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The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study
Winkler, Thomas W; Justice, Anne E; Graff, Mariaelisa; Barata, Llilda; Feitosa, Mary F; Chu, Su; Czajkowski, Jacek; Esko, Tonu; Fall, Tove; Kilpelainen, Tuomas O; Lu, Yingchang; Magi, Reedik; Mihailov, Evelin; Pers, Tune H; Rueger, Sina; Teumer, Alexander; Ehret, Georg B; Ferreira, Teresa; Heard-Costa, Nancy L; Karjalainen, Juha; Lagou, Vasiliki; Mahajan, Anubha; Neinast, Michael D; Prokopenko, Inga; Simino, Jeannette; Teslovich, Tanya M; Jansen, Rick; Westra, Harm-Jan; White, Charles C; Absher, Devin; Ahluwalia, Tarunveer S; Ahmad, Shafqat; Albrecht, Eva; Alves, Alexessander Couto; Bragg-Gresham, Jennifer L; de Craen, Anton J M; Bis, Joshua C; Bonnefond, Amelie; Boucher, Gabrielle; Cadby, Gemma; Cheng, Yu-Ching; Chiang, Charleston W K; Delgado, Graciela; Demirkan, Ayse; Dueker, Nicole; Eklund, Niina; Eiriksdottir, Gudny; Eriksson, Joel; Feenstra, Bjarke; Fischer, Krista; Frau, Francesca; Galesloot, Tessel E; Geller, Frank; Goel, Anuj; Gorski, Mathias; Grammer, Tanja B; Gustafsson, Stefan; Haitjema, Saskia; Hottenga, Jouke-Jan; Huffman, Jennifer E; Jackson, Anne U; Jacobs, Kevin B; Johansson, Asa; Kaakinen, Marika; Kleber, Marcus E; Lahti, Jari; Mateo Leach, Irene; Lehne, Benjamin; Liu, Youfang; Lo, Ken Sin; Lorentzon, Mattias; Luan, Jian'an; Madden, Pamela A F; Mangino, Massimo; McKnight, Barbara; Medina-Gomez, Carolina; Monda, Keri L; Montasser, May E; Muller, Gabriele; Muller-Nurasyid, Martina; Nolte, Ilja M; Panoutsopoulou, Kalliope; Pascoe, Laura; Paternoster, Lavinia; Rayner, Nigel W; Renstrom, Frida; Rizzi, Federica; Rose, Lynda M; Ryan, Kathy A; Salo, Perttu; Sanna, Serena; Scharnagl, Hubert; Shi, Jianxin; Smith, Albert Vernon; Southam, Lorraine; Stancakova, Alena; Steinthorsdottir, Valgerdur; Strawbridge, Rona J; Sung, Yun Ju; Tachmazidou, Ioanna; Tanaka, Toshiko; Thorleifsson, Gudmar; Trompet, Stella; Pervjakova, Natalia; Tyrer, Jonathan P; Vandenput, Liesbeth; van der Laan, Sander W; van der Velde, Nathalie; van Setten, Jessica; van Vliet-Ostaptchouk, Jana V; Verweij, Niek; Vlachopoulou, Efthymia; Waite, Lindsay L; Wang, Sophie R; Wang, Zhaoming; Wild, Sarah H; Willenborg, Christina; Wilson, James F; Wong, Andrew; Yang, Jian; Yengo, Loic; Yerges-Armstrong, Laura M; Yu, Lei; Zhang, Weihua; Zhao, Jing Hua; Andersson, Ehm A; Bakker, Stephan J L; Baldassarre, Damiano; Banasik, Karina; Barcella, Matteo; Barlassina, Cristina; Bellis, Claire; Benaglio, Paola; Blangero, John; Bluher, Matthias; Bonnet, Fabrice; Bonnycastle, Lori L; Boyd, Heather A; Bruinenberg, Marcel; Buchman, Aron S; Campbell, Harry; Chen, Yii-Der Ida; Chines, Peter S; Claudi-Boehm, Simone; Cole, John; Collins, Francis S; de Geus, Eco J C; de Groot, Lisette C P G M; Dimitriou, Maria; Duan, Jubao; Enroth, Stefan; Eury, Elodie; Farmaki, Aliki-Eleni; Forouhi, Nita G; Friedrich, Nele; Gejman, Pablo V; Gigante, Bruna; Glorioso, Nicola; Go, Alan S; Gottesman, Omri; Grassler, Jurgen; Grallert, Harald; Grarup, Niels; Gu, Yu-Mei; Broer, Linda; Ham, Annelies C; Hansen, Torben; Harris, Tamara B; Hartman, Catharina A; Hassinen, Maija; Hastie, Nicholas; Hattersley, Andrew T; Heath, Andrew C; Henders, Anjali K; Hernandez, Dena; Hillege, Hans; Holmen, Oddgeir; Hovingh, Kees G; Hui, Jennie; Husemoen, Lise L; Hutri-Kahonen, Nina; Hysi, Pirro G; Illig, Thomas; De Jager, Philip L; Jalilzadeh, Shapour; Jorgensen, Torben; Jukema, J Wouter; Juonala, Markus; Kanoni, Stavroula; Karaleftheri, Maria; Khaw, Kay Tee; Kinnunen, Leena; Kittner, Steven J; Koenig, Wolfgang; Kolcic, Ivana; Kovacs, Peter; Krarup, Nikolaj T; Kratzer, Wolfgang; Kruger, Janine; Kuh, Diana; Kumari, Meena; Kyriakou, Theodosios; Langenberg, Claudia; Lannfelt, Lars; Lanzani, Chiara; Lotay, Vaneet; Launer, Lenore J; Leander, Karin; Lindstrom, Jaana; Linneberg, Allan; Liu, Yan-Ping; Lobbens, Stephane; Luben, Robert; Lyssenko, Valeriya; Mannisto, Satu; Magnusson, Patrik K; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Milani, Lili; Montgomery, Grant W; Morris, Andrew P; Narisu, Narisu; Nelis, Mari; Ong, Ken K; Palotie, Aarno; Perusse, Louis; Pichler, Irene; Pilia, Maria G; Pouta, Anneli; Rheinberger, Myriam; Ribel-Madsen, Rasmus; Richards, Marcus; Rice, Kenneth M; Rice, Treva K; Rivolta, Carlo; Salomaa, Veikko; Sanders, Alan R; Sarzynski, Mark A; Scholtens, Salome; Scott, Robert A; Scott, William R; Sebert, Sylvain; Sengupta, Sebanti; Sennblad, Bengt; Seufferlein, Thomas; Silveira, Angela; Slagboom, P Eline; Smit, Jan H; Sparso, Thomas H; Stirrups, Kathleen; Stolk, Ronald P; Stringham, Heather M; Swertz, Morris A; Swift, Amy J; Syvanen, Ann-Christine; Tan, Sian-Tsung; Thorand, Barbara; Tonjes, Anke; Tremblay, Angelo; Tsafantakis, Emmanouil; van der Most, Peter J; Volker, Uwe; Vohl, Marie-Claude; Vonk, Judith M; Waldenberger, Melanie; Walker, Ryan W; Wennauer, Roman; Widen, Elisabeth; Willemsen, Gonneke; Wilsgaard, Tom; Wright, Alan F; Zillikens, M Carola; van