ALBERT

Description: 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) approximately 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximately 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751588/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751588/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rietveld, Cornelius A -- Medland, Sarah E -- Derringer, Jaime -- Yang, Jian -- Esko, Tonu -- Martin, Nicolas W -- Westra, Harm-Jan -- Shakhbazov, Konstantin -- Abdellaoui, Abdel -- Agrawal, Arpana -- Albrecht, Eva -- Alizadeh, Behrooz Z -- Amin, Najaf -- Barnard, John -- Baumeister, Sebastian E -- Benke, Kelly S -- Bielak, Lawrence F -- Boatman, Jeffrey A -- Boyle, Patricia A -- Davies, Gail -- de Leeuw, Christiaan -- Eklund, Niina -- Evans, Daniel S -- Ferhmann, Rudolf -- Fischer, Krista -- Gieger, Christian -- Gjessing, Hakon K -- Hagg, Sara -- Harris, Jennifer R -- Hayward, Caroline -- Holzapfel, Christina -- Ibrahim-Verbaas, Carla A -- Ingelsson, Erik -- Jacobsson, Bo -- Joshi, Peter K -- Jugessur, Astanand -- Kaakinen, Marika -- Kanoni, Stavroula -- Karjalainen, Juha -- Kolcic, Ivana -- Kristiansson, Kati -- Kutalik, Zoltan -- Lahti, Jari -- Lee, Sang H -- Lin, Peng -- Lind, Penelope A -- Liu, Yongmei -- Lohman, Kurt -- Loitfelder, Marisa -- McMahon, George -- Vidal, Pedro Marques -- Meirelles, Osorio -- Milani, Lili -- Myhre, Ronny -- Nuotio, Marja-Liisa -- Oldmeadow, Christopher J -- Petrovic, Katja E -- Peyrot, Wouter J -- Polasek, Ozren -- Quaye, Lydia -- Reinmaa, Eva -- Rice, John P -- Rizzi, Thais S -- Schmidt, Helena -- Schmidt, Reinhold -- Smith, Albert V -- Smith, Jennifer A -- Tanaka, Toshiko -- Terracciano, Antonio -- van der Loos, Matthijs J H M -- Vitart, Veronique -- Volzke, Henry -- Wellmann, Jurgen -- Yu, Lei -- Zhao, Wei -- Allik, Juri -- Attia, John R -- Bandinelli, Stefania -- Bastardot, Francois -- Beauchamp, Jonathan -- Bennett, David A -- Berger, Klaus -- Bierut, Laura J -- Boomsma, Dorret I -- Bultmann, Ute -- Campbell, Harry -- Chabris, Christopher F -- Cherkas, Lynn -- Chung, Mina K -- Cucca, Francesco -- de Andrade, Mariza -- De Jager, Philip L -- De Neve, Jan-Emmanuel -- Deary, Ian J -- Dedoussis, George V -- Deloukas, Panos -- Dimitriou, Maria -- Eiriksdottir, Guethny -- Elderson, Martin F -- Eriksson, Johan G -- Evans, David M -- Faul, Jessica D -- Ferrucci, Luigi -- Garcia, Melissa E -- Gronberg, Henrik -- Guethnason, Vilmundur -- Hall, Per -- Harris, Juliette M -- Harris, Tamara B -- Hastie, Nicholas D -- Heath, Andrew C -- Hernandez, Dena G -- Hoffmann, Wolfgang -- Hofman, Adriaan -- Holle, Rolf -- Holliday, Elizabeth G -- Hottenga, Jouke-Jan -- Iacono, William G -- Illig, Thomas -- Jarvelin, Marjo-Riitta -- Kahonen, Mika -- Kaprio, Jaakko -- Kirkpatrick, Robert M -- Kowgier, Matthew -- Latvala, Antti -- Launer, Lenore J -- Lawlor, Debbie A -- Lehtimaki, Terho -- Li, Jingmei -- Lichtenstein, Paul -- Lichtner, Peter -- Liewald, David C -- Madden, Pamela A -- Magnusson, Patrik K E -- Makinen, Tomi E -- Masala, Marco -- McGue, Matt -- Metspalu, Andres -- Mielck, Andreas -- Miller, Michael B -- Montgomery, Grant W -- Mukherjee, Sutapa -- Nyholt, Dale R -- Oostra, Ben A -- Palmer, Lyle J -- Palotie, Aarno -- Penninx, Brenda W J H -- Perola, Markus -- Peyser, Patricia A -- Preisig, Martin -- Raikkonen, Katri -- Raitakari, Olli T -- Realo, Anu -- Ring, Susan M -- Ripatti, Samuli -- Rivadeneira, Fernando -- Rudan, Igor -- Rustichini, Aldo -- Salomaa, Veikko -- Sarin, Antti-Pekka -- Schlessinger, David -- Scott, Rodney J -- Snieder, Harold -- St Pourcain, Beate -- Starr, John M -- Sul, Jae Hoon -- Surakka, Ida -- Svento, Rauli -- Teumer, Alexander -- LifeLines Cohort Study -- Tiemeier, Henning -- van Rooij, Frank J A -- Van Wagoner, David R -- Vartiainen, Erkki -- Viikari, Jorma -- Vollenweider, Peter -- Vonk, Judith M -- Waeber, Gerard -- Weir, David R -- Wichmann, H-Erich -- Widen, Elisabeth -- Willemsen, Gonneke -- Wilson, James F -- Wright, Alan F -- Conley, Dalton -- Davey-Smith, George -- Franke, Lude -- Groenen, Patrick J F -- Hofman, Albert -- Johannesson, Magnus -- Kardia, Sharon L R -- Krueger, Robert F -- Laibson, David -- Martin, Nicholas G -- Meyer, Michelle N -- Posthuma, Danielle -- Thurik, A Roy -- Timpson, Nicholas J -- Uitterlinden, Andre G -- van Duijn, Cornelia M -- Visscher, Peter M -- Benjamin, Daniel J -- Cesarini, David -- Koellinger, Philipp D -- AA09367/AA/NIAAA NIH HHS/ -- AA11886/AA/NIAAA NIH HHS/ -- BB/F019394/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- CZB/4/710/Chief Scientist Office/United Kingdom -- DA024417/DA/NIDA NIH HHS/ -- DA029377/DA/NIDA NIH HHS/ -- DA05147/DA/NIDA NIH HHS/ -- DA13240/DA/NIDA NIH HHS/ -- ETM/55/Chief Scientist Office/United Kingdom -- F31 DA029377/DA/NIDA NIH HHS/ -- G0600705/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- K05 AA017688/AA/NIAAA NIH HHS/ -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_UU_12013/1/Medical Research Council/United Kingdom -- MC_UU_12013/3/Medical Research Council/United Kingdom -- MC_UU_12013/5/Medical Research Council/United Kingdom -- MH016880/MH/NIMH NIH HHS/ -- MH066140/MH/NIMH NIH HHS/ -- MR/K026992/1/Medical Research Council/United Kingdom -- P01 AG005842/AG/NIA NIH HHS/ -- P01 CA089392/CA/NCI NIH HHS/ -- P01 GM099568/GM/NIGMS NIH HHS/ -- P01-AG005842/AG/NIA NIH HHS/ -- P01-AG005842-20S2/AG/NIA NIH HHS/ -- P30 AG012810/AG/NIA NIH HHS/ -- P30-AG012810/AG/NIA NIH HHS/ -- R01 AA009367/AA/NIAAA NIH HHS/ -- R01 AA011886/AA/NIAAA NIH HHS/ -- R01 DA013240/DA/NIDA NIH HHS/ -- R01 HL090620/HL/NHLBI NIH HHS/ -- R01 HL105756/HL/NHLBI NIH HHS/ -- R01 HL111314/HL/NHLBI NIH HHS/ -- R01 MH066140/MH/NIMH NIH HHS/ -- R37 DA005147/DA/NIDA NIH HHS/ -- T32 AG000186/AG/NIA NIH HHS/ -- T32 MH016880/MH/NIMH NIH HHS/ -- T32-AG000186-23/AG/NIA NIH HHS/ -- U01 AG009740/AG/NIA NIH HHS/ -- U01 DA024417/DA/NIDA NIH HHS/ -- Z01 AG001050-01/Intramural NIH HHS/ -- ZIA AG000196-03/Intramural NIH HHS/ -- ZIA AG000196-04/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 Jun 21;340(6139):1467-71. doi: 10.1126/science.1235488. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722424" target="_blank"〉PubMed〈/a〉

Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516141/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516141/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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, Jeffrey 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 -- BioBank Japan Project -- 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 R -- 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 -- 068545/Wellcome Trust/United Kingdom -- 072856/Wellcome Trust/United Kingdom -- 072960/Wellcome Trust/United Kingdom -- 079771/Wellcome Trust/United Kingdom -- 084723/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 099194/Wellcome Trust/United Kingdom -- 105022/Wellcome Trust/United Kingdom -- 250157/European Research Council/International -- 280559/European Research Council/International -- 323195/European Research Council/International -- BARCVBRU-2012-1/Department of Health/United Kingdom -- BB/F019394/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- CZB/4/276/Chief Scientist Office/United Kingdom -- CZB/4/505/Chief Scientist Office/United Kingdom -- CZB/4/710/Chief Scientist Office/United Kingdom -- CZD/16/6/Chief Scientist Office/United Kingdom -- CZD/16/6/2/Chief Scientist Office/United Kingdom -- CZD/16/6/3/Chief Scientist Office/United Kingdom -- CZD/16/6/4/Chief Scientist Office/United Kingdom -- ETM/55/Chief Scientist Office/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- MC_UU_12013/3/Medical