bakker, Paul I W A1 - Groot, Mark C H A1 - Mutsert, Renée A1 - Ian J Deary A1 - George Dedoussis A1 - Demerath, Ellen W A1 - Heijer, Martin A1 - Anneke I den Hollander A1 - Hester M den Ruijter A1 - Joe G Dennis A1 - Denny, Josh C A1 - Angelantonio, Emanuele A1 - Drenos, Fotios A1 - Du, Mengmeng A1 - Dubé, Marie-Pierre A1 - Dunning, Alison M A1 - Easton, Douglas F A1 - Edwards, Todd L A1 - Ellinghaus, David A1 - Ellinor, Patrick T A1 - Elliott, Paul A1 - Evangelou, Evangelos A1 - Farmaki, Aliki-Eleni A1 - Farooqi, I Sadaf A1 - Jessica D Faul A1 - Fauser, Sascha A1 - Feng, Shuang A1 - Ferrannini, Ele A1 - Ferrières, Jean A1 - Florez, Jose C A1 - Ford, Ian A1 - Myriam Fornage A1 - Franco, Oscar H A1 - Franke, Andre A1 - Franks, Paul W A1 - Friedrich, Nele A1 - Frikke-Schmidt, Ruth A1 - Galesloot, Tessel E A1 - Gan, Wei A1 - Gandin, Ilaria A1 - Paolo P. Gasparini A1 - Gibson, Jane A1 - Giedraitis, Vilmantas A1 - Gjesing, Anette P A1 - Gordon-Larsen, Penny A1 - Gorski, Mathias A1 - Grabe, Hans-Jörgen A1 - Grant, Struan F A A1 - Grarup, Niels A1 - Griffiths, Helen L A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Jeffrey Haessler A1 - Hakonarson, Hakon A1 - Anke R Hammerschlag A1 - Hansen, Torben A1 - Tamara B Harris A1 - Hattersley, Andrew T A1 - Have, Christian T A1 - Caroline Hayward A1 - He, Liang A1 - Heard-Costa, Nancy L A1 - Heath, Andrew C A1 - Heid, Iris M A1 - Helgeland, Øyvind A1 - Hernesniemi, Jussi A1 - Hewitt, Alex W A1 - Oddgeir L Holmen A1 - Hovingh, G Kees A1 - Howson, Joanna M M A1 - Hu, Yao A1 - Huang, Paul L A1 - Huffman, Jennifer E A1 - Mohammed Arfan Ikram A1 - Ingelsson, Erik A1 - Jackson, Anne U A1 - Jansson, Jan-Håkan A1 - Jarvik, Gail P A1 - Jensen, Gorm B A1 - Jia, Yucheng A1 - Johansson, Stefan A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Jukema, J Wouter A1 - Kahali, Bratati A1 - Kahn, René S A1 - Kähönen, Mika A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Kaprio, Jaakko A1 - Karaleftheri, Maria A1 - Sharon L R Kardia A1 - Karpe, Fredrik A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Lambertus A Kiemeney A1 - Eric S Kim A1 - Kitajima, Hidetoshi A1 - Komulainen, Pirjo A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Korhonen, Tellervo A1 - Kovacs, Peter A1 - Kuivaniemi, Helena A1 - Kutalik, Zoltán A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lamparter, David A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langenberg, Claudia A1 - Eric B Larson A1 - Lee, Nanette R A1 - Lehtimäki, Terho A1 - Lewis, Cora E A1 - Li, Huaixing A1 - Li, Jin A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Lin, Keng-Hung A1 - Lin, Li-An A1 - Lin, Xu A1 - Lars Lind A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Dajiang J A1 - Yongmei Liu A1 - Ken Sin Lo A1 - Lophatananon, Artitaya A1 - Lotery, Andrew J A1 - Loukola, Anu A1 - Luan, Jian'an A1 - Lubitz, Steven A A1 - Lyytikäinen, Leo-Pekka A1 - Männistö, Satu A1 - Marenne, Gaëlle A1 - Mazul, Angela L A1 - McCarthy, Mark I A1 - McKean-Cowdin, Roberta A1 - Sarah E Medland A1 - Meidtner, Karina A1 - Lili Milani A1 - Mistry, Vanisha A1 - Mitchell, Paul A1 - Mohlke, Karen L A1 - Moilanen, Leena A1 - Moitry, Marie A1 - Grant W Montgomery A1 - Dennis O Mook-Kanamori A1 - Moore, Carmel A1 - Mori, Trevor A A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Michael A Nalls A1 - Narisu, Narisu A1 - Nelson, Christopher P A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Nikus, Kjell A1 - Njølstad, Pål R A1 - Nordestgaard, Børge G A1 - Nyholt, Dale R A1 - O'Connel, Jeffrey R A1 - O'Donoghue, Michelle L A1 - Ophoff, Roel A A1 - Owen, Katharine R A1 - Packard, Chris J A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Palmer, Nicholette D A1 - Pasterkamp, Gerard A1 - Patel, Aniruddh P A1 - Pattie, Alison A1 - Pedersen, Oluf A1 - Peissig, Peggy L A1 - Peloso, Gina M A1 - Pennell, Craig E A1 - Markus Perola A1 - Perry, James A A1 - Perry, John R B A1 - Pers, Tune H A1 - Person, Thomas N A1 - Peters, Annette A1 - Petersen, Eva R B A1 - Peyser, Patricia A A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Tinca J Polderman A1 - Puolijoki, Hannu A1 - Olli T Raitakari A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Renstrom, Frida A1 - Rheinberger, Myriam A1 - Ridker, Paul M A1 - Rioux, John D A1 - Rivas, Manuel A A1 - Roberts, David J A1 - Neil R Robertson A1 - Robino, Antonietta A1 - Rolandsson, Olov A1 - Rudan, Igor A1 - Ruth, Katherine S A1 - Saleheen, Danish A1 - Veikko Salomaa A1 - Nilesh J Samani A1 - Sapkota, Yadav A1 - Sattar, Naveed A1 - Schoen, Robert E A1 - Schreiner, Pamela J A1 - Schulze, Matthias B A1 - Scott, Robert A A1 - Segura-Lepe, Marcelo P A1 - Svati H Shah A1 - Sheu, Wayne H-H A1 - Sim, Xueling A1 - Slater, Andrew J A1 - Small, Kerrin S A1 - Albert Vernon Smith A1 - Southam, Lorraine A1 - Tim D Spector A1 - Speliotes, Elizabeth K A1 - John M Starr A1 - Stefansson, Kari A1 - Steinthorsdottir, Valgerdur A1 - Kathleen E Stirrups A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Sun, Liang A1 - Surendran, Praveen A1 - Swift, Amy J A1 - Tada, Hayato A1 - Tansey, Katherine E A1 - Tardif, Jean-Claude A1 - Kent D Taylor