Dijk, Suzanne C; van Schoor, Natasja M; Asselbergs, Folkert W; de Bakker, Paul I W; Beckmann, Jacques S; Beilby, John; Bennett, David A; Bergman, Richard N; Bergmann, Sven; Boger, Carsten A; Boehm, Bernhard O; Boerwinkle, Eric; Boomsma, Dorret I; Bornstein, Stefan R; Bottinger, Erwin P; Bouchard, Claude; Chambers, John C; Chanock, Stephen J; Chasman, Daniel I; Cucca, Francesco; Cusi, Daniele; Dedoussis, George; Erdmann, Jeanette; Eriksson, Johan G; Evans, Denis A; de Faire, Ulf; Farrall, Martin; Ferrucci, Luigi; Ford, Ian; Franke, Lude; Franks, Paul W; Froguel, Philippe; Gansevoort, Ron T; Gieger, Christian; Gronberg, Henrik; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Per; Hamsten, Anders; van der Harst, Pim; Hayward, Caroline; Heliovaara, Markku; Hengstenberg, Christian; Hicks, Andrew A; Hingorani, Aroon; Hofman, Albert; Hu, Frank; Huikuri, Heikki V; Hveem, Kristian; James, Alan L; Jordan, Joanne M; Jula, Antti; Kahonen, Mika; Kajantie, Eero; Kathiresan, Sekar; Kiemeney, Lambertus A L M; Kivimaki, Mika; Knekt, Paul B; Koistinen, Heikki A; Kooner, Jaspal S; Koskinen, Seppo; Kuusisto, Johanna; Maerz, Winfried; Martin, Nicholas G; Laakso, Markku; Lakka, Timo A; Lehtimaki, Terho; Lettre, Guillaume; Levinson, Douglas F; Lind, Lars; Lokki, Marja-Liisa; Mantyselka, Pekka; Melbye, Mads; Metspalu, Andres; Mitchell, Braxton D; Moll, Frans L; Murray, Jeffrey C; Musk, Arthur W; Nieminen, Markku S; Njolstad, Inger; Ohlsson, Claes; Oldehinkel, Albertine J; Oostra, Ben A; Palmer, Lyle J; Pankow, James S; Pasterkamp, Gerard; Pedersen, Nancy L; Pedersen, Oluf; Penninx, Brenda W; Perola, Markus; Peters, Annette; Polasek, Ozren; Pramstaller, Peter P; Psaty, Bruce M; Qi, Lu; Quertermous, Thomas; Raitakari, Olli T; Rankinen, Tuomo; Rauramaa, Rainer; Ridker, Paul M; Rioux, John D; Rivadeneira, Fernando; Rotter, Jerome I; Rudan, Igor; den Ruijter, Hester M; Saltevo, Juha; Sattar, Naveed; Schunkert, Heribert; Schwarz, Peter E H; Shuldiner, Alan R; Sinisalo, Juha; Snieder, Harold; Sorensen, Thorkild I A; Spector, Tim D; Staessen, Jan A; Stefania, Bandinelli; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tardif, Jean-Claude; Tremoli, Elena; Tuomilehto, Jaakko; Uitterlinden, Andre G; Uusitupa, Matti; Verbeek, Andre L M; Vermeulen, Sita H; Viikari, Jorma S; Vitart, Veronique; Volzke, Henry; Vollenweider, Peter; Waeber, Gerard; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Zeggini, Eleftheria; Chakravarti, Aravinda; Clegg, Deborah J; Cupples, L Adrienne; Gordon-Larsen, Penny; Jaquish, Cashell E; Rao, D C; Abecasis, Goncalo R; Assimes, Themistocles L; Barroso, Ines; Berndt, Sonja I; Boehnke, Michael; Deloukas, Panos; Fox, Caroline S; Groop, Leif C; Hunter, David J; Ingelsson, Erik; Kaplan, Robert C; McCarthy, Mark I; Mohlke, Karen L; O'Connell, Jeffrey R; Schlessinger, David; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Hirschhorn, Joel N; Lindgren, Cecilia M; Heid, Iris M; North, Kari E; Borecki, Ingrid B; Kutalik, Zoltan; Loos, Ruth J F
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (>/=50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
PMCID:4591371
PMID: 26426971
ISSN: 1553-7404
CID: 2746662
Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns
Turner, Tychele N; Douville, Christopher; Kim, Dewey; Stenson, Peter D; Cooper, David N; Chakravarti, Aravinda; Karchin, Rachel
The role of rare missense variants in disease causation remains difficult to interpret. We explore whether the clustering pattern of rare missense variants (MAF < 0.01) in a protein is associated with mode of inheritance. Mutations in genes associated with autosomal dominant (AD) conditions are known to result in either loss or gain of function, whereas mutations in genes associated with autosomal recessive (AR) conditions invariably result in loss-of-function. Loss-of-function mutations tend to be distributed uniformly along protein sequence, whereas gain-of-function mutations tend to localize to key regions. It has not previously been ascertained whether these patterns hold in general for rare missense mutations. We consider the extent to which rare missense variants are located within annotated protein domains and whether they form clusters, using a new unbiased method called CLUstering by Mutation Position. These approaches quantified a significant difference in clustering between AD and AR diseases. Proteins linked to AD diseases exhibited more clustering of rare missense mutations than those linked to AR diseases (Wilcoxon P = 5.7 x 10(-4), permutation P = 8.4 x 10(-4)). Rare missense mutation in proteins linked to either AD or AR diseases was more clustered than controls (1000G) (Wilcoxon P = 2.8 x 10(-15) for AD and P = 4.5 x 10(-4) for AR, permutation P = 3.1 x 10(-12) for AD and P = 0.03 for AR). The differences in clustering patterns persisted even after removal of the most prominent genes. Testing for such non-random patterns may reveal novel aspects of disease etiology in large sample studies.