Research Council/United Kingdom -- MC_UU_12015/1/Medical Research Council/United Kingdom -- MR/K026992/1/Medical Research Council/United Kingdom -- P20 MD006899/MD/NIMHD NIH HHS/ -- P30 DK020572/DK/NIDDK NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R03 DC013373/DC/NIDCD NIH HHS/ -- RG/2001004/12869/British Heart Foundation/United Kingdom -- RP-PG-0407-10371/Department of Health/United Kingdom -- SAG09977/Biotechnology and Biological Sciences Research Council/United Kingdom -- UL1 TR000124/TR/NCATS NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2015 Jul 23;523(7561):459-62. doi: 10.1038/nature14618. Epub 2015 Jul 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141 Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [4] Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; 1] Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. ; Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. ; Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, 34149 Trieste, Italy. ; Institute of Genetics and Biophysics "A. Buzzati-Traverso" CNR, via Pietro Castellino, 111, 80131 Naples, Italy. ; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [2] The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; 1] Icelandic Heart Association, Holtasmari 1, 201, Kopavogur, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. ; 1] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. [2] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland. ; Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, Michigan 48104, USA. ; Department of Epidemiology, University of Michigan, 1415 Washington Heights, Ann Arbor, Michigan 48109, USA. ; Cardiovascular Health Research Unit, Departments of Biostatistics and Medicine, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; Institute of Population Genetics, National Research Council, Trav. La Crucca n. 3 - Reg. Baldinca, 07100 Sassari, Italy. ; Epidemiology, University of North Carolina, 137 E. Franklin St., Suite 306, Chapel Hill, North Carolina 27599, USA. ; Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden. ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK. ; Department of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; 1] Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, California 90502, USA. [2] Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90502, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, East, Harvard Medical School, Boston, Boston, Massachusetts 02215, USA. ; Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. ; 1] Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, Lausanne, 1005, Switzerland. [2] Swiss Institute of Bioinformatics, Quartier Sorge - batiment genopode, Lausanne, 1015, Switzerland. ; Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India. ; Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA. ; 1] Department of Twin Research &Genetic Epidemiology, King's College London, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London SE1 7EH, UK. [2] NIHR Biomedical Research Centre, Guy's and St. Thomas' Foundation Trust, Westminster Bridge Road, London SE1 7EH, UK. ; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy. ; Department of Nutrition and Dietetics, Harokopio University of Athens, 70, El. Venizelou Ave, Athens 17671, Greece. ; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15A, Greifswald 17475, Germany. ; Center for Human Genetic Research, 55 Fruit Street, Massachusetts General Hospital, Massachusetts 02114, USA. ; Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ; Genomics and Molecular Medicine, CSIR-Institute of Genomics &Integrative Biology, Mathura Road, New Delhi, 110025, India. ; The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ; Department of Genetics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, Missouri 63108, USA. ; 1] Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria. [2] Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz2, Graz, A-8036, Austria. ; Erasmus School of Economics, Erasmus University Rotterdam, Burgemeester Oudlaan 50, Rotterdam, 3000 DR, The Netherlands. ; Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden. ; 1] Channing Division of Network Medicine, Brigham &Women's Hospital, 181 Longwood, Boston, Massachusetts 02115, USA. [2] Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, Massachusetts 02215, USA. ; Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), 39100 Bolzano, Italy (affiliated Institute of the University of Lubeck, D-23562 Lubeck, Germany). ; University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [3] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; Department of Biological Psychology, VU University Amsterdam, Van der Boechorststraat 1, Amsterdam, 1081 BT, The Netherlands. ; 1] Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. [2] NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. ; Department of Medicine, University of Mississippi Medical Center, 2500 N. State St., Jackson, Mississippi 39216, USA. ; Pennington Biomedical Research Center, 6400 Perkins Rd, Baton Rouge, Louisiana 70808, USA. ; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. ; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. ; Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, GPO Box 2434, Brisbane Queensland 4001, Australia. ; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, Wisconsin 53226, USA. ; Quantitative Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane Queensland 4006, Australia. ; Dipartimento di Scienze della Vita e della Riproduzione, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000 Lille, France. ; Department of Biostatistics, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, Alabama 35294, USA. ; Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, P.O. box 30.001, 9700 RB, Groningen, The Netherlands. ; Center for Research on Genomics and Global Health, National Human Genome Research Institute, Building 12A/Room 4047, 12 South Dr., Bethesda, Maryland 20892, USA. ; Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. ; MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. ; 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, Maryland 20850, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; 1] Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin 14195, Germany. [2] Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195 Germany. ; 1] Charite Research Group on Geriatrics, Charite - Universitatsmedizin Berlin, Reinickendorferstr. 61, 13347 Berlin, Germany. [2] Institute of Medical and Human Genetics, Charite - Universitatsmedizin Berlin, Augustenburger Platz 1, Berlin 13353, Germany. ; Division of Population Health Sciences, Medical Research Institute, University of Dundee, Ninewells Hospital and School of Medicine, Dundee DD2 4BF, UK. ; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. ; Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. ; Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. ; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK. ; 1] COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Copenhagen, Denmark. [2] Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark. [3] Steno Diabetes Centre, Niels Steensens Vej 2, Gentofte, 2820, Denmark. ; Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. ; Department of Health Sciences, University of Milan, via A. di Rudini 8, 20142 Milan, Italy. ; Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, 2 Verdun Street, Perth, Western Australia 6009, Australia. ; Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark. ; Clinical Epidemiology, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; Department of Human Genetics, University of Chicago, 920 E. 58th Street, Chicago, Illinois 60637, USA. ; Department of Family and Preventive Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; 1] Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands. [3] Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, Gower Street, London WC1E 6BT, UK. ; University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; Department of Medicine, Columbia University, 622 W. 168th Street, New York, New York 10032, USA. ; Institute for Community Medicine, University Medicine Greifswald, W.