A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Thuesen, Betina H A1 - Tönjes, Anke A1 - Tromp, Gerard A1 - Trompet, Stella A1 - Tsafantakis, Emmanouil A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - Tyrer, Jonathan P A1 - Uher, Rudolf A1 - André G Uitterlinden A1 - Uusitupa, Matti A1 - Laan, Sander W A1 - Duijn, Cornelia M A1 - Leeuwen, Nienke A1 - van Setten, Jessica A1 - Vanhala, Mauno A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Varma, Rohit A1 - Digna R Velez Edwards A1 - Vermeulen, Sita H A1 - Veronesi, Giovanni A1 - Vestergaard, Henrik A1 - Vitart, Veronique A1 - Vogt, Thomas F A1 - Völker, Uwe A1 - Vuckovic, Dragana A1 - Wagenknecht, Lynne E A1 - Walker, Mark A1 - Wallentin, Lars A1 - Wang, Feijie A1 - Wang, Carol A A1 - Wang, Shuai A1 - Wang, Yiqin A1 - Erin B Ware A1 - Wareham, Nicholas J A1 - Warren, Helen R A1 - Dawn M Waterworth A1 - Wessel, Jennifer A1 - White, Harvey D A1 - Willer, Cristen J A1 - Wilson, James G A1 - Witte, Daniel R A1 - Andrew R Wood A1 - Wu, Ying A1 - Yaghootkar, Hanieh A1 - Yao, Jie A1 - Yao, Pang A1 - Laura M Yerges-Armstrong A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhan, Xiaowei A1 - Zhang, Weihua A1 - Wei Zhao A1 - Zhou, Wei A1 - Krina T Zondervan A1 - Rotter, Jerome I A1 - Pospisilik, John A A1 - Fernando Rivadeneira A1 - Ingrid B Borecki A1 - Deloukas, Panos A1 - Timothy M Frayling A1 - Lettre, Guillaume A1 - North, Kari E A1 - Lindgren, Cecilia M A1 - Joel N Hirschhron A1 - Ruth J F Loos AB -Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

VL - 50 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29273807?dopt=Abstract ER - TY - JOUR T1 - The complex genetics of gait speed: genome-wide meta-analysis approach. JF - Aging (Albany NY) Y1 - 2017 A1 - Ben-Avraham, Dan A1 - Karasik, David A1 - Joe Verghese A1 - Kathryn L Lunetta A1 - John D Eicher A1 - Vered, Rotem A1 - Deelen, Joris A1 - Alice M. Arnold A1 - Aron S Buchman A1 - Toshiko Tanaka A1 - Jessica D Faul A1 - Nethander, Maria A1 - Myriam Fornage A1 - Hieab H. Adams A1 - Amy M Matteini A1 - Michele L Callisaya A1 - Albert Vernon Smith A1 - Lei Yu A1 - Philip L. De Jager A1 - Denis A Evans A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Pattie, Alison A1 - Corley, Janie A1 - Lenore J Launer A1 - Davis S Knopman A1 - Parimi, Neeta A1 - Stephen T Turner A1 - Bandinelli, Stefania A1 - Beekman, Marian A1 - Gutman, Danielle A1 - Sharvit, Lital A1 - Simon P Mooijaart A1 - David C Liewald A1 - Jeanine J Houwing-Duistermaat A1 - Ohlsson, Claes A1 - Moed, Matthijs A1 - Vincent J Verlinden A1 - Mellström, Dan A1 - Jos N van der Geest A1 - Karlsson, Magnus A1 - Dena G Hernandez A1 - McWhirter, Rebekah A1 - Yongmei Liu A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - André G Uitterlinden A1 - David R Weir A1 - Wei Zhao A1 - John M Starr A1 - Mohammed Arfan Ikram A1 - David A Bennett A1 - Steven R Cummings A1 - Ian J Deary A1 - Tamara B Harris A1 - Sharon L R Kardia A1 - Thomas H Mosley A1 - Velandai K Srikanth A1 - Beverly G Windham A1 - Anne B Newman A1 - Jeremy D Walston A1 - Gail Davies A1 - Daniel S Evans A1 - Eline P Slagboom A1 - Luigi Ferrucci A1 - Douglas P Kiel A1 - Joanne M Murabito A1 - Atzmon, Gil KW - Genetics KW - GWAS AB - Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging. VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28077804?dopt=Abstract ER - TY - JOUR T1 - Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies. JF - Int J Environ Res Public Health Y1 - 2017 A1 - Wei Zhao A1 - Yasutake, Kalyn A1 - August, Carmella A1 - Scott M Ratliff A1 - Jessica D Faul A1 - Boerwinkle, Eric A1 - Chakravarti, Aravinda A1 - Ana V. Diez-Roux A1 - Gao, Yan A1 - Michael E. Griswold A1 - Gerardo Heiss A1 - Sharon L R Kardia A1 - Alanna C Morrison A1 - Musani, Solomon K A1 - Mwasongwe, Stanford A1 - North, Kari E A1 - Rose, Kathryn M A1 - Sims, Mario A1 - Yan V Sun A1 - David R Weir A1 - Belinda L Needham KW - Blood pressure KW - Genetics KW - GWAS KW - Meta-analyses KW - Psychosocial KW - Socioeconomic factors AB - Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region (p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region (p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors. VL - 14 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29258278?dopt=Abstract ER - TY - JOUR T1 - Interaction between Social/Psychosocial Factors and Genetic Variants on Body Mass Index: A Gene-Environment Interaction Analysis in a Longitudinal Setting JF - International Journal of Environmental Research and Public Health Y1 - 2017 A1 - Wei Zhao A1 - Erin B Ware A1 - He, Zihuai A1 - Sharon L R Kardia A1 - Jessica D Faul KW - BMI KW - Genetics KW - Obesity AB - Obesity, which develops over time, is one of the leading causes of chronic diseases such as cardiovascular disease. However, hundreds of BMI (body mass index)-associated genetic loci identified through large-scale genome-wide association studies (GWAS) only explain about 2.7% of BMI variation. Most common human traits are believed to be influenced by both genetic and environmental factors. Past studies suggest a variety of environmental features that are associated with