PMID: 26246501
ISSN: 1460-2083
CID: 2746692
HPASubC: A suite of tools for user subclassification of human protein atlas tissue images
Cornish, Toby C; Chakravarti, Aravinda; Kapoor, Ashish; Halushka, Marc K
BACKGROUND: The human protein atlas (HPA) is a powerful proteomic tool for visualizing the distribution of protein expression across most human tissues and many common malignancies. The HPA includes immunohistochemically-stained images from tissue microarrays (TMAs) that cover 48 tissue types and 20 common malignancies. The TMA data are used to provide expression information at the tissue, cellular, and occasionally, subcellular level. The HPA also provides subcellular data from confocal immunofluorescence data on three cell lines. Despite the availability of localization data, many unique patterns of cellular and subcellular expression are not documented. MATERIALS AND METHODS: To get at this more granular data, we have developed a suite of Python scripts, HPASubC, to aid in subcellular, and cell-type specific classification of HPA images. This method allows the user to download and optimize specific HPA TMA images for review. Then, using a playstation-style video game controller, a trained observer can rapidly step through 10's of 1000's of images to identify patterns of interest. RESULTS: We have successfully used this method to identify 703 endothelial cell (EC) and/or smooth muscle cell (SMCs) specific proteins discovered within 49,200 heart TMA images. This list will assist us in subdividing cardiac gene or protein array data into expression by one of the predominant cell types of the myocardium: Myocytes, SMCs or ECs. CONCLUSIONS: The opportunity to further characterize unique staining patterns across a range of human tissues and malignancies will accelerate our understanding of disease processes and point to novel markers for tissue evaluation in surgical pathology.
PMCID:4485190
PMID: 26167380
ISSN: 2229-5089
CID: 2746702
Direct Estimates of the Genomic Contributions to Blood Pressure Heritability within a Population-Based Cohort (ARIC)
Salfati, Elias; Morrison, Alanna C; Boerwinkle, Eric; Chakravarti, Aravinda
Blood pressure (BP) is a heritable trait with multiple environmental and genetic contributions, with current heritability estimates from twin and family studies being ~ 40%. Here, we use genome-wide polymorphism data from the Atherosclerosis Risk in Communities (ARIC) study to estimate BP heritability from genomic relatedness among cohort members. We utilized data on 6,365,596 and 9,578,528 genotyped and imputed common single nucleotide polymorphisms (SNPs), in 8,901 European ancestry (EA) and 2,860 African Ancestry (AA) ARIC participants, respectively, and a mixed linear model for analyses, to make four observations. First, for BP measurements, the heritability is ~20%/~50% and ~27%/~39% for systolic (SBP)/diastolic (DBP) blood pressure in European and African ancestry individuals, respectively, consistent with prior studies. Second, common variants with allele frequency >10% recapitulate most of the BP heritability in these data. Third, the vast majority of BP heritability varies by chromosome, depending on its length, and is largely concentrated in noncoding genomic regions annotated as DNaseI hypersensitive sites (DHSs). Fourth, the majority of this heritability arises from loci not harboring currently known cardiovascular and renal genes. Recent meta-analyses of large-scale genome-wide association studies (GWASs) and admixture mapping have identified ~50 loci associated with BP and hypertension (HTN), and yet they account for only a small fraction (~2%) of the heritability.