-Rathenau-Str. 48, Greifswald 17475, Germany. ; 1] Department of Economics, Cornell University, 480 Uris Hall, Ithaca, New York 14853, USA. [2] Department of Economics and Center for Economic and Social Research, University of Southern California, 314C Dauterive Hall, 635 Downey Way, Los Angeles, California 90089, USA. ; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Pressler Street, Suite 453E, Houston, Texas 77030, USA. ; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. ; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, 02141 Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [3] Department of Genetics, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA. ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Rockville, Maryland 20850, USA. ; Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, 665 Huntington Ave, Boston, Massachusetts 02115, USA. ; Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; College of Medicine, Dentistry and Nursing, Ninewells Hospital and Medical School, College Office, Level 10, Dundee DD1 9SY, UK. ; 1] Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, Massachusetts 02118, USA. [2] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. ; 1] Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department of Internal Medicine B, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, Greifswald 17475, Germany. ; 1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. [2] Cardiology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil, 4, Geneve 14, 1211, Switzerland. ; Robertson Centre, University of Glasgow, Boyd Orr Building, Glasgow G12 8QQ, Scotland. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, Massachusetts 02115, USA. ; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Str. NK, 17475 Greifswald, Germany. ; Department of Twin Research &Genetic Epidemiology, King's College London, South Wing, Block D, 3rd Floor, Westminster Bridge Road, London SE1 7EH, UK. ; Nutrition, Harvard School of Public Health, 401 Park Drive, Boston, Massachusetts 02215, USA. ; Division of Biostatistics, Washington University, 660 S Euclid, St Louis, Missouri 63110, USA. ; 1] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK. [2] Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Edinburgh EH25 9RG, UK. ; 1] Centre for Genomic and Experimental Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; National Institutes on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Department of Neurology, Boston University School of Medicine, 72 E Concord St, Boston, Massachusetts 02118, USA. ; Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland. ; Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. ; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Radiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [2] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, SE-17121, Sweden. ; 1] Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, SE-75108 Uppsala, Sweden. [2] Uppsala Clinical Research Center, Uppsala University, Uppsala, SE-75237, Sweden. ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. ; Department of Cardiology C5-P, Leiden University Medical Center, PO Box 9600, Leiden, 2300 RC, The Netherlands. ; Department of Clinical Physiology, University of Tampere and Tampere University Hospital, P.O. Box 2000, Tampere, FI-33521, Finland. ; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; 1] Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland. [3] Minerva Foundation Institute for Medical Research, Biomedicum 2U, Tukholmankatu 8, Helsinki, FI-00290, Finland. ; Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. ; Laboratory for Genotyping Development RCfIMS, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. ; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, FI-70210, Finland. ; 1] Institute of Behavioural Sciences, University of Helsinki, P.O. Box 9, University of Helsinki, Helsinki, FI-00014, Finland. [2] Folkhalsan Reasearch Centre, PB 63, Helsinki, FI-00014 University of Helsinki, Finland. ; Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. ; Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, Tampere, FI-33520, Finland. ; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department of Medical Sciences, University Hospital, Uppsala, 75185, Sweden. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, 138648, Singapore. ; Transplantation laboratory, Haartman Institute, University of Helsinki, P.O. Box 21, Helsinki, FI-00014, Finland. ; National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA. ; Ophthalmology, Massachusetts Eye and Ear, 243 Charles Street, Boston, Massachusetts 02114, USA. ; Department of Statistics, University of Auckland, 303.325 Science Centre, Private Bag 92019, Auckland, 1142, New Zealand. ; Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. ; Department of Internal Medicine, University Hospital, Rue du Bugnon 44, Lausanne, 1011, Switzerland. ; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA. ; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. ; Division of General Internal Medicine, Massachusetts General Hospital, 50 Staniford St, Boston, Massachusetts 02114, USA. ; Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; 1] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Human Genetics, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Str. 22, Munchen 81675, Germany. ; Molecular Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Genome Science Institute, Boston University School of Medicine, 72 East Concord Street, E-304, Boston, Massachusetts 02118, USA. ; HUCH Heart and Lung center, Helsinki University Central Hospital, P.O. Box 340, Helsinki, FI-00029, Finland. ; 1] National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Ave, Framingham, Massachusetts 01702, USA. [2] Pulmonary Center and Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, Massachusetts 02118, USA. ; Department of Medicine, University of Ibadan, Ibadan, Nigeria. ; ICAMS, University of Glasgow, 126 University Way, Glasgow G12 8TA, UK. ; Division of Epidemiology and Community Health, University of Minnesota, 1300 S 2nd Street, Minneapolis, Minnesota 55454, USA. ; Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. [2] Department of Medicine, Division of Endocrinology, Helsinki University Central Hospital, P.O.Box 340, Haartmaninkatu 4, Helsinki, FI-00029, Finland. [3] Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, P.O.Box 63, Haartmaninkatu 8, FI-00014, Helsinki, Finland. ; International Centre for Circulatory Health, Imperial College London, London W2 1LA, UK. ; Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK. ; Department of Cardiology and Cardio thoracic Surgery Hero DMC Heart Institute, Civil Lines, 141001, Ludhiana, India. ; Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; Department Public Health Sciences, University of Virginia School of Medicine, 3232 West Complex, Charlottesville, Virginia 22908, USA. ; Department