obesity, including socioeconomic status and psychosocial factors. This study combines both gene/regions and environmental factors to explore whether social/psychosocial factors (childhood and adult socioeconomic status, social support, anger, chronic burden, stressful life events, and depressive symptoms) modify the effect of sets of genetic variants on BMI in European American and African American participants in the Health and Retirement Study (HRS). In order to incorporate longitudinal phenotype data collected in the HRS and investigate entire sets of single nucleotide polymorphisms (SNPs) within gene/region simultaneously, we applied a novel set-based test for gene-environment interaction in longitudinal studies (LGEWIS). Childhood socioeconomic status (parental education) was found to modify the genetic effect in the gene/region around SNP rs9540493 on BMI in European Americans in the HRS. The most significant SNP (rs9540488) by childhood socioeconomic status interaction within the rs9540493 gene/region was suggestively replicated in the Multi-Ethnic Study of Atherosclerosis (MESA) (p = 0.07). VL - 14 UR - http://www.mdpi.com/1660-4601/14/10/1153http://www.mdpi.com/1660-4601/14/10/1153/pdf IS - 10 JO - IJERPH ER - TY - JOUR T1 - Rare and low-frequency coding variants alter human adult height. JF - Nature Y1 - 2017 A1 - Marouli, Eirini A1 - Graff, Mariaelisa A1 - Medina-Gomez, Carolina A1 - Ken Sin Lo A1 - Andrew R Wood A1 - Kjaer, Troels R A1 - Fine, Rebecca S A1 - Lu, Yingchang A1 - Schurmann, Claudia A1 - Highland, Heather M A1 - Rüeger, Sina A1 - Thorleifsson, Gudmar A1 - Justice, Anne E A1 - Lamparter, David A1 - Kathleen E Stirrups A1 - Turcot, Valérie A1 - Young, Kristin L A1 - Winkler, Thomas W A1 - Tõnu Esko A1 - Karaderi, Tugce A1 - Locke, Adam E A1 - Masca, Nicholas G D A1 - Ng, Maggie C Y A1 - Mudgal, Poorva A1 - Rivas, Manuel A A1 - Vedantam, Sailaja A1 - Mahajan, Anubha A1 - Guo, Xiuqing A1 - Gonçalo R Abecasis A1 - Aben, Katja K A1 - Adair, Linda S A1 - Alam, Dewan S A1 - Albrecht, Eva A1 - Allin, Kristine H A1 - Matthew A. Allison A1 - Amouyel, Philippe A1 - Appel, Emil V A1 - Arveiler, Dominique A1 - Asselbergs, Folkert W A1 - Auer, Paul L A1 - Balkau, Beverley A1 - Banas, Bernhard A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bergmann, Sven A1 - Bielak, Lawrence F A1 - Blüher, Matthias A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Böger, Carsten A A1 - Bonnycastle, Lori L A1 - Bork-Jensen, Jette A1 - Bots, Michiel L A1 - Erwin P Bottinger A1 - Bowden, Donald W A1 - Brandslund, Ivan A1 - Breen, Gerome A1 - Brilliant, Murray H A1 - Broer, Linda A1 - Burt, Amber A A1 - Adam S Butterworth A1 - Carey, David J A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Yii-Der I Chen A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Cook, James P A1 - Corley, Janie A1 - Jordi Corominas Galbany A1 - Cox, Amanda J A1 - Cuellar-Partida, Gabriel A1 - Danesh, John A1 - Gail Davies A1 - de Bakker, Paul I W A1 - de Borst, Gert J A1 - de Denus, Simon A1 - de Groot, Mark C H A1 - de Mutsert, Renée A1 - Ian J Deary A1 - George Dedoussis A1 - Demerath, Ellen W A1 - Anneke I den Hollander A1 - Joe G Dennis A1 - Di Angelantonio, Emanuele A1 - Drenos, Fotios A1 - Du, Mengmeng A1 - Dunning, Alison M A1 - Easton, Douglas F A1 - Ebeling, Tapani A1 - Edwards, Todd L A1 - Ellinor, Patrick T A1 - Elliott, Paul A1 - Evangelou, Evangelos A1 - Farmaki, Aliki-Eleni A1 - Jessica D Faul A1 - Feitosa, Mary F A1 - Feng, Shuang A1 - Ferrannini, Ele A1 - Ferrario, Marco M A1 - Ferrières, Jean A1 - Florez, Jose C A1 - Ford, Ian A1 - Myriam Fornage A1 - Franks, Paul W A1 - Frikke-Schmidt, Ruth A1 - Galesloot, Tessel E A1 - Gan, Wei A1 - Gandin, Ilaria A1 - Paolo P. Gasparini A1 - Giedraitis, Vilmantas A1 - Giri, Ayush A1 - Giorgia G Girotto A1 - Gordon, Scott D A1 - Gordon-Larsen, Penny A1 - Gorski, Mathias A1 - Grarup, Niels A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Hansen, Torben A1 - Kathleen Mullan Harris A1 - Tamara B Harris A1 - Hattersley, Andrew T A1 - Caroline Hayward A1 - He, Liang A1 - Heid, Iris M A1 - Heikkilä, Kauko A1 - Helgeland, Øyvind A1 - Hernesniemi, Jussi A1 - Hewitt, Alex W A1 - Hocking, Lynne J A1 - Hollensted, Mette A1 - Oddgeir L Holmen A1 - Hovingh, G Kees A1 - Howson, Joanna M M A1 - Hoyng, Carel B A1 - Huang, Paul L A1 - Hveem, Kristian A1 - Mohammed Arfan Ikram A1 - Ingelsson, Erik A1 - Jackson, Anne U A1 - Jansson, Jan-Håkan A1 - Jarvik, Gail P A1 - Jensen, Gorm B A1 - Jhun, Min A A1 - Jia, Yucheng A1 - Jiang, Xuejuan A1 - Johansson, Stefan A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kahali, Bratati A1 - Kahn, René S A1 - Kähönen, Mika A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Kaprio, Jaakko A1 - Karaleftheri, Maria A1 - Sharon L R Kardia A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Keeman, Renske A1 - Lambertus A Kiemeney A1 - Kitajima, Hidetoshi A1 - Kluivers, Kirsten B A1 - Kocher, Thomas A1 - Komulainen, Pirjo A1 - Kontto, Jukka A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kuivaniemi, Helena A1 - Küry, Sébastien A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Eric B