PMCID:4498745
PMID: 26162070
ISSN: 1932-6203
CID: 2746712
Directional dominance on stature and cognition in diverse human populations
Joshi, Peter K; Esko, Tonu; Mattsson, Hannele; Eklund, Niina; Gandin, Ilaria; Nutile, Teresa; Jackson, Anne U; Schurmann, Claudia; Smith, Albert V; Zhang, Weihua; Okada, Yukinori; Stancakova, Alena; Faul, Jessica D; Zhao, Wei; Bartz, Traci M; Concas, Maria Pina; Franceschini, Nora; Enroth, Stefan; Vitart, Veronique; Trompet, Stella; Guo, Xiuqing; Chasman, Daniel I; O'Connel, Jeffery R; Corre, Tanguy; Nongmaithem, Suraj S; Chen, Yuning; Mangino, Massimo; Ruggiero, Daniela; Traglia, Michela; Farmaki, Aliki-Eleni; Kacprowski, Tim; Bjonnes, Andrew; van der Spek, Ashley; Wu, Ying; Giri, Anil K; Yanek, Lisa R; Wang, Lihua; Hofer, Edith; Rietveld, Cornelius A; McLeod, Olga; Cornelis, Marilyn C; Pattaro, Cristian; Verweij, Niek; Baumbach, Clemens; Abdellaoui, Abdel; Warren, Helen R; Vuckovic, Dragana; Mei, Hao; Bouchard, Claude; Perry, John R B; Cappellani, Stefania; Mirza, Saira S; Benton, Miles C; Broeckel, Ulrich; Medland, Sarah E; Lind, Penelope A; Malerba, Giovanni; Drong, Alexander; Yengo, Loic; Bielak, Lawrence F; Zhi, Degui; van der Most, Peter J; Shriner, Daniel; Magi, Reedik; Hemani, Gibran; Karaderi, Tugce; Wang, Zhaoming; Liu, Tian; Demuth, Ilja; Zhao, Jing Hua; Meng, Weihua; Lataniotis, Lazaros; van der Laan, Sander W; Bradfield, Jonathan P; Wood, Andrew R; Bonnefond, Amelie; Ahluwalia, Tarunveer S; Hall, Leanne M; Salvi, Erika; Yazar, Seyhan; Carstensen, Lisbeth; de Haan, Hugoline G; Abney, Mark; Afzal, Uzma; Allison, Matthew A; Amin, Najaf; Asselbergs, Folkert W; Bakker, Stephan J L; Barr, R Graham; Baumeister, Sebastian E; Benjamin, Daniel J; Bergmann, Sven; Boerwinkle, Eric; Bottinger, Erwin P; Campbell, Archie; Chakravarti, Aravinda; Chan, Yingleong; Chanock, Stephen J; Chen, Constance; Chen, Y-D Ida; Collins, Francis S; Connell, John; Correa, Adolfo; Cupples, L Adrienne; Smith, George Davey; Davies, Gail; Dorr, Marcus; Ehret, Georg; Ellis, Stephen B; Feenstra, Bjarke; Feitosa, Mary F; Ford, Ian; Fox, Caroline S; Frayling, Timothy M; Friedrich, Nele; Geller, Frank; Scotland, Generation; Gillham-Nasenya, Irina; Gottesman, Omri; Graff, Misa; Grodstein, Francine; Gu, Charles; Haley, Chris; Hammond, Christopher J; Harris, Sarah E; Harris, Tamara B; Hastie, Nicholas D; Heard-Costa, Nancy L; Heikkila, Kauko; Hocking, Lynne J; Homuth, Georg; Hottenga, Jouke-Jan; Huang, Jinyan; Huffman, Jennifer E; Hysi, Pirro G; Ikram, M Arfan; Ingelsson, Erik; Joensuu, Anni; Johansson, Asa; Jousilahti, Pekka; Jukema, J Wouter; Kahonen, Mika; Kamatani, Yoichiro; Kanoni, Stavroula; Kerr, Shona M; Khan, Nazir M; Koellinger, Philipp; Koistinen, Heikki A; Kooner, Manraj K; Kubo, Michiaki; Kuusisto, Johanna; Lahti, Jari; Launer, Lenore J; Lea, Rodney A; Lehne, Benjamin; Lehtimaki, Terho; Liewald, David C M; Lind, Lars; Loh, Marie; Lokki, Marja-Liisa; London, Stephanie J; Loomis, Stephanie J; Loukola, Anu; Lu, Yingchang; Lumley, Thomas; Lundqvist, Annamari; Mannisto, Satu; Marques-Vidal, Pedro; Masciullo, Corrado; Matchan, Angela; Mathias, Rasika A; Matsuda, Koichi; Meigs, James B; Meisinger, Christa; Meitinger, Thomas; Menni, Cristina; Mentch, Frank D; Mihailov, Evelin; Milani, Lili; Montasser, May E; Montgomery, Grant W; Morrison, Alanna; Myers, Richard H; Nadukuru, Rajiv; Navarro, Pau; Nelis, Mari; Nieminen, Markku S; Nolte, Ilja M; O'Connor, George T; Ogunniyi, Adesola; Padmanabhan, Sandosh; Palmas, Walter R; Pankow, James S; Patarcic, Inga; Pavani, Francesca; Peyser, Patricia A; Pietilainen, Kirsi; Poulter, Neil; Prokopenko, Inga; Ralhan, Sarju; Redmond, Paul; Rich, Stephen S; Rissanen, Harri; Robino, Antonietta; Rose, Lynda M; Rose, Richard; Sala, Cinzia; Salako, Babatunde; Salomaa, Veikko; Sarin, Antti-Pekka; Saxena, Richa; Schmidt, Helena; Scott, Laura J; Scott, William R; Sennblad, Bengt; Seshadri, Sudha; Sever, Peter; Shrestha, Smeeta; Smith, Blair H; Smith, Jennifer A; Soranzo, Nicole; Sotoodehnia, Nona; Southam, Lorraine; Stanton, Alice V; Stathopoulou, Maria G; Strauch, Konstantin; Strawbridge, Rona J; Suderman, Matthew J; Tandon, Nikhil; Tang, Sian-Tsun; Taylor, Kent D; Tayo, Bamidele O; Toglhofer, Anna Maria; Tomaszewski, Maciej; Tsernikova, Natalia; Tuomilehto, Jaakko; Uitterlinden, Andre G; Vaidya, Dhananjay; van Hylckama Vlieg, Astrid; van Setten, Jessica; Vasankari, Tuula; Vedantam, Sailaja; Vlachopoulou, Efthymia; Vozzi, Diego; Vuoksimaa, Eero; Waldenberger, Melanie; Ware, Erin B; Wentworth-Shields, William; Whitfield, John B; Wild, Sarah; Willemsen, Gonneke; Yajnik, Chittaranjan S; Yao, Jie; Zaza, Gianluigi; Zhu, Xiaofeng; Project, The BioBank Japan; Salem, Rany M; Melbye, Mads; Bisgaard, Hans; Samani, Nilesh J; Cusi, Daniele; Mackey, David A; Cooper, Richard S; Froguel, Philippe; Pasterkamp, Gerard; Grant, Struan F A; Hakonarson, Hakon; Ferrucci, Luigi; Scott, Robert A; Morris, Andrew D; Palmer, Colin N A; Dedoussis, George; Deloukas, Panos; Bertram, Lars; Lindenberger, Ulman; Berndt, Sonja I; Lindgren, Cecilia M; Timpson, Nicholas J; Tonjes, Anke; Munroe, Patricia B; Sorensen, Thorkild I A; Rotimi, Charles N; Arnett, Donna K; Oldehinkel, Albertine J; Kardia, Sharon L R; Balkau, Beverley; Gambaro, Giovanni; Morris, Andrew