of Psychological &Brain Sciences, Indiana University Bloomington, 1101 E. 10th Street, Bloomington, Indiana 47405, USA. ; Institute of Molecular Biology and Biochemistry, Medical University Graz, Harrachgasse 21, Graz, A-8010, Austria. ; 1] Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, CMM L8:03, Karolinska University Hospital, Solna, Stockholm, 171 76, Sweden. [2] Science for Life Laboratory, Karolinska Institutet, Stockholm, SE-17121, Sweden. ; University of Dundee, Kirsty Semple Way, Dundee DD2 4DB, UK. ; Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [2] Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK. ; Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland. ; UMR INSERM U1122; IGE-PCV "Interactions Gene-Environnement en Physiopathologie Cardio-Vasculaire", INSERM, University of Lorraine, 30 Rue Lionnois, 54000 Nancy, France. ; 1] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitat, Munich 81377, Germany. ; Department of Endocrinology, All India Institute of Medical Sciences, Ansari Nagar East, New Delhi, 110029, India. ; National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK. ; Department of Public Health Sciences, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA. ; 1] Department of Cardiovascular Sciences, University of Leicester, BHF Cardiovascular Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. [2] NIHR Leicester Cardiovascular Biomedical Research Unit, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Institute of Molecular and Cell Biology, University of Tartu, Riia 23, Tartu, 51010, Estonia. ; 1] Diabetes Prevention Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria. [3] Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; Finnish Lung Health Association, Sibeliuksenkatu 11 A 1, Helsinki, FI-00250, Finland. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Ingolstadter Landstr. 1, Neuherberg 85764, Germany. ; Genetic Epidemiology, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Centre for Population Health Sciences, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. ; Diabetes Unit, KEM Hospital and Research Centre, Rasta Peth, Pune, 411011, India. ; Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, 1124 W. Carson Street, Torrance, California 90502, USA. ; Renal Unit, Department of Medicine, University of Verona, Piazzale A. Stefani 1, 37124 Verona, Italy. ; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA. ; 1] Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen, 2300, Denmark. [2] Department of Medicine, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA. ; COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Copenhagen, Denmark. ; 1] CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille 2 University, 1 Rue du Professeur Calmette, 59000 Lille, France. [2] Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK. ; 1] Center for Applied Genomics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. [2] Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. ; Translational Gerontology Branch, National institute on Aging, Baltimore, Maryland 21225, USA. ; Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, No. 9 Edinburgh Bioquarter, 9 Little France Road, Edinburgh EH16 4UX, UK. ; Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, University of Dundee, Ninewells Hospital and School of Medicine, Dundee DD1 9SY, UK. ; 1] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK [2] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia. ; 1] Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 72, Berlin, 14195 Germany. [2] Faculty of Medicine, Imperial College London, Charing Cross Campus, St Dunstan's Road, London W6 8RP, UK. [3] Institutes for Neurogenetics and Integrative &Experimental Genomics, University of Lubeck, Lubeck 23562, Germany. ; Center for Lifespan Psychology, Max Planck Institute for Human Development, Lentzeallee 94, Berlin 14195, Germany. ; 1] Program in Medical and Population Genetics, Broad Institute, Cambridge Center 7, Cambridge, Massachusetts 02242, USA. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; Department of Medicine, University of Leipzig, Leipzig 04103, Germany. ; 1] MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. [2] Novo Nordisk Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, Copenhagen, 2100, Denmark. [3] Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, 2000, Denmark. ; Department of Epidemiology, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, Alabama 35294, USA. ; Department of Psychiatry, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, Groningen, 9700 RB, The Netherlands. ; Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse, Inserm, CESP Center for Research in Epidemiology and Population Health U1018, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif, France. ; Dipartimento di Scienze Mediche, Catholic University of the Sacred Heart, Via G. Moscati 31/34, 00168 Roma, Italy. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. [3] Department of Biostatistics, University of Liverpool, Duncan Building, Daulby Stree, Liverpool L69 3GA, UK. ; 1] Department of Chronic Disease Prevention, National Institute for Health and Welfare, P.O. Box 30, Helsinki, FI-00271, Finland. [2] Department of General Practice and Primary Health Care, University of Helsinki, P.O. Box 20, University of Helsinki, Helsinki, FI-00014, Finland. [3] Vasa Central Hospital, Sandviksgatan 2-4, Vasa, FI-65130, Finland. [4] Folkhalsan Reasearch Centre, PB 63, University of Helsinki, Helsinki, FI-00014, Finland. [5] Unit of General Practice, Helsinki University Central Hospital, Haartmaninkatu 4, Helsinki, FI-00290, Finland. ; Neuro-Imaging Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia. ; Cardiovascular Genetics Division, University of Utah, 420 Chipeta Way, Room 1160, Salt Lake City, Utah 84117, USA. ; 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. [2] Alzheimer Scotland Research Centre, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK. ; 1] Department of Epidemiology, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. [2] Department of Psychiatry, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands. ; 1] Department of Medical Sciences, University of Trieste, Strada di Fiume 447 - Osp. di Cattinara, 34149 Trieste, Italy. [2] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, P.O. Box 20, Helsinki, FI-00014, Finland. [2] Department of Public Health, University of Helsinki, Hjelt Institute, P.O.Box 41, Mannerheimintie 172, Helsinki, FI-00014, Finland. [3] National Institute for Health and Welfare (THL), P.O.Box 30, Mannerheimintie 166, Helsinki, FI-00271, Finland. ; Department of Kinesiology, Laval University, 2300 rue de la Terrasse, Quebec G1V 0A6, Canada. ; Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, Mississippi 39216, USA. ; 1] Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, FI-20521, Finland. [2] Research Center of Applied and Preventive Cardiovascular medicine, University of Turku, Turku, FI-20521, Finland. ; 1] University of Groningen, University Medical Center Groningen, Department of Cardiology, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. [2] Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Catharijnesingel 52, Utrecht, 3501 DG, The Netherlands. [3] University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, Groningen, 9700 RB, The Netherlands. ; Department of Economics, Stockholm School of Economics, Box 6501, Stockholm, SE-113 83, Sweden. ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, SE-171 77, Sweden. ; Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Auenbruggerplatz 22, Graz, A-8036, Austria. ; Department of Genetics and Biostatistics, Washington University School of Medicine, 4444 Forest Park Boulevard, Saint Louis, Missouri 63108, USA. ; 1] The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. [2] Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; 1] Genomics and Molecular Medicine, CSIR-Institute of Genomics &Integrative Biology, Mathura Road, New Delhi, 110025, India. [2] School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. ; 1] Department of Pediatrics, University of Oklahoma Health Sciences Center, 940 Stanton Young Boulevard, Oklahoma City, Oklahoma 73104, USA. [2] Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. ; 1] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", via dell'Istria 65, 34137 Trieste, Italy. [2] Sidra Medical and Research Centre, Doha, Qatar. ; 1] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [2] The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. [3] The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA. ; 1] Genomic Research on Complex Diseases (GRC) Group, CSIR-Centre for Cellular and Molecular Biology, Habshiguda, Uppal Road, Hyderabad, 500007, India. [2] Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore. ; 1] Division of Endocrinology, Diabetes, and Nutrition and Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. [2] Program for Personalised and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, 685 Baltimore St. MSTF, Baltimore, Maryland 21201, USA. [3] Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, 685 W Baltimore MSTF, Baltimore, Maryland 21201, USA. ; BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. ; 1] Epidemiology, University of North Carolina, 137 E. Franklin St., Suite 306, Chapel Hill, North Carolina 27599, USA. [2] Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, 137 E. Franklin Street, Suite 306, Chapel Hill, North Carolina 27599, USA. ; 1] Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. [2] Group Health Research Institute, Group Health Cooperative, 1730 Minor Ave, Suite 1360, Seattle, Washington 98101, USA. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. [2] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. [3] Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London W2 1NY, UK. ; 1] Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex UB1 3HW, UK. [2] National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK. [3] Imperial College Healthcare NHS Trust, Imperial College London, Praed Street, London W2 1NY, UK. ; Population Health Research Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK. ; 1] Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia. [2] Unit of Public Health Genomics, National Institute for Health and Welfare, P.O. Box 104, Helsinki, FI-00251, Finland. ; 1] Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] Centre for Global Health and Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia. ; 1] Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU Edinburgh, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26131930" target="_blank"〉PubMed〈/a〉

Description: Osteoporosis and other diseases of bone loss are a major public health problem. Here it is shown that the statins, drugs widely used for lowering serum cholesterol, also enhance new bone formation in vitro and in rodents. This effect was associated with increased expression of the bone morphogenetic protein-2 (BMP-2) gene in bone cells. Lovastatin and simvastatin increased bone formation when injected subcutaneously over the calvaria of mice and increased cancellous bone volume when orally administered to rats. Thus, in appropriate doses, statins may have therapeutic applications for the treatment of osteoporosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mundy, G -- Garrett, R -- Harris, S -- Chan, J -- Chen, D -- Rossini, G -- Boyce, B -- Zhao, M -- Gutierrez, G -- New York, N.Y. -- Science. 1999 Dec 3;286(5446):1946-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉OsteoScreen, 2040 Babcock Road, San Antonio, TX 78229, USA. mundy@uthscsa.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10583956" target="_blank"〉PubMed〈/a〉

Description: Interferons (IFN) alpha/beta and gamma induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss of GAF and ISGF3 activation but is dominant for one cellular phenotype and recessive for the other. It impairs the nuclear accumulation of GAF but not of ISGF3 in heterozygous cells stimulated by IFNs. Thus, the antimycobacterial, but not the antiviral, effects of human IFNs are principally mediated by GAF.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dupuis, S -- Dargemont, C -- Fieschi, C -- Thomassin, N -- Rosenzweig, S -- Harris, J -- Holland, S M -- Schreiber, R D -- Casanova, J L -- New York, N.Y. -- Science. 2001 Jul 13;293(5528):300-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratoire de Genetique Humaine des Maladies Infectieuses, Universite de Paris Rene Descartes-INSERM UMR550, Faculte de Medecine Necker-Enfants Malades, 75015 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11452125" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gruber, Stephen B -- Ellis, Nathan A -- Scott, Karen K -- Almog, Ronit -- Kolachana, Prema -- Bonner, Joseph D -- Kirchhoff, Tomas -- Tomsho, Lynn P -- Nafa, Khedoudja -- Pierce, Heather -- Low, Marcelo -- Satagopan, Jaya -- Rennert, Hedy -- Huang, Helen -- Greenson, Joel K -- Groden, Joanna -- Rapaport, Beth -- Shia, Jinru -- Johnson, Stephen -- Gregersen, Peter K -- Harris, Curtis C -- Boyd, Jeff -- Rennert, Gad -- Offit, Kenneth -- R01CA81488/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2002 Sep 20;297(5589):2013.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12242432" target="_blank"〉PubMed〈/a〉

Description: A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venter, J C -- Adams, M D -- Myers, E W -- Li, P W -- Mural, R J -- Sutton, G G -- Smith, H O -- Yandell, M -- Evans, C A -- Holt, R A -- Gocayne, J D -- Amanatides, P -- Ballew, R M -- Huson, D H -- Wortman, J R -- Zhang, Q -- Kodira, C D -- Zheng, X H -- Chen, L -- Skupski, M -- Subramanian, G -- Thomas, P D -- Zhang, J -- Gabor Miklos, G L -- Nelson, C -- Broder, S -- Clark, A G -- Nadeau, J -- McKusick, V A -- Zinder, N -- Levine, A J -- Roberts, R J -- Simon, M -- Slayman, C -- Hunkapiller, M -- Bolanos, R -- Delcher, A -- Dew, I -- Fasulo, D -- Flanigan, M -- Florea, L -- Halpern, A -- Hannenhalli, S -- Kravitz, S -- Levy, S -- Mobarry, C -- Reinert, K -- Remington, K -- Abu-Threideh, J -- Beasley, E -- Biddick, K -- Bonazzi, V -- Brandon, R -- Cargill, M -- Chandramouliswaran, I -- Charlab, R -- Chaturvedi, K -- Deng, Z -- Di Francesco, V -- Dunn, P -- Eilbeck, K -- Evangelista, C -- Gabrielian, A E -- Gan, W -- Ge, W -- Gong, F -- Gu, Z -- Guan, P -- Heiman, T J -- Higgins, M E -- Ji, R R -- Ke, Z -- Ketchum, K A -- Lai, Z -- Lei, Y -- Li, Z -- Li, J -- Liang, Y -- Lin, X -- Lu, F -- Merkulov, G V -- Milshina, N -- Moore, H M -- Naik, A K -- Narayan, V A -- Neelam, B -- Nusskern, D -- Rusch, D B -- Salzberg, S -- Shao, W -- Shue, B -- Sun, J -- Wang, Z -- Wang, A -- Wang, X -- Wang, J -- Wei, M -- Wides, R -- Xiao, C -- Yan, C -- Yao, A -- Ye, J -- Zhan, M -- Zhang, W -- Zhang, H -- Zhao, Q -- Zheng, L -- Zhong, F -- Zhong, W -- Zhu, S -- Zhao, S -- Gilbert, D -- Baumhueter, S -- Spier, G -- Carter, C -- Cravchik, A -- Woodage, T -- Ali, F -- An, H -- Awe, A -- Baldwin, D -- Baden, H -- Barnstead, M -- Barrow, I -- Beeson, K -- Busam, D -- Carver, A -- Center, A -- Cheng, M L -- Curry, L -- Danaher, S -- Davenport, L -- Desilets, R -- Dietz, S -- Dodson, K -- Doup, L -- Ferriera, S -- Garg, N -- Gluecksmann, A -- Hart, B -- Haynes, J -- Haynes, C -- Heiner, C -- Hladun, S -- Hostin, D -- Houck, J -- Howland, T -- Ibegwam, C -- Johnson, J -- Kalush, F -- Kline, L -- Koduru, S -- Love, A -- Mann, F -- May, D -- McCawley, S -- McIntosh, T -- McMullen, I -- Moy, M -- Moy, L -- Murphy, B -- Nelson, K -- Pfannkoch, C -- Pratts, E -- Puri, V -- Qureshi, H -- Reardon, M -- Rodriguez, R -- Rogers, Y H -- Romblad, D -- Ruhfel, B -- Scott, R -- Sitter, C -- Smallwood, M -- Stewart, E -- Strong, R -- Suh, E -- Thomas, R -- Tint, N N -- Tse, S -- Vech, C -- Wang, G -- Wetter, J -- Williams, S -- Williams, M -- Windsor, S -- Winn-Deen, E -- Wolfe, K -- Zaveri, J -- Zaveri, K -- Abril, J F -- Guigo, R -- Campbell, M J -- Sjolander, K V -- Karlak, B -- Kejariwal, A -- Mi, H -- Lazareva, B -- Hatton, T -- Narechania, A -- Diemer, K -- Muruganujan, A -- Guo, N -- Sato, S -- Bafna, V -- Istrail, S -- Lippert, R -- Schwartz, R -- Walenz, B -- Yooseph, S -- Allen, D -- Basu, A -- Baxendale, J -- Blick, L -- Caminha, M -- Carnes-Stine, J -- Caulk, P -- Chiang, Y H -- Coyne, M -- Dahlke, C -- Mays, A -- Dombroski, M -- Donnelly, M -- Ely, D -- Esparham, S -- Fosler, C -- Gire, H -- Glanowski, S -- Glasser, K -- Glodek, A -- Gorokhov, M -- Graham, K -- Gropman, B -- Harris, M -- Heil, J -- Henderson, S -- Hoover, J -- Jennings, D -- Jordan, C -- Jordan, J -- Kasha, J -- Kagan, L -- Kraft, C -- Levitsky, A -- Lewis, M -- Liu, X -- Lopez, J -- Ma, D -- Majoros, W -- McDaniel, J -- Murphy, S -- Newman, M -- Nguyen, T -- Nguyen, N -- Nodell, M -- Pan, S -- Peck, J -- Peterson, M -- Rowe, W -- Sanders, R -- Scott, J -- Simpson, M -- Smith, T -- Sprague, A -- Stockwell, T -- Turner, R -- Venter, E -- Wang, M -- Wen, M -- Wu, D -- Wu, M -- Xia, A -- Zandieh, A -- Zhu, X -- New York, N.Y. -- Science. 2001 Feb 16;291(5507):1304-51.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Celera Genomics, 45 West Gude Drive, Rockville, MD 20850, USA. humangenome@celera.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11181995" target="_blank"〉PubMed〈/a〉

Description: Dorsal-ventral patterning in vertebrate and invertebrate embryos is mediated by a conserved system of secreted proteins that establishes a bone morphogenetic protein (BMP) gradient. Although the Drosophila embryonic Decapentaplegic (Dpp) gradient has served as a model to understand how morphogen gradients are established, no role for the extracellular matrix has been previously described. Here we show that type IV collagen extracellular matrix proteins bind Dpp and regulate its signalling in both the Drosophila embryo and ovary. We provide evidence that the interaction between Dpp and type IV collagen augments Dpp signalling in the embryo by promoting gradient formation, yet it restricts the signalling range in the ovary through sequestration of the Dpp ligand. Together, these results identify a critical function of type IV collagens in modulating Dpp in the extracellular space during Drosophila development. On the basis of our findings that human type IV collagen binds BMP4, we predict that this role of type IV collagens will be conserved.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiaomeng -- Harris, Robin E -- Bayston, Laura J -- Ashe, Hilary L -- BBS/B/11672/Biotechnology and Biological Sciences Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2008 Sep 4;455(7209):72-7. doi: 10.1038/nature07214.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester M13 9PT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18701888" target="_blank"〉PubMed〈/a〉

Description: We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803040/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Wesley C -- Hillier, LaDeana W -- Marshall Graves, Jennifer A -- Birney, Ewan -- Ponting, Chris P -- Grutzner, Frank -- Belov, Katherine -- Miller, Webb -- Clarke, Laura -- Chinwalla, Asif T -- Yang, Shiaw-Pyng -- Heger, Andreas -- Locke, Devin P -- Miethke, Pat -- Waters, Paul D -- Veyrunes, Frederic -- Fulton, Lucinda -- Fulton, Bob -- Graves, Tina -- Wallis, John -- Puente, Xose S -- Lopez-Otin, Carlos -- Ordonez, Gonzalo R -- Eichler, Evan E -- Chen, Lin -- Cheng, Ze -- Deakin, Janine E -- Alsop, Amber -- Thompson, Katherine -- Kirby, Patrick -- Papenfuss, Anthony T -- Wakefield, Matthew J -- Olender, Tsviya -- Lancet, Doron -- Huttley, Gavin A -- Smit, Arian F A -- Pask, Andrew -- Temple-Smith, Peter -- Batzer, Mark A -- Walker, Jerilyn A -- Konkel, Miriam K -- Harris, Robert S -- Whittington, Camilla M -- Wong, Emily S W -- Gemmell, Neil J -- Buschiazzo, Emmanuel -- Vargas Jentzsch, Iris M -- Merkel, Angelika -- Schmitz, Juergen -- Zemann, Anja -- Churakov, Gennady -- Kriegs, Jan Ole -- Brosius, Juergen -- Murchison, Elizabeth P -- Sachidanandam, Ravi -- Smith, Carly -- Hannon, Gregory J -- Tsend-Ayush, Enkhjargal -- McMillan, Daniel -- Attenborough, Rosalind -- Rens, Willem -- Ferguson-Smith, Malcolm -- Lefevre, Christophe M -- Sharp, Julie A -- Nicholas, Kevin R -- Ray, David A -- Kube, Michael -- Reinhardt, Richard -- Pringle, Thomas H -- Taylor, James -- Jones, Russell C -- Nixon, Brett -- Dacheux, Jean-Louis -- Niwa, Hitoshi -- Sekita, Yoko -- Huang, Xiaoqiu -- Stark, Alexander -- Kheradpour, Pouya -- Kellis, Manolis -- Flicek, Paul -- Chen, Yuan -- Webber, Caleb -- Hardison, Ross -- Nelson, Joanne -- Hallsworth-Pepin, Kym -- Delehaunty, Kim -- Markovic, Chris -- Minx, Pat -- Feng, Yucheng -- Kremitzki, Colin -- Mitreva, Makedonka -- Glasscock, Jarret -- Wylie, Todd -- Wohldmann, Patricia -- Thiru, Prathapan -- Nhan, Michael N -- Pohl, Craig S -- Smith, Scott M -- Hou, Shunfeng -- Nefedov, Mikhail -- de Jong, Pieter J -- Renfree, Marilyn B -- Mardis, Elaine R -- Wilson, Richard K -- 062023/Wellcome Trust/United Kingdom -- HG002238/HG/NHGRI NIH HHS/ -- MC_U137761446/Medical Research Council/United Kingdom -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA013106-37/CA/NCI NIH HHS/ -- R01 GM59290/GM/NIGMS NIH HHS/ -- R01 HG002939/HG/NHGRI NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG004037-02/HG/NHGRI NIH HHS/ -- R01HG02385/HG/NHGRI NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2008 May 8;453(7192):175-83. doi: 10.1038/nature06936.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Sequencing Center, Washington University School of Medicine, Campus Box 8501, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. wwarren@wustl.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18464734" target="_blank"〉PubMed〈/a〉