Larson A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Lewis, Cora E A1 - Li, Huaixing A1 - Li, Jin A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Lin, Li-An A1 - Lin, Xu A1 - Lars Lind A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Liu, Yeheng A1 - Yongmei Liu A1 - Lophatananon, Artitaya A1 - Luan, Jian'an A1 - Lubitz, Steven A A1 - Lyytikäinen, Leo-Pekka A1 - Mackey, David A A1 - Pamela A F Madden A1 - Manning, Alisa K A1 - Männistö, Satu A1 - Marenne, Gaëlle A1 - Marten, Jonathan A1 - Nicholas G Martin A1 - Mazul, Angela L A1 - Meidtner, Karina A1 - Andres Metspalu A1 - Mitchell, Paul A1 - Mohlke, Karen L A1 - Dennis O Mook-Kanamori A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Michael A Nalls A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Nikus, Kjell A1 - Njølstad, Pål R A1 - Nordestgaard, Børge G A1 - Ntalla, Ioanna A1 - O'Connel, Jeffrey R A1 - Oksa, Heikki A1 - Loes M Olde Loohuis A1 - Ophoff, Roel A A1 - Owen, Katharine R A1 - Packard, Chris J A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasterkamp, Gerard A1 - Patel, Aniruddh P A1 - Pattie, Alison A1 - Pedersen, Oluf A1 - Peissig, Peggy L A1 - Peloso, Gina M A1 - Pennell, Craig E A1 - Markus Perola A1 - Perry, James A A1 - Perry, John R B A1 - Person, Thomas N A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Olli T Raitakari A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Ridker, Paul M A1 - Rioux, John D A1 - Neil R Robertson A1 - Robino, Antonietta A1 - Rolandsson, Olov A1 - Rudan, Igor A1 - Ruth, Katherine S A1 - Saleheen, Danish A1 - Veikko Salomaa A1 - Nilesh J Samani A1 - Sandow, Kevin A1 - Sapkota, Yadav A1 - Sattar, Naveed A1 - Schmidt, Marjanka K A1 - Schreiner, Pamela J A1 - Schulze, Matthias B A1 - Scott, Robert A A1 - Segura-Lepe, Marcelo P A1 - Svati H Shah A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Albert Vernon Smith A1 - Jennifer A Smith A1 - Southam, Lorraine A1 - Tim D Spector A1 - Speliotes, Elizabeth K A1 - John M Starr A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Surendran, Praveen A1 - 't Hart, Leen M A1 - Tansey, Katherine E A1 - Tardif, Jean-Claude A1 - Kent D Taylor A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Thorsteinsdottir, Unnur A1 - Thuesen, Betina H A1 - Tönjes, Anke A1 - Tromp, Gerard A1 - Trompet, Stella A1 - Tsafantakis, Emmanouil A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - Tyrer, Jonathan P A1 - Uher, Rudolf A1 - André G Uitterlinden A1 - Ulivi, Sheila A1 - van der Laan, Sander W A1 - Van Der Leij, Andries R A1 - Cornelia M van Duijn A1 - van Schoor, Natasja M A1 - van Setten, Jessica A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Varma, Rohit A1 - Digna R Velez Edwards A1 - Vermeulen, Sita H A1 - Vestergaard, Henrik A1 - Vitart, Veronique A1 - Vogt, Thomas F A1 - Vozzi, Diego A1 - Walker, Mark A1 - Wang, Feijie A1 - Wang, Carol A A1 - Wang, Shuai A1 - Wang, Yiqin A1 - Wareham, Nicholas J A1 - Warren, Helen R A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Wilson, James G A1 - Witte, Daniel R A1 - Woods, Michael O A1 - Wu, Ying A1 - Yaghootkar, Hanieh A1 - Yao, Jie A1 - Yao, Pang A1 - Laura M Yerges-Armstrong A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhan, Xiaowei A1 - Zhang, Weihua A1 - Jing Hua Zhao A1 - Wei Zhao A1 - Wei Zhao A1 - Zheng, He A1 - Zhou, Wei A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - Kathiresan, Sekar A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Stefansson, Kari A1 - Ingrid B Borecki A1 - Liu, Dajiang J A1 - North, Kari E A1 - Heard-Costa, Nancy L A1 - Pers, Tune H A1 - Lindgren, Cecilia M A1 - Oxvig, Claus A1 - Kutalik, Zoltán A1 - Fernando Rivadeneira A1 - Ruth J F Loos A1 - Timothy M Frayling A1 - Joel N Hirschhron A1 - Deloukas, Panos A1 - Lettre, Guillaume AB -Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

VL - 542 IS - 7640 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract ER - TY - JOUR T1 - Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. JF - Nat Commun Y1 - 2016 A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Chu, Audrey Y A1 - Li, Man A1 - Mijatovic, Vladan A1 - Garnaas, Maija A1 - Tin, Adrienne A1 - Sorice, Rossella A1 - Yong Li A1 - Taliun, Daniel A1 - Olden, Matthias A1 - Foster, Meredith A1 - Qiong Yang A1 - Chen, Ming-Huei A1 - Pers, Tune H A1 - Andrew D Johnson A1 - Ko, Yi-An A1 - Fuchsberger, Christian A1 - Bamidele O Tayo A1 - Michael A Nalls A1 - Feitosa, Mary F A1 - Isaacs, Aaron A1 - Dehghan, Abbas A1 - d'Adamo, Pio A1 - Adebawole Adeyemo A1 - Dieffenbach, Aida Karina A1 - Alan B Zonderman A1 - Ilja M Nolte A1 - van der Most, Peter J A1 - Alan F Wright A1 - Alan R Shuldiner A1 - Alanna C Morrison A1 - Hofman, Albert A1 - Albert Vernon Smith A1 - Dreisbach, Albert W A1 - Franke, Andre A1 - André G Uitterlinden A1 - Andres Metspalu A1 - Tönjes, Anke A1 - Lupo, Antonio A1 - Robino, Antonietta A1 - Johansson, Åsa A1 - Demirkan, Ayse A1 - Kollerits, Barbara A1 - Freedman, Barry I A1 - Ponte, Belen A1 - Ben A Oostra A1 - Paulweber, Bernhard A1 - Krämer, Bernhard K A1 - Mitchell, Braxton D A1 - Buckley, Brendan M A1 - Peralta, Carmen A A1 - Caroline Hayward A1 - Helmer, Catherine A1 - Rotimi, Charles N A1 - Shaffer, Christian M A1 - Müller, Christian A1 - Cinzia Felicita Sala A1 - Cornelia M van Duijn A1 - Saint-Pierre, Aude A1 - Daniel Ackermann A1 - Shriner, Daniel A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Lu, Yingchang A1 - Cusi, Daniele A1 - Czamara, Darina A1 - Ellinghaus, David A1 - Siscovick, David S A1 - Ruderfer, Douglas A1 - Gieger, Christian A1 - Grallert, Harald A1 - Rochtchina, Elena A1 - Atkinson, Elizabeth J A1 - Holliday, Elizabeth G A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Erwin P Bottinger A1 - Murgia, Federico A1 - Fernando Rivadeneira A1 - Ernst, Florian A1 - Kronenberg, Florian A1 - Hu, Frank B A1 - Navis, Gerjan J A1 - Curhan, Gary C A1 - Georg B Ehret A1 - Homuth, Georg A1 - Coassin, Stefan A1 - Thun, Gian-Andri A1 - Pistis, Giorgio A1 - Gambaro, Giovanni A1 - Malerba, Giovanni A1 - Grant W Montgomery A1 - Guðny Eiríksdóttir A1 - Jacobs, Gunnar A1 - Guo Li A1 - Wichmann, H-Erich A1 - Campbell, Harry A1 - Schmidt, Helena A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Brenner, Hermann A1 - Kroemer, Heyo K A1 - Kramer, Holly A1 - Lin, Honghuang A1 - Irene Mateo Leach A1 - Ford, Ian A1 - Guessous, Idris A1 - Rudan, Igor A1 - Prokopenko, Inga A1 - Ingrid B Borecki A1 - Heid, Iris M A1 - Kolcic, Ivana A1 - Persico, Ivana A1 - Jukema, J Wouter A1 - James F Wilson A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Lambert, Jean-Charles A1 - Stafford, Jeanette M A1 - Gaspoz, Jean-Michel A1 - Jennifer A Smith A1 - Jessica D Faul A1 - Wang, Jie Jin A1 - Ding, Jingzhong A1 - Joel N Hirschhron A1 - John R. Attia A1 - Whitfield, John B A1 - Chalmers, John A1 - Viikari, Jorma A1 - Coresh, Josef A1 - Denny, Joshua C A1 - Karjalainen, Juha A1 - Fernandes, Jyotika K A1 - Endlich, Karlhans A1 - Butterbach, Katja A1 - Keene, Keith L A1 - Lohman, Kurt A1 - Portas, Laura A1 - Lenore J Launer A1 - Lyytikäinen, Leo-Pekka A1 - Yengo, Loic A1 - Lude L Franke A1 - Luigi Ferrucci A1 - Rose, Lynda M A1 - Kedenko, Lyudmyla A1 - Rao, Madhumathi A1 - Struchalin, Maksim A1 - Kleber, Marcus E A1 - Cavalieri, Margherita A1 - Haun, Margot A1 - Marilyn C Cornelis A1 - Ciullo, Marina A1 - Pirastu, Mario A1 - de Andrade, Mariza A1 - McEvoy, Mark A A1 - Woodward, Mark A1 - Adam, Martin A1 - Cocca, Massimiliano A1 - Nauck, Matthias A1 - Imboden, Medea A1 - Waldenberger, Melanie A1 - Pruijm, Menno A1 - Metzger, Marie A1 - Stumvoll, Michael A1 - Michele K Evans A1 - Sale, Michele M A1 - Kähönen, Mika A1 - Boban, Mladen A1 - Bochud, Murielle A1 - Rheinberger, Myriam A1 - Verweij, Niek A1 - Bouatia-Naji, Nabila A1 - Nicholas G Martin A1 - Nicholas D Hastie A1 - Probst-Hensch, Nicole A1 - Soranzo, Nicole A1 - Devuyst, Olivier A1 - Olli T Raitakari A1 - Gottesman, Omri A1 - Franco, Oscar H A1 - Polasek, Ozren A1 - Paolo P. Gasparini A1 - Munroe, Patricia B A1 - Ridker, Paul M A1 - Mitchell, Paul A1 - Muntner, Paul A1 - Meisinger, Christa A1 - Johannes Smit A1 - Kovacs, Peter A1 - Wild, Philipp S A1 - Froguel, Philippe A1 - Rettig, Rainer A1 - Mägi, Reedik A1 - Biffar, Reiner A1 - Schmidt, Reinhold A1 - Middelberg, Rita P S A1 - Carroll, Robert J A1 - Brenda W J H Penninx A1 - Rodney J Scott A1 - Katz, Ronit A1 - Sedaghat, Sanaz A1 - Sarah Wild A1 - Sharon L R Kardia A1 - Ulivi, Sheila A1 - Hwang, Shih-Jen A1 - Enroth, Stefan A1 - Kloiber, Stefan A1 - Trompet, Stella A1 - Stengel, Benedicte A1 - Hancock, Stephen J A1 - Stephen T Turner A1 - Rosas, Sylvia E A1 - Stracke, Sylvia A1 - Tamara B Harris A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Lehtimäki, Terho A1 - Illig, Thomas A1 - Aspelund, Thor A1 - Nikopensius, Tiit A1 - Tõnu Esko A1 - Toshiko Tanaka A1 - Gyllensten, Ulf A1 - Völker, Uwe A1 - Emilsson, Valur A1 - Vitart, Veronique A1 - Aalto, Ville A1 - Gudnason, Vilmundur A1 - Chouraki, Vincent A1 - Chen, Wei-Min A1 - Igl, Wilmar A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Ruth J F Loos A1 - Yongmei Liu A1 - Snieder, Harold A1 - Pramstaller, Peter P A1 - Parsa, Afshin A1 - O'Connell, Jeffrey R A1 - Susztak, Katalin A1 - Hamet, Pavel A1 - Tremblay, Johanne A1 - de Boer, Ian H A1 - Böger, Carsten A A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Köttgen, Anna A1 - Kao, W H Linda A1 - Fox, Caroline S KW - Chronic disease KW - Genome-Wide Association Study KW - Genotype KW - Humans AB -Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26831199?dopt=Abstract ER - TY - JOUR T1 - Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. JF - Nat Genet Y1 - 2016 A1 - Okbay, Aysu A1 - Baselmans, Bart M L A1 - De Neve, Jan-Emmanuel A1 - Turley, Patrick A1 - Nivard, Michel G A1 - Mark Alan Fontana A1 - Meddens, S Fleur W A1 - Richard Karlsson Linnér A1 - Cornelius A Rietveld A1 - Derringer, Jaime A1 - Gratten, Jacob A1 - Lee, James J A1 - Liu, Jimmy Z A1 - de Vlaming, Ronald A1 - Ahluwalia, Tarunveer S A1 - Buchwald, Jadwiga A1 - Cavadino, Alana A1 - Frazier-Wood, Alexis C A1 - Furlotte, Nicholas A A1 - Garfield, Victoria A1 - Geisel, Marie Henrike A1 - Gonzalez, Juan R A1 - Haitjema, Saskia A1 - Karlsson, Robert A1 - van der Laan, Sander W A1 - Ladwig, Karl-Heinz A1 - J. Lahti A1 - Sven J