P; Eriksson, Johan G; Wright, Margie J; Martin, Nicholas G; Hunt, Steven C; Starr, John M; Deary, Ian J; Griffiths, Lyn R; Tiemeier, Henning; Pirastu, Nicola; Kaprio, Jaakko; Wareham, Nicholas J; Perusse, Louis; Wilson, James G; Girotto, Giorgia; Caulfield, Mark J; Raitakari, Olli; Boomsma, Dorret I; Gieger, Christian; van der Harst, Pim; Hicks, Andrew A; Kraft, Peter; Sinisalo, Juha; Knekt, Paul; Johannesson, Magnus; Magnusson, Patrik K E; Hamsten, Anders; Schmidt, Reinhold; Borecki, Ingrid B; Vartiainen, Erkki; Becker, Diane M; Bharadwaj, Dwaipayan; Mohlke, Karen L; Boehnke, Michael; van Duijn, Cornelia M; Sanghera, Dharambir K; Teumer, Alexander; Zeggini, Eleftheria; Metspalu, Andres; Gasparini, Paolo; Ulivi, Sheila; Ober, Carole; Toniolo, Daniela; Rudan, Igor; Porteous, David J; Ciullo, Marina; Spector, Tim D; Hayward, Caroline; Dupuis, Josee; Loos, Ruth J F; Wright, Alan F; Chandak, Giriraj R; Vollenweider, Peter; Shuldiner, Alan; Ridker, Paul M; Rotter, Jerome I; Sattar, Naveed; Gyllensten, Ulf; North, Kari E; Pirastu, Mario; Psaty, Bruce M; Weir, David R; Laakso, Markku; Gudnason, Vilmundur; Takahashi, Atsushi; Chambers, John C; Kooner, Jaspal S; Strachan, David P; Campbell, Harry; Hirschhorn, Joel N; Perola, Markus; Polasek, Ozren; Wilson, James F
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 x 10(-300), 2.1 x 10(-6), 2.5 x 10(-10) and 1.8 x 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.
PMCID:4516141
PMID: 26131930
ISSN: 1476-4687
CID: 2746722
Global implementation of genomic medicine: We are not alone
Manolio, Teri A; Abramowicz, Marc; Al-Mulla, Fahd; Anderson, Warwick; Balling, Rudi; Berger, Adam C; Bleyl, Steven; Chakravarti, Aravinda; Chantratita, Wasun; Chisholm, Rex L; Dissanayake, Vajira H W; Dunn, Michael; Dzau, Victor J; Han, Bok-Ghee; Hubbard, Tim; Kolbe, Anne; Korf, Bruce; Kubo, Michiaki; Lasko, Paul; Leego, Erkki; Mahasirimongkol, Surakameth; Majumdar, Partha P; Matthijs, Gert; McLeod, Howard L; Metspalu, Andres; Meulien, Pierre; Miyano, Satoru; Naparstek, Yaakov; O'Rourke, P Pearl; Patrinos, George P; Rehm, Heidi L; Relling, Mary V; Rennert, Gad; Rodriguez, Laura Lyman; Roden, Dan M; Shuldiner, Alan R; Sinha, Sukdeb; Tan, Patrick; Ulfendahl, Mats; Ward, Robyn; Williams, Marc S; Wong, John E L; Green, Eric D; Ginsburg, Geoffrey S
Around the world, innovative genomic-medicine programs capitalize on singular capabilities arising from local health care systems, cultural or political milieus, and unusual selected risk alleles or disease burdens. Such individual efforts might benefit from the sharing of approaches and lessons learned in other locales. The U.S. National Human Genome Research Institute and the National Academy of Medicine recently brought together 25 of these groups to compare projects, to examine the current state of implementation and desired near-term capabilities, and to identify opportunities for collaboration that promote the responsible practice of genomic medicine. Efforts to coalesce these groups around concrete but compelling signature projects should accelerate the responsible implementation of genomic medicine in efforts to improve clinical care worldwide.
PMCID:4898888
PMID: 26041702
ISSN: 1946-6242
CID: 2746732
Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability
Jiang, Qian; Arnold, Stacey; Heanue, Tiffany; Kilambi, Krishna Praneeth; Doan, Betty; Kapoor, Ashish; Ling, Albee Yun; Sosa, Maria X; Guy, Moltu; Jiang, Qingguang; Burzynski, Grzegorz; West, Kristen; Bessling, Seneca; Griseri, Paola; Amiel, Jeanne; Fernandez, Raquel M; Verheij, Joke B G M; Hofstra, Robert M W; Borrego, Salud; Lyonnet, Stanislas; Ceccherini, Isabella; Gray, Jeffrey J; Pachnis, Vassilis; McCallion, Andrew S; Chakravarti, Aravinda
Innervation of the gut is segmentally lost in Hirschsprung disease (HSCR), a consequence of cell-autonomous and non-autonomous defects in enteric neuronal cell differentiation, proliferation, migration, or survival. Rare, high-penetrance coding variants and common, low-penetrance non-coding variants in 13 genes are known to underlie HSCR risk, with the most frequent variants in the ret proto-oncogene (RET). We used a genome-wide association (220 trios) and replication (429 trios) study to reveal a second non-coding variant distal to RET and a non-coding allele on chromosome 7 within the class 3 Semaphorin gene cluster. Analysis in Ret wild-type and Ret-null mice demonstrates specific expression of Sema3a, Sema3c, and Sema3d in the enteric nervous system (ENS). In zebrafish embryos, sema3 knockdowns show reduction of migratory ENS precursors with complete ablation under conjoint ret loss of function. Seven candidate receptors of Sema3 proteins are also expressed within the mouse ENS and their expression is also lost in the ENS of Ret-null embryos. Sequencing of SEMA3A, SEMA3C, and SEMA3D in 254 HSCR-affected subjects followed by in silico protein structure modeling and functional analyses identified five disease-associated alleles with loss-of-function defects in semaphorin dimerization and binding to their cognate neuropilin and plexin receptors. Thus, semaphorin 3C/3D signaling is an evolutionarily conserved regulator of ENS development whose dys-regulation is a cause of enteric aganglionosis.