Description: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in 〉100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P 〈 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039276/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3039276/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Teslovich, Tanya M -- Musunuru, Kiran -- Smith, Albert V -- Edmondson, Andrew C -- Stylianou, Ioannis M -- Koseki, Masahiro -- Pirruccello, James P -- Ripatti, Samuli -- Chasman, Daniel I -- Willer, Cristen J -- Johansen, Christopher T -- Fouchier, Sigrid W -- Isaacs, Aaron -- Peloso, Gina M -- Barbalic, Maja -- Ricketts, Sally L -- Bis, Joshua C -- Aulchenko, Yurii S -- Thorleifsson, Gudmar -- Feitosa, Mary F -- Chambers, John -- Orho-Melander, Marju -- Melander, Olle -- Johnson, Toby -- Li, Xiaohui -- Guo, Xiuqing -- Li, Mingyao -- Shin Cho, Yoon -- Jin Go, Min -- Jin Kim, Young -- Lee, Jong-Young -- Park, Taesung -- Kim, Kyunga -- Sim, Xueling -- Twee-Hee Ong, Rick -- Croteau-Chonka, Damien C -- Lange, Leslie A -- Smith, Joshua D -- Song, Kijoung -- Hua Zhao, Jing -- Yuan, Xin -- Luan, Jian'an -- Lamina, Claudia -- Ziegler, Andreas -- Zhang, Weihua -- Zee, Robert Y L -- Wright, Alan F -- Witteman, Jacqueline C M -- Wilson, James F -- Willemsen, Gonneke -- Wichmann, H-Erich -- Whitfield, John B -- Waterworth, Dawn M -- Wareham, Nicholas J -- Waeber, Gerard -- Vollenweider, Peter -- Voight, Benjamin F -- Vitart, Veronique -- Uitterlinden, Andre G -- Uda, Manuela -- Tuomilehto, Jaakko -- Thompson, John R -- Tanaka, Toshiko -- Surakka, Ida -- Stringham, Heather M -- Spector, Tim D -- Soranzo, Nicole -- Smit, Johannes H -- Sinisalo, Juha -- Silander, Kaisa -- Sijbrands, Eric J G -- Scuteri, Angelo -- Scott, James -- Schlessinger, David -- Sanna, Serena -- Salomaa, Veikko -- Saharinen, Juha -- Sabatti, Chiara -- Ruokonen, Aimo -- Rudan, Igor -- Rose, Lynda M -- Roberts, Robert -- Rieder, Mark -- Psaty, Bruce M -- Pramstaller, Peter P -- Pichler, Irene -- Perola, Markus -- Penninx, Brenda W J H -- Pedersen, Nancy L -- Pattaro, Cristian -- Parker, Alex N -- Pare, Guillaume -- Oostra, Ben A -- O'Donnell, Christopher J -- Nieminen, Markku S -- Nickerson, Deborah A -- Montgomery, Grant W -- Meitinger, Thomas -- McPherson, Ruth -- McCarthy, Mark I -- McArdle, Wendy -- Masson, David -- Martin, Nicholas G -- Marroni, Fabio -- Mangino, Massimo -- Magnusson, Patrik K E -- Lucas, Gavin -- Luben, Robert -- Loos, Ruth J F -- Lokki, Marja-Liisa -- Lettre, Guillaume -- Langenberg, Claudia -- Launer, Lenore J -- Lakatta, Edward G -- Laaksonen, Reijo -- Kyvik, Kirsten O -- Kronenberg, Florian -- Konig, Inke R -- Khaw, Kay-Tee -- Kaprio, Jaakko -- Kaplan, Lee M -- Johansson, Asa -- Jarvelin, Marjo-Riitta -- Janssens, A Cecile J W -- Ingelsson, Erik -- Igl, Wilmar -- Kees Hovingh, G -- Hottenga, Jouke-Jan -- Hofman, Albert -- Hicks, Andrew A -- Hengstenberg, Christian -- Heid, Iris M -- Hayward, Caroline -- Havulinna, Aki S -- Hastie, Nicholas D -- Harris, Tamara B -- Haritunians, Talin -- Hall, Alistair S -- Gyllensten, Ulf -- Guiducci, Candace -- Groop, Leif C -- Gonzalez, Elena -- Gieger, Christian -- Freimer, Nelson B -- Ferrucci, Luigi -- Erdmann, Jeanette -- Elliott, Paul -- Ejebe, Kenechi G -- Doring, Angela -- Dominiczak, Anna F -- Demissie, Serkalem -- Deloukas, Panagiotis -- de Geus, Eco J C -- de Faire, Ulf -- Crawford, Gabriel -- Collins, Francis S -- Chen, Yii-der I -- Caulfield, Mark J -- Campbell, Harry -- Burtt, Noel P -- Bonnycastle, Lori L -- Boomsma, Dorret I -- Boekholdt, S Matthijs -- Bergman, Richard N -- Barroso, Ines -- Bandinelli, Stefania -- Ballantyne, Christie M -- Assimes, Themistocles L -- Quertermous, Thomas -- Altshuler, David -- Seielstad, Mark -- Wong, Tien Y -- Tai, E-Shyong -- Feranil, Alan B -- Kuzawa, Christopher W -- Adair, Linda S -- Taylor, Herman A Jr -- Borecki, Ingrid B -- Gabriel, Stacey B -- Wilson, James G -- Holm, Hilma -- Thorsteinsdottir, Unnur -- Gudnason, Vilmundur -- Krauss, Ronald M -- Mohlke, Karen L -- Ordovas, Jose M -- Munroe, Patricia B -- Kooner, Jaspal S -- Tall, Alan R -- Hegele, Robert A -- Kastelein, John J P -- Schadt, Eric E -- Rotter, Jerome I -- Boerwinkle, Eric -- Strachan, David P -- Mooser, Vincent -- Stefansson, Kari -- Reilly, Muredach P -- Samani, Nilesh J -- Schunkert, Heribert -- Cupples, L Adrienne -- Sandhu, Manjinder S -- Ridker, Paul M -- Rader, Daniel J -- van Duijn, Cornelia M -- Peltonen, Leena -- Abecasis, Goncalo R -- Boehnke, Michael -- Kathiresan, Sekar -- 068545/Z/02/Wellcome Trust/United Kingdom -- 076113/B/04/Z/Wellcome Trust/United Kingdom -- 077016/Z/05/Z/Wellcome Trust/United Kingdom -- 079895/Wellcome Trust/United Kingdom -- 1Z01 HG000024/HG/NHGRI NIH HHS/ -- 5R01DK06833603/DK/NIDDK NIH HHS/ -- 5R01DK07568102/DK/NIDDK NIH HHS/ -- 5R01HL087679-02/HL/NHLBI NIH HHS/ -- 5R01HL08770003/HL/NHLBI NIH HHS/ -- 5R01HL08821502/HL/NHLBI NIH HHS/ -- CA 047988/CA/NCI NIH HHS/ -- CZB/4/710/Chief Scientist Office/United Kingdom -- DK062370/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK072193/DK/NIDDK NIH HHS/ -- DK078150/DK/NIDDK NIH HHS/ -- DK56350/DK/NIDDK NIH HHS/ -- ES10126/ES/NIEHS NIH HHS/ -- G0000934/Medical Research Council/United Kingdom -- G0401527/Medical Research Council/United Kingdom -- G0601966/Medical Research Council/United Kingdom -- G0700931/Medical Research Council/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G0801566/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- G9521010D/Medical Research Council/United Kingdom -- HHSN268200625226C/PHS HHS/ -- HL 04381/HL/NHLBI NIH HHS/ -- HL 080467/HL/NHLBI NIH HHS/ -- HL-54776/HL/NHLBI NIH HHS/ -- HL085144/HL/NHLBI NIH HHS/ -- K99 HL098364/HL/NHLBI NIH HHS/ -- K99 HL098364-01/HL/NHLBI NIH HHS/ -- K99HL094535/HL/NHLBI NIH HHS/ -- M01-RR00425/RR/NCRR NIH HHS/ -- MC_QA137934/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- N01 HC-15103/HC/NHLBI NIH HHS/ -- N01 HC-55222/HC/NHLBI NIH HHS/ -- N01-AG-12100/AG/NIA NIH HHS/ -- N01-HC-25195/HC/NHLBI NIH HHS/ -- N01-HC-35129/HC/NHLBI NIH HHS/ -- N01-HC-45133/HC/NHLBI NIH HHS/ -- N01-HC-55015/HC/NHLBI NIH HHS/ -- N01-HC-55016/HC/NHLBI NIH HHS/ -- N01-HC-55018/HC/NHLBI NIH HHS/ -- N01-HC-55019/HC/NHLBI NIH HHS/ -- N01-HC-55020/HC/NHLBI NIH HHS/ -- N01-HC-55021/HC/NHLBI NIH HHS/ -- N01-HC-55022/HC/NHLBI NIH HHS/ -- N01-HC-75150/HC/NHLBI NIH HHS/ -- N01-HC-85079/HC/NHLBI NIH HHS/ -- N01-HC-85080/HC/NHLBI NIH HHS/ -- N01-HC-85081/HC/NHLBI NIH HHS/ -- N01-HC-85082/HC/NHLBI NIH HHS/ -- N01-HC-85083/HC/NHLBI NIH HHS/ -- N01-HC-85084/HC/NHLBI NIH HHS/ -- N01-HC-85085/HC/NHLBI NIH HHS/ -- N01-HC-85086/HC/NHLBI NIH HHS/ -- N01-HG-65403/HG/NHGRI NIH HHS/ -- N02-HL-6-4278/HL/NHLBI NIH HHS/ -- PG/02/128/British Heart Foundation/United Kingdom -- PG/08/094/British Heart Foundation/United Kingdom -- PG/08/094/26019/British Heart Foundation/United Kingdom -- R01 DK072193/DK/NIDDK NIH HHS/ -- R01 DK078150/DK/NIDDK NIH HHS/ -- R01 HL087647/HL/NHLBI NIH HHS/ -- R01 HL087676/HL/NHLBI NIH HHS/ -- R01 HL089650/HL/NHLBI NIH HHS/ -- R01HL086694/HL/NHLBI NIH HHS/ -- R01HL087641/HL/NHLBI NIH HHS/ -- R01HL087652/HL/NHLBI NIH HHS/ -- R01HL59367/HL/NHLBI NIH HHS/ -- R24 HD050924/HD/NICHD NIH HHS/ -- RC1 HL099634/HL/NHLBI NIH HHS/ -- RC1 HL099634-02/HL/NHLBI NIH HHS/ -- RC1 HL099793/HL/NHLBI NIH HHS/ -- RC2 HL101864,/HL/NHLBI NIH HHS/ -- RC2 HL102419/HL/NHLBI NIH HHS/ -- RG/07/005/23633/British Heart Foundation/United Kingdom -- RR20649/RR/NCRR NIH HHS/ -- SP/08/005/25115/British Heart Foundation/United Kingdom -- T32 GM007092/GM/NIGMS NIH HHS/ -- T32 HG00040/HG/NHGRI NIH HHS/ -- T32HL007208/HL/NHLBI NIH HHS/ -- TW05596/TW/FIC NIH HHS/ -- U01 DK062370/DK/NIDDK NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL080295/HL/NHLBI NIH HHS/ -- U01HG004402/HG/NHGRI NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1RR025005/RR/NCRR NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):707-13. doi: 10.1038/nature09270.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686565" target="_blank"〉PubMed〈/a〉