van der Lee A1 - Penelope A Lind A1 - Tian Liu A1 - Lindsay K Matteson A1 - Mihailov, Evelin A1 - Michael B Miller A1 - Minica, Camelia C A1 - Ilja M Nolte A1 - Dennis O Mook-Kanamori A1 - van der Most, Peter J A1 - Christopher J Oldmeadow A1 - Qian, Yong A1 - Olli T Raitakari A1 - Rawal, Rajesh A1 - Realo, Anu A1 - Rueedi, Rico A1 - Schmidt, Börge A1 - Albert Vernon Smith A1 - Stergiakouli, Evie A1 - Toshiko Tanaka A1 - Kent D Taylor A1 - Wedenoja, Juho A1 - Jürgen Wellmann A1 - Westra, Harm-Jan A1 - Willems, Sara M A1 - Wei Zhao A1 - Amin, Najaf A1 - Bakshi, Andrew A1 - Patricia A. Boyle A1 - Cherney, Samantha A1 - Cox, Simon R A1 - Gail Davies A1 - Davis, Oliver S P A1 - Ding, Jun A1 - Nese Direk A1 - Eibich, Peter A1 - Emeny, Rebecca T A1 - Fatemifar, Ghazaleh A1 - Jessica D Faul A1 - Luigi Ferrucci A1 - Andreas J Forstner A1 - Gieger, Christian A1 - Gupta, Richa A1 - Tamara B Harris A1 - Harris, Juliette M A1 - Holliday, Elizabeth G A1 - Jouke-Jan Hottenga A1 - Philip L. De Jager A1 - Marika A Kaakinen A1 - Kajantie, Eero A1 - Karhunen, Ville A1 - Kolcic, Ivana A1 - Kumari, Meena A1 - Lenore J Launer A1 - Lude L Franke A1 - Li-Gao, Ruifang A1 - Koini, Marisa A1 - Loukola, Anu A1 - Marques-Vidal, Pedro A1 - Grant W Montgomery A1 - Mosing, Miriam A A1 - Paternoster, Lavinia A1 - Pattie, Alison A1 - Petrovic, Katja E A1 - Pulkki-Raback, Laura A1 - Quaye, Lydia A1 - Katri Räikkönen A1 - Rudan, Igor A1 - Rodney J Scott A1 - Jennifer A Smith A1 - Angelina R Sutin A1 - Trzaskowski, Maciej A1 - Anna A E Vinkhuyzen A1 - Lei Yu A1 - Zabaneh, Delilah A1 - John R. Attia A1 - David A Bennett A1 - Klaus Berger A1 - Bertram, Lars A1 - Dorret I Boomsma A1 - Snieder, Harold A1 - Chang, Shun-Chiao A1 - Francesco Cucca A1 - Ian J Deary A1 - Cornelia M van Duijn A1 - Johan G. Eriksson A1 - Bültmann, Ute A1 - Eco J. C. de Geus A1 - Groenen, Patrick J F A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Catharina A Hartman A1 - Haworth, Claire M A A1 - Caroline Hayward A1 - Heath, Andrew C A1 - Hinds, David A A1 - Hyppönen, Elina A1 - Iacono, William G A1 - Järvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Kaprio, Jaakko A1 - Sharon L R Kardia A1 - Keltikangas-Järvinen, Liisa A1 - Kraft, Peter A1 - Laura D Kubzansky A1 - Lehtimäki, Terho A1 - Patrik K E Magnusson A1 - Nicholas G Martin A1 - McGue, Matt A1 - Andres Metspalu A1 - Melinda C Mills A1 - de Mutsert, Renée A1 - Oldehinkel, Albertine J A1 - Pasterkamp, Gerard A1 - Nancy L Pedersen A1 - Plomin, Robert A1 - Polasek, Ozren A1 - Power, Christine A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Hester M. den Ruijter A1 - Schlessinger, David A1 - Schmidt, Helena A1 - Svento, Rauli A1 - Schmidt, Reinhold A1 - Alizadeh, Behrooz Z A1 - Thorkild I. A. Sørensen A1 - Tim D Spector A1 - Steptoe, Andrew A1 - Antonio Terracciano A1 - A. Roy Thurik A1 - Nicholas J Timpson A1 - Henning Tiemeier A1 - André G Uitterlinden A1 - Vollenweider, Peter A1 - Wagner, Gert G A1 - David R Weir A1 - Yang, Jian A1 - Dalton C Conley A1 - Hofman, Albert A1 - Johannesson, Magnus A1 - David I Laibson A1 - Sarah E Medland A1 - Meyer, Michelle N A1 - Pickrell, Joseph K A1 - Tõnu Esko A1 - Krueger, Robert F A1 - Jonathan P. Beauchamp A1 - Philipp D Koellinger A1 - Daniel J. Benjamin A1 - Bartels, Meike A1 - Cesarini, David KW - Anxiety Disorders KW - Bayes Theorem KW - depression KW - Genome-Wide Association Study KW - Humans KW - Neuroticism KW - Phenotype KW - Polymorphism, Single Nucleotide AB -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 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27089181?dopt=Abstract 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 - James F Wilson A1 - Chasman, Daniel I A1 - Ilja M Nolte 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 M Yerges-Armstrong A1 - Atzmon, Gil A1 - Auro, Kirsi A1 - Kristin L. Ayers A1 - Bakshi, Andrew A1 - Ben-Avraham, Danny A1 - Klaus Berger 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 Alan Fontana A1 - Lude L Franke A1 - Gandin, Ilaria A1 - Gaskins, Audrey J A1 - Gieger, Christian A1 - Gunderson, Erica P A1 - Guo, Xiuqing A1 - Caroline Hayward A1 - He, Chunyan A1 - Edith Hofer 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 - Tian Liu A1 - Makalic, Enes A1 - Mamasoula, Crysovalanto A1 - Lindsay K Matteson A1 - Mbarek, Hamdi A1 - McArdle, Patrick F A1 - McMahon, George A1 - Meddens, S Fleur W A1 - Mihailov, Evelin A1 - Michael B Miller A1 - Missmer, Stacey A A1 - Monnereau, Claire A1 - van der Most, Peter J A1 - Myhre, Ronny A1 - Michael 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 - Jürgen Wellmann 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 Felicita Sala A1 - Froguel, Philippe A1 - Paolo P. Gasparini A1 - Giorgia G 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 - Vincent Jaddoe 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 - Yongmei Liu 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 J H 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 - A. Roy Thurik 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 - Alan F Wright A1 - Krina T Zondervan A1 - Stefansson, Kari A1 - Krueger, Robert F A1 - Lee, James J A1 - Daniel J. Benjamin A1 - Cesarini, David A1 - Philipp D 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 (GWAS) AND GENOME-WIDE BY ENVIRONMENT INTERACTION STUDY (GWEIS) OF DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN AND HISPANIC/LATINA WOMEN. JF - Depress Anxiety Y1 - 2016 A1 - Dunn, Erin C A1 - Wiste, Anna A1 - Radmanesh, Farid A1 - Almli, Lynn M A1 - Gogarten, Stephanie M A1 - Sofer, Tamar A1 - Jessica D Faul A1 - Sharon L R Kardia A1 - Jennifer A Smith A1 - David R Weir A1 - Wei Zhao A1 - Soare, Thomas W A1 - Saira S Mirza A1 - Karin Hek A1 - Henning Tiemeier A1 - Goveas, Joseph S A1 - Sarto, Gloria E A1 - Snively, Beverly M A1 - Marilyn C Cornelis A1 - Karestan C Koenen A1 - Kraft, Peter A1 - Purcell, Shaun A1 - Ressler, Kerry J A1 - Rosand, Jonathan A1 - Wassertheil-Smoller, Sylvia A1 - Smoller, Jordan W KW - African Americans KW - Aged KW - depression KW - Female KW - Gene-Environment Interaction KW - Genome-Wide Association Study KW - Hispanic Americans KW - Humans KW - Life Change Events KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Self Report AB -**BACKGROUND: **Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms.

**METHODS: **Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts.

**RESULTS: **No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10(-8) ) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10(-7) ). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10(-7) ) and rs4542757 (intronic to DCC, P = 7.31 × 10(-7) ). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10(-10) ; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample.

**CONCLUSIONS: **Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

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 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Amy M Matteini A1 - Toshiko Tanaka A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - John D Eicher A1 - Andrew D Johnson A1 - Alice M. Arnold A1 - Michele L Callisaya A1 - Gail Davies A1 - Daniel S Evans A1 - Holtfreter, Birte A1 - Lohman, Kurt A1 - Kathryn L Lunetta A1 - Mangino, Massimo A1 - Albert Vernon Smith A1 - Jennifer A Smith A1 - Teumer, Alexander A1 - Lei Yu A1 - Dan E Arking A1 - Aron S Buchman A1 - Chibinik, Lori B A1 - Philip L. De Jager A1 - Jessica D Faul A1 - Melissa E Garcia A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - David C Liewald A1 - Yongmei Liu A1 - Lopez, Lorna A1 - Fernando Rivadeneira A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - John M Starr A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - André G Uitterlinden A1 - Völker, Uwe A1 - Völzke, Henry A1 - David R Weir A1 - Kristine Yaffe A1 - Wei Zhao A1 - Wei Vivian Zhuang A1 - Zmuda, Joseph M A1 - David A Bennett A1 - Steven R Cummings A1 - Ian J Deary A1 - Luigi Ferrucci A1 - Tamara B Harris A1 - Sharon L R Kardia A1 - Kocher, Thomas A1 - Stephen B. Kritchevsky A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Tim D Spector A1 - Velandai K Srikanth A1 - Beverly G Windham A1 - Zillikens, M Carola A1 - Anne B Newman A1 - Jeremy D Walston A1 - Douglas P Kiel A1 - Joanne M Murabito KW - Adult KW - Aged KW - Chromatin Immunoprecipitation KW - Cohort Studies KW - Epigenesis, Genetic KW - Genome-Wide Association Study KW - Hand Strength KW - Humans KW - Molecular Sequence Annotation KW - Muscle Strength KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results AB -Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?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 - Kenneth Rice A1 - Alanna C Morrison A1 - Lu, Yingchang A1 - Weiss, Stefan A1 - Guo, Xiuqing A1 - Walter R 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 J 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 D 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 - Yongmei Liu 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 B 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 - Personality Polygenes, Positive Affect, and Life Satisfaction. JF - Twin Res Hum Genet Y1 - 2016 A1 - Weiss, Alexander A1 - Baselmans, Bart M L A1 - Edith Hofer A1 - Yang, Jingyun A1 - Okbay, Aysu A1 - Penelope A Lind A1 - Michael B Miller A1 - Ilja M Nolte A1 - Wei Zhao A1 - Hagenaars, Saskia P A1 - Jouke-Jan Hottenga A1 - Lindsay K Matteson A1 - Snieder, Harold A1 - Jessica D Faul A1 - Catharina A Hartman A1 - Patricia A. Boyle A1 - Henning Tiemeier A1 - Mosing, Miriam A A1 - Pattie, Alison A1 - Gail Davies A1 - David C Liewald A1 - Schmidt, Reinhold A1 - Philip L. De Jager A1 - Heath, Andrew C A1 - Markus Jokela A1 - John M Starr A1 - Oldehinkel, Albertine J A1 - Johannesson, Magnus A1 - Cesarini, David A1 - Hofman, Albert A1 - Sarah E Harris A1 - Jennifer A Smith A1 - Keltikangas-Järvinen, Liisa A1 - Pulkki-Raback, Laura A1 - Schmidt, Helena A1 - Jacqui Smith A1 - Iacono, William G A1 - McGue, Matt A1 - David A Bennett A1 - Nancy L Pedersen A1 - Patrik K E Magnusson A1 - Ian J Deary A1 - Nicholas G Martin A1 - Dorret I Boomsma A1 - Bartels, Meike A1 - Luciano, Michelle KW - Genetics KW - Happiness KW - Polygenic Prediction KW - SSGAC KW - Well-being AB -Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.