PMCID:4385176
PMID: 25839327
ISSN: 1537-6605
CID: 2746742
Loss of delta-catenin function in severe autism
Turner, Tychele N; Sharma, Kamal; Oh, Edwin C; Liu, Yangfan P; Collins, Ryan L; Sosa, Maria X; Auer, Dallas R; Brand, Harrison; Sanders, Stephan J; Moreno-De-Luca, Daniel; Pihur, Vasyl; Plona, Teri; Pike, Kristen; Soppet, Daniel R; Smith, Michael W; Cheung, Sau Wai; Martin, Christa Lese; State, Matthew W; Talkowski, Michael E; Cook, Edwin; Huganir, Richard; Katsanis, Nicholas; Chakravarti, Aravinda
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
PMCID:4383723
PMID: 25807484
ISSN: 1476-4687
CID: 2746752
Genetic studies of body mass index yield new insights for obesity biology
Locke, Adam E; Kahali, Bratati; Berndt, Sonja I; Justice, Anne E; Pers, Tune H; Day, Felix R; Powell, Corey; Vedantam, Sailaja; Buchkovich, Martin L; Yang, Jian; Croteau-Chonka, Damien C; Esko, Tonu; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Kutalik, Zoltan; Luan, Jian'an; Magi, Reedik; Randall, Joshua C; Winkler, Thomas W; Wood, Andrew R; Workalemahu, Tsegaselassie; Faul, Jessica D; Smith, Jennifer A; Zhao, Jing Hua; Zhao, Wei; Chen, Jin; Fehrmann, Rudolf; Hedman, Asa K; Karjalainen, Juha; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bolton, Jennifer L; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Deng, Guohong; Ehret, Georg B; Feenstra, Bjarke; Feitosa, Mary F; Fischer, Krista; Goel, Anuj; Gong, Jian; Jackson, Anne U; Kanoni, Stavroula; Kleber, Marcus E; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Medland, Sarah E; Nalls, Michael A; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Shungin, Dmitry; Stancakova, Alena; Strawbridge, Rona J; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V; Wang, Zhaoming; Yengo, Loic; Zhang, Weihua; Isaacs, Aaron; Albrecht, Eva; Arnlov, Johan; Arscott, Gillian M; Attwood, Antony P; Bandinelli, Stefania; Barrett, Amy; Bas, Isabelita N; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blagieva, Roza; Bluher, Matthias; Bohringer, Stefan; Bonnycastle, Lori L; Bottcher, Yvonne; Boyd, Heather A; Bruinenberg, Marcel; Caspersen, Ida H; Chen, Yii-Der Ida; Clarke, Robert; Daw, E Warwick; de Craen, Anton J M; Delgado, Graciela; Dimitriou, Maria; Doney, Alex S F; Eklund, Niina; Estrada, Karol; Eury, Elodie; Folkersen, Lasse; Fraser, Ross M; Garcia, Melissa E; Geller, Frank; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Goodall, Alison H; Gordon, Scott D; Gorski, Mathias; Grabe, Hans-Jorgen; Grallert, Harald; Grammer, Tanja B; Grassler, Jurgen; Gronberg, Henrik; Groves, Christopher J; Gusto, Gaelle; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L; Helmer, Quinta; Hengstenberg, Christian; Holmen, Oddgeir; Hottenga, Jouke-Jan; James, Alan L; Jeff, Janina M; Johansson, Asa; Jolley, Jennifer; Juliusdottir, Thorhildur; Kinnunen, Leena; Koenig, Wolfgang; Koskenvuo, Markku; Kratzer, Wolfgang; Laitinen, Jaana; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindstrom, Jaana; Lo, Ken Sin; Lobbens, Stephane; Lorbeer, Roberto; Lu, Yingchang; Mach, Francois; Magnusson, Patrik K E; Mahajan, Anubha; McArdle, Wendy L; McLachlan, Stela; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Moayyeri, Alireza; Monda, Keri L; Morken, Mario A; Mulas, Antonella; Muller, Gabriele; Muller-Nurasyid, Martina; Musk, Arthur W; Nagaraja, Ramaiah; Nothen, Markus M; Nolte, Ilja M; Pilz, Stefan; Rayner, Nigel W; Renstrom, Frida; Rettig, Rainer; Ried, Janina S; Ripke, Stephan; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R; Scott, William R; Seufferlein, Thomas; Shi, Jianxin; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Stringham, Heather M; Sundstrom, Johan; Swertz, Morris A; Swift, Amy J; Syvanen, Ann-Christine; Tan, Sian-Tsung; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tyrer, Jonathan P; Uh, Hae-Won; Vandenput, Liesbeth; Verhulst, Frank C; Vermeulen, Sita H; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Warren, Helen R; Waterworth, Dawn; Weedon, Michael N; Wilkens, Lynne R; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Wright, Alan F; Zhang, Qunyuan; Brennan, Eoin P; Choi, Murim; Dastani, Zari; Drong, Alexander W; Eriksson, Per; Franco-Cereceda, Anders; Gadin, Jesper R; Gharavi, Ali G; Goddard, Michael