Description: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF 〈/= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hou-Feng -- Forgetta, Vincenzo -- Hsu, Yi-Hsiang -- Estrada, Karol -- Rosello-Diez, Alberto -- Leo, Paul J -- Dahia, Chitra L -- Park-Min, Kyung Hyun -- Tobias, Jonathan H -- Kooperberg, Charles -- Kleinman, Aaron -- Styrkarsdottir, Unnur -- Liu, Ching-Ti -- Uggla, Charlotta -- Evans, Daniel S -- Nielson, Carrie M -- Walter, Klaudia -- Pettersson-Kymmer, Ulrika -- McCarthy, Shane -- Eriksson, Joel -- Kwan, Tony -- Jhamai, Mila -- Trajanoska, Katerina -- Memari, Yasin -- Min, Josine -- Huang, Jie -- Danecek, Petr -- Wilmot, Beth -- Li, Rui -- Chou, Wen-Chi -- Mokry, Lauren E -- Moayyeri, Alireza -- Claussnitzer, Melina -- Cheng, Chia-Ho -- Cheung, Warren -- Medina-Gomez, Carolina -- Ge, Bing -- Chen, Shu-Huang -- Choi, Kwangbom -- Oei, Ling -- Fraser, James -- Kraaij, Robert -- Hibbs, Matthew A -- Gregson, Celia L -- Paquette, Denis -- Hofman, Albert -- Wibom, Carl -- Tranah, Gregory J -- Marshall, Mhairi -- Gardiner, Brooke B -- Cremin, Katie -- Auer, Paul -- Hsu, Li -- Ring, Sue -- Tung, Joyce Y -- Thorleifsson, Gudmar -- Enneman, Anke W -- van Schoor, Natasja M -- de Groot, Lisette C P G M -- van der Velde, Nathalie -- Melin, Beatrice -- Kemp, John P -- Christiansen, Claus -- Sayers, Adrian -- Zhou, Yanhua -- Calderari, Sophie -- van Rooij, Jeroen -- Carlson, Chris -- Peters, Ulrike -- Berlivet, Soizik -- Dostie, Josee -- Uitterlinden, Andre G -- Williams, Stephen R -- Farber, Charles -- Grinberg, Daniel -- LaCroix, Andrea Z -- Haessler, Jeff -- Chasman, Daniel I -- Giulianini, Franco -- Rose, Lynda M -- Ridker, Paul M -- Eisman, John A -- Nguyen, Tuan V -- Center, Jacqueline R -- Nogues, Xavier -- Garcia-Giralt, Natalia -- Launer, Lenore L -- Gudnason, Vilmunder -- Mellstrom, Dan -- Vandenput, Liesbeth -- Amin, Najaf -- van Duijn, Cornelia M -- Karlsson, Magnus K -- Ljunggren, Osten -- Svensson, Olle -- Hallmans, Goran -- Rousseau, Francois -- Giroux, Sylvie -- Bussiere, Johanne -- Arp, Pascal P -- Koromani, Fjorda -- Prince, Richard L -- Lewis, Joshua R -- Langdahl, Bente L -- Hermann, A Pernille -- Jensen, Jens-Erik B -- Kaptoge, Stephen -- Khaw, Kay-Tee -- Reeve, Jonathan -- Formosa, Melissa M -- Xuereb-Anastasi, Angela -- Akesson, Kristina -- McGuigan, Fiona E -- Garg, Gaurav -- Olmos, Jose M -- Zarrabeitia, Maria T -- Riancho, Jose A -- Ralston, Stuart H -- Alonso, Nerea -- Jiang, Xi -- Goltzman, David -- Pastinen, Tomi -- Grundberg, Elin -- Gauguier, Dominique -- Orwoll, Eric S -- Karasik, David -- Davey-Smith, George -- AOGC Consortium -- Smith, Albert V -- Siggeirsdottir, Kristin -- Harris, Tamara B -- Zillikens, M Carola -- van Meurs, Joyce B J -- Thorsteinsdottir, Unnur -- Maurano, Matthew T -- Timpson, Nicholas J -- Soranzo, Nicole -- Durbin, Richard -- Wilson, Scott G -- Ntzani, Evangelia E -- Brown, Matthew A -- Stefansson, Kari -- Hinds, David A -- Spector, Tim -- Cupples, L Adrienne -- Ohlsson, Claes -- Greenwood, Celia M T -- UK10K Consortium -- Jackson, Rebecca D -- Rowe, David W -- Loomis, Cynthia A -- Evans, David M -- Ackert-Bicknell, Cheryl L -- Joyner, Alexandra L -- Duncan, Emma L -- Kiel, Douglas P -- Rivadeneira, Fernando -- Richards, J Brent -- G1000143/Medical Research Council/United Kingdom -- K01 AR062655/AR/NIAMS NIH HHS/ -- MC_UU_12013/3/Medical Research Council/United Kingdom -- R01 AG005394/AG/NIA NIH HHS/ -- R01 AG005407/AG/NIA NIH HHS/ -- R01 AG027574/AG/NIA NIH HHS/ -- R01 AG027576/AG/NIA NIH HHS/ -- R01 AR035582/AR/NIAMS NIH HHS/ -- R01 AR035583/AR/NIAMS NIH HHS/ -- RC2 AR058973/AR/NIAMS NIH HHS/ -- U01 AG018197/AG/NIA NIH HHS/ -- U01 AG042140/AG/NIA NIH HHS/ -- U01 AG042143/AG/NIA NIH HHS/ -- U01 AR045580/AR/NIAMS NIH HHS/ -- U01 AR045583/AR/NIAMS NIH HHS/ -- U01 AR045614/AR/NIAMS NIH HHS/ -- U01 AR045632/AR/NIAMS NIH HHS/ -- U01 AR045647/AR/NIAMS NIH HHS/ -- U01 AR045654/AR/NIAMS NIH HHS/ -- U01 AR066160/AR/NIAMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada. ; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal H3T 1E2, Canada. ; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA. ; The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA. ; Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA. ; School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Department of Research, 23andMe, Mountain View, California 94041, USA. ; Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; California Pacific Medical Center Research Institute, San Francisco, California 94158, USA. ; Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Departments of Pharmacology and Clinical Neurosciences, Umea University, Umea S-901 87, Sweden. ; Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. ; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Human Genetics, McGill University, Montreal H3A 1B1, Canada. ; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands. ; Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal H3G 1Y6, Canada. ; Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA. ; Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK. ; Department of Radiation Sciences, Umea University, Umea S-901 87, Sweden. ; School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands. ; Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands. ; Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; Nordic Bioscience, Herlev 2730, Denmark. ; Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France. ; Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France. ; Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Genetics, University of Barcelona, Barcelona 08028, Spain. ; U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain. ; Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. ; Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia. ; School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia. ; St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia. ; Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mediques, Barcelona 08003, Spain. ; Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain. ; Department of Internal Medicine, Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona 08193, Spain. ; Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Icelandic Heart Association, Kopavogur IS-201, Iceland. ; Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland. ; Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands. ; Department of Orthopaedics, Skane University Hospital Malmo 205 02, Sweden. ; Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden. ; Department of Surgical and Perioperative Sciences, Umea Unviersity, Umea 901 85, Sweden. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City G1V 0A6, Canada. ; Axe Sante des Populations et Pratiques Optimales en Sante, Centre de recherche du CHU de Quebec, Quebec City G1V 4G2, Canada. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia. ; Department of Medicine, University of Western Australia, Perth 6009, Australia. ; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark. ; Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark. ; Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark. ; Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK. ; Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. ; Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta. ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmo, Lund University, 205 02, Sweden. ; Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain. ; Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain. ; Department of Legal Medicine, University of Cantabria, Santander 39011, Spain. ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; Department of Medicine and Physiology, McGill University, Montreal H4A 3J1, Canada. ; Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel. ; Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. ; Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal H3A 1A2, Canada. ; Department of Oncology, Gerald Bronfman Centre, McGill University, Montreal H2W 1S6, Canada. ; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA. ; The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367794" target="_blank"〉PubMed〈/a〉