VL - 19 IS - 5 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 - Psychol Med Y1 - 2016 A1 - Demirkan, A A1 - J. Lahti A1 - Nese Direk A1 - Viktorin, A. A1 - Kathryn L Lunetta A1 - Antonio Terracciano A1 - Michael A Nalls A1 - Toshiko Tanaka A1 - Karin Hek A1 - Myriam Fornage A1 - Jürgen Wellmann A1 - Marilyn C Cornelis A1 - Ollila, H. M. A1 - Lei Yu A1 - Luke C Pilling A1 - Isaacs, A A1 - Aarno Palotie A1 - Wei Vivian 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 - Yongmei Liu 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 - Klaus Berger A1 - Tamara B Harris A1 - Nancy L Pedersen A1 - Joanne M Murabito A1 - Henning Tiemeier A1 - Cornelia M van Duijn A1 - Katri Räikkönen KW - depression KW - Depressive Disorder, Major KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Receptor, Melatonin, MT1 KW - Somatoform Disorders 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 - Rudolf Ferhmann 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 B 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 - Irene Mateo Leach A1 - Medina-Gomez, Carolina A1 - Sarah E Medland A1 - Michael 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 - Jana V. van Vliet-Ostaptchouk 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 - Jeffrey Haessler A1 - Hall, Per A1 - Haller, Toomas A1 - Hallmans, Göran A1 - Catharina A Hartman A1 - Hassinen, Maija A1 - Caroline Hayward A1 - Heard-Costa, Nancy L A1 - Helmer, Quinta A1 - Hengstenberg, Christian A1 - Oddgeir L 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 Sin 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 - Markus M Nöthen A1 - Ilja M Nolte A1 - Pilz, Stefan A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rettig, Rainer A1 - Ried, Janina S A1 - Ripke, Stephan A1 - Neil R 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 - Jianxin Shi A1 - Albert Vernon Smith A1 - Smolonska, Joanna A1 - Stanton, Alice V A1 - Steinthorsdottir, Valgerdur A1 - Kathleen E 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 O 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 - Lindsay L Waite A1 - Warren, Helen R A1 - Dawn M Waterworth A1 - Michael N Weedon A1 - Wilkens, Lynne R A1 - Willenborg, Christina A1 - Wilsgaard, Tom A1 - Wojczynski, Mary K A1 - Wong, Andrew A1 - Alan F Wright A1 - Zhang, Qunyuan A1 - Brennan, Eoin P A1 - Murim Choi A1 - Dastani, Zari A1 - Alexander W 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 - Ferdinand M van 't Hooft A1 - Anna A 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 den 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 - Loic Le Marchand 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 F 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 J Samani A1 - Saramies, Jouko A1 - Sarzynski, Mark A A1 - Schunkert, Heribert A1 - Schwarz, Peter E H A1 - Sever, Peter A1 - Alan R Shuldiner 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 Kivimäki A1 - Kuh, Diana A1 - Laakso, Markku A1 - Yongmei Liu 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 - James F Wilson 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 R 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 N Hirschhron 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 - J Gerontol A Biol Sci Med Sci 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 T 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 - Aged KW - Aged, 80 and over KW - Apolipoproteins E KW - Cell Adhesion Molecules KW - Cohort Studies KW - Female KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Kainic Acid 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 - Genetic diversity is a predictor of mortality in humans. JF - BMC Genet Y1 - 2014 A1 - Bihlmeyer, Nathan A A1 - Brody, Jennifer A A1 - Albert Vernon Smith A1 - Kathryn L Lunetta A1 - Michael 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 - Yongmei Liu 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 - Mohammed 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 - Genome-Wide Association Study KW - Heterozygote KW - Humans KW - Mortality KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models 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 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23972371?dopt=Abstract 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 - Rudolf Ferhmann A1 - Fischer, Krista A1 - Gieger, Christian A1 - Gjessing, Håkon K A1 - Hägg, Sara A1 - Harris, Jennifer R A1 - Caroline Hayward 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 - Yongmei Liu 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 J 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 - Klaus Berger 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 - Nicholas D Hastie A1 - Heath, Andrew C A1 - Dena G 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 F 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 J H 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 - Rodney J Scott 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 - James F Wilson A1 - Alan F Wright 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 D Koellinger KW - Cognition KW - Educational Status KW - Endophenotypes KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide 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 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23722424?dopt=Abstract ER - TY - JOUR T1 - Mechanisms for racial and ethnic disparities in glycemic control in middle-aged and older Americans in the health and retirement study. JF - Arch Intern Med Y1 - 2007 A1 - Michele M Heisler A1 - Jessica D Faul A1 - Rodney A. Hayward A1 - Kenneth M. Langa A1 - Caroline S Blaum A1 - David R Weir KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Glycated Hemoglobin A KW - Health Services Accessibility KW - Hispanic Americans KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Patient Compliance KW - Socioeconomic factors KW - Treatment Refusal KW - United States AB -**BACKGROUND: **Mechanisms for racial/ethnic disparities in glycemic control are poorly understood.

**METHODS: **A nationally representative sample of 1901 respondents 55 years or older with diabetes mellitus completed a mailed survey in 2003; 1233 respondents completed valid at-home hemoglobin A(1c) (HbA(1c)) kits. We constructed multivariate regression models with survey weights to examine racial/ethnic differences in HbA(1c) control and to explore the association of HbA(1c) level with sociodemographic and clinical factors, access to and quality of diabetes health care, and self-management behaviors and attitudes.

**RESULTS: **There were no significant racial/ethnic differences in HbA(1c) levels in respondents not taking antihyperglycemic medications. In 1034 respondents taking medications, the mean HbA(1c) value (expressed as percentage of total hemoglobin) was 8.07% in black respondents and 8.14% in Latino respondents compared with 7.22% in white respondents (P < .001). Black respondents had worse medication adherence than white respondents, and Latino respondents had more diabetes-specific emotional distress (P < .001). Adjusting for hypothesized mechanisms accounted for 14.0% of the higher HbA(1c) levels in black respondents and 19.0% in Latinos, with the full model explaining 22.0% of the variance. Besides black and Latino ethnicity, only insulin use (P < .001), age younger than 65 years (P = .007), longer diabetes duration (P = .004), and lower self-reported medication adherence (P = .04) were independently associated with higher HbA(1c) levels.

**CONCLUSIONS: **Latino and African American respondents had worse glycemic control than white respondents. Socioeconomic, clinical, health care, and self-management measures explained approximately a fifth of the HbA(1c) differences. One potentially modifiable factor for which there were racial disparities--medication adherence--was among the most significant independent predictors of glycemic control.