E; Handsaker, Robert E; Huang, Jinyan; Karpe, Fredrik; Kathiresan, Sekar; Keildson, Sarah; Kiryluk, Krzysztof; Kubo, Michiaki; Lee, Jong-Young; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McCarroll, Steven A; McKnight, Amy J; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Okada, Yukinori; Perry, John R B; Dorajoo, Rajkumar; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Scott, Robert A; Stolk, Lisette; Takahashi, Atsushi; Tanaka, Toshihiro; van 't Hooft, Ferdinand M; Vinkhuyzen, Anna A E; Westra, Harm-Jan; Zheng, Wei; Zondervan, Krina T; Heath, Andrew C; Arveiler, Dominique; Bakker, Stephan J L; Beilby, John; Bergman, Richard N; Blangero, John; Bovet, Pascal; Campbell, Harry; Caulfield, Mark J; Cesana, Giancarlo; Chakravarti, Aravinda; Chasman, Daniel I; Chines, Peter S; Collins, Francis S; Crawford, Dana C; Cupples, L Adrienne; Cusi, Daniele; Danesh, John; de Faire, Ulf; den Ruijter, Hester M; Dominiczak, Anna F; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G; Farrall, Martin; Felix, Stephan B; Ferrannini, Ele; Ferrieres, Jean; Ford, Ian; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gejman, Pablo V; Gieger, Christian; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Alistair S; Harris, Tamara B; Hattersley, Andrew T; Hicks, Andrew A; Hindorff, Lucia A; Hingorani, Aroon D; Hofman, Albert; Homuth, Georg; Hovingh, G Kees; Humphries, Steve E; Hunt, Steven C; Hypponen, Elina; Illig, Thomas; Jacobs, Kevin B; Jarvelin, Marjo-Riitta; Jockel, Karl-Heinz; Johansen, Berit; Jousilahti, Pekka; Jukema, J Wouter; Jula, Antti M; Kaprio, Jaakko; Kastelein, John J P; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Knekt, Paul; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Marchand, Loic Le; Lehtimaki, Terho; Lyssenko, Valeriya; Mannisto, Satu; Marette, Andre; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Moll, Frans L; Morris, Andrew D; Morris, Andrew P; Murray, Jeffrey C; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Madden, Pamela A F; Pasterkamp, Gerard; Peden, John F; Peters, Annette; Postma, Dirkje S; Pramstaller, Peter P; Price, Jackie F; Qi, Lu; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ridker, Paul M; Rioux, John D; Ritchie, Marylyn D; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schunkert, Heribert; Schwarz, Peter E H; Sever, Peter; Shuldiner, Alan R; Sinisalo, Juha; Stolk, Ronald P; Strauch, Konstantin; Tonjes, Anke; Tregouet, David-Alexandre; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Volker, Uwe; Waeber, Gerard; Willemsen, Gonneke; Witteman, Jacqueline C; Zillikens, M Carola; Adair, Linda S; Amouyel, Philippe; Asselbergs, Folkert W; Assimes, Themistocles L; Bochud, Murielle; Boehm, Bernhard O; Boerwinkle, Eric; Bornstein, Stefan R; Bottinger, Erwin P; Bouchard, Claude; Cauchi, Stephane; Chambers, John C; Chanock, Stephen J; Cooper, Richard S; de Bakker, Paul I W; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Groop, Leif C; Haiman, Christopher A; Hamsten, Anders; Hui, Jennie; Hunter, David J; Hveem, Kristian; Kaplan, Robert C; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G; Marz, Winfried; Melbye, Mads; Metspalu, Andres; Moebus, Susanne; Munroe, Patricia B; Njolstad, Inger; Oostra, Ben A; Palmer, Colin N A; Pedersen, Nancy L; Perola, Markus; Perusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sattar, Naveed; Schadt, Eric E; Schlessinger, David; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, Andre G; Uusitupa, Matti; van der Harst, Pim; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wichmann, H-Erich; Wilson, James F; Zanen, Pieter; Borecki, Ingrid B; Deloukas, Panos; Fox, Caroline S; Heid, Iris M; O'Connell, Jeffrey R; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Abecasis, Goncalo R; Franke, Lude; Frayling, Timothy M; McCarthy, Mark I; Visscher, Peter M; Scherag, Andre; Willer, Cristen J; Boehnke, Michael; Mohlke, Karen L; Lindgren, Cecilia M; Beckmann, Jacques S; Barroso, Ines; North, Kari E; Ingelsson, Erik; Hirschhorn, Joel N; Loos, Ruth J F; Speliotes, Elizabeth K
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 x 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 approximately 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.
PMCID:4382211
PMID: 25673413
ISSN: 1476-4687
CID: 2746772
New genetic loci link adipose and insulin biology to body fat distribution
Shungin, Dmitry; Winkler, Thomas W; Croteau-Chonka, Damien C; Ferreira, Teresa; Locke, Adam E; Magi, Reedik; Strawbridge, Rona J; Pers, Tune H; Fischer, Krista; Justice, Anne E; Workalemahu, Tsegaselassie; Wu, Joseph M W; Buchkovich, Martin L; Heard-Costa, Nancy L; Roman, Tamara S; Drong, Alexander W; Song, Ci; Gustafsson, Stefan; Day, Felix R; Esko, Tonu; Fall, Tove; Kutalik, Zoltan; Luan, Jian'an; Randall, Joshua C; Scherag, Andre; Vedantam, Sailaja; Wood, Andrew R; Chen, Jin; Fehrmann, Rudolf; Karjalainen, Juha; Kahali, Bratati; Liu, Ching-Ti; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Ehret, Georg B; Feitosa, Mary F; Goel, Anuj; Jackson, Anne U; Johnson, Toby; Kleber, Marcus E; Kristiansson, Kati; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Stancakova, Alena; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Van Vliet-Ostaptchouk, Jana V; Yengo, Loic; Zhang, Weihua; Albrecht, Eva; Arnlov, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Bluher, Matthias; Bohringer, Stefan; Bonnet, Fabrice; Bottcher, Yvonne; Bruinenberg, Marcel; Carba, Delia B; Caspersen, Ida H; Clarke, Robert; Daw, E Warwick; Deelen, Joris; Deelman, Ewa; Delgado, Graciela; Doney, Alex Sf; Eklund, Niina; Erdos, Michael R; Estrada, Karol; Eury, Elodie; Friedrich, Nele; Garcia, Melissa E; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Grallert, Harald; Grammer, Tanja B; Grassler, Jurgen; Grewal, Jagvir; Groves, Christopher J; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heikkila, Kauko; Herzig, Karl-Heinz; Helmer, Quinta; Hillege, Hans L; Holmen, Oddgeir; Hunt, Steven C; Isaacs, Aaron; Ittermann, Till; James, Alan L; Johansson, Ingegerd; Juliusdottir, Thorhildur; Kalafati, Ioanna-Panagiota; Kinnunen, Leena; Koenig, Wolfgang; Kooner, Ishminder K; Kratzer, Wolfgang; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindstrom, Jaana; Lobbens, Stephane; Lorentzon, Mattias; Mach, Francois; Magnusson, Patrik Ke; Mahajan, Anubha; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Moayyeri, Alireza; Monda, Keri L; Mooijaart, Simon P; Muhleisen, Thomas W; Mulas, Antonella; Muller, Gabriele; Muller-Nurasyid, Martina; Nagaraja, Ramaiah; Nalls, Michael A; Narisu, Narisu; Glorioso, Nicola; Nolte, Ilja M; Olden, Matthias; Rayner, Nigel W; Renstrom, Frida; Ried, Janina S; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Sennblad, Bengt; Seufferlein, Thomas; Sitlani, Colleen M; Smith, Albert Vernon; Stirrups, Kathleen; Stringham, Heather M; Sundstrom, Johan; Swertz, Morris A; Swift, Amy J; Syvanen, Ann-Christine; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tomaschitz, Andreas; Troffa, Chiara; van Oort, Floor Va; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Wennauer, Roman; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Zhang, Qunyuan; Zhao, Jing Hua; Brennan, Eoin P; Choi, Murim; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Gharavi, Ali G; Hedman, Asa K; Hivert, Marie-France; Huang, Jinyan; Kanoni, Stavroula; Karpe, Fredrik; Keildson, Sarah; Kiryluk, Krzysztof; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McKnight, Amy J; McPherson, Ruth; Metspalu, Andres; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Olsson, Christian; Perry, John Rb; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Schadt, Eric E; Scott, Robert A; Stolk, Lisette; Vallejo, Edgar E; Westra, Harm-Jan; Zondervan, Krina T; Amouyel, Philippe; Arveiler, Dominique; Bakker, Stephan Jl; Beilby, John; Bergman, Richard N; Blangero, John; Brown, Morris J; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chines, Peter S; Claudi-Boehm, Simone; Collins, Francis S; Crawford, Dana C; Danesh, John; de Faire, Ulf; de Geus, Eco Jc; Dorr, Marcus; Erbel, Raimund; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrieres, Jean; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gieger, Christian; Gudnason, Vilmundur; Haiman, Christopher A; Harris, Tamara B; Hattersley, Andrew T; Heliovaara, Markku; Hicks, Andrew A; Hingorani, Aroon D; Hoffmann, Wolfgang; Hofman, Albert; Homuth, Georg; Humphries, Steve E; Hypponen, Elina; Illig, Thomas; Jarvelin, Marjo-Riitta; Johansen, Berit; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimaki, Terho; Lyssenko, Valeriya; Mannisto, Satu; Marette, Andre; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Musk, Arthur W; Mohlenkamp, Stefan; Morris, Andrew D; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Palmer, Lyle J; Penninx, Brenda W; Peters, Annette; Pramstaller, Peter P; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ridker, Paul M; Ritchie, Marylyn D; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter Eh; Shuldiner, Alan R; Staessen, Jan A; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Strauch, Konstantin; Tonjes, Anke; Tremblay, Angelo; Tremoli, Elena; Vohl, Marie-Claude; Volker, Uwe; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Adair, Linda S; Bochud, Murielle; Boehm, Bernhard O; Bornstein, Stefan R; Bouchard, Claude; Cauchi, Stephane; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Cooper, Richard S; Dedoussis, George; Ferrucci, Luigi; Froguel, Philippe; Grabe, Hans-Jorgen; Hamsten, Anders; Hui, Jennie; Hveem, Kristian; Jockel, Karl-Heinz; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Marz, Winfried; Munroe, Patricia B; Njolstad, Inger; Oostra, Ben A; Palmer, Colin Na; Pedersen, Nancy L; Perola, Markus; Perusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sinisalo, Juha; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Stefansson, Kari; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, Andre G; Uusitupa, Matti; van der Harst, Pim; Veronesi, Giovanni; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Abecasis, Goncalo R; Assimes, Themistocles L; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Franke, Lude; Frayling, Timothy M; Groop, Leif C; Hunter, David J; Kaplan, Robert C; O'Connell, Jeffrey R; Qi, Lu; Schlessinger, David; Strachan, David P; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Willer, Cristen J; Visscher, Peter M; Yang, Jian; Hirschhorn, Joel N; Zillikens, M Carola; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Fox, Caroline S; Barroso, Ines; Franks, Paul W; Ingelsson, Erik; Heid, Iris M; Loos, Ruth Jf; Cupples, L Adrienne; Morris, Andrew P; Lindgren, Cecilia M; Mohlke, Karen L
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
PMCID:4338562
PMID: 25673412
ISSN: 1476-4687
CID: 2746782
