%0 Journal Article %J Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stéphanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Boerwinkle, Eric %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A de Borst, Martin H %A de Geus, Eco J %A Deary, Ian J %A Deelen, Joris %A del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Järvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Åsa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/30224653?dopt=Abstract %R 10.1038/s41588-018-0205-x %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, René %A Zhu, Gu %A Macé, Aurélien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michele M %A Chen, Yii-Der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A LaChance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Järvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/30388399?dopt=Abstract %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Munzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %K Atrial Function %K Atrioventricular Node %K Electrocardiography %K Electrophysiological Phenomena %K Female %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Male %K Mutation, Missense %K Risk Factors %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 07 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30046033?dopt=Abstract %R 10.1038/s41467-018-04766-9 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Järvelin, Marjo-Riitta %A Johansson, Åsa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stéphanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near , , , , , and , and provide new replication evidence for a further 2 signals in and Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

%B Hypertension %8 2017 Jul 24 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28739976?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.117.09438 %0 Journal Article %J Nature %D 2015 %T Directional dominance on stature and cognition in diverse human populations. %A Joshi, Peter K %A Esko, Tõnu %A Mattsson, Hannele %A Eklund, Niina %A Gandin, Ilaria %A Nutile, Teresa %A Jackson, Anne U %A Schurmann, Claudia %A Smith, Albert V %A Zhang, Weihua %A Okada, Yukinori %A Stančáková, Alena %A Faul, Jessica D %A Zhao, Wei %A Bartz, Traci M %A Concas, Maria Pina %A Franceschini, Nora %A Enroth, Stefan %A Vitart, Veronique %A Trompet, Stella %A Guo, Xiuqing %A Chasman, Daniel I %A O'Connel, Jeffrey R %A Corre, Tanguy %A Nongmaithem, Suraj S %A Chen, Yuning %A Mangino, Massimo %A Ruggiero, Daniela %A Traglia, Michela %A Farmaki, Aliki-Eleni %A Kacprowski, Tim %A Bjonnes, Andrew %A van der Spek, Ashley %A Wu, Ying %A Giri, Anil K %A Yanek, Lisa R %A Wang, Lihua %A Hofer, Edith %A Rietveld, Cornelius A %A McLeod, Olga %A Cornelis, Marilyn C %A Pattaro, Cristian %A Verweij, Niek %A Baumbach, Clemens %A Abdellaoui, Abdel %A Warren, Helen R %A Vuckovic, Dragana %A Mei, Hao %A Bouchard, Claude %A Perry, John R B %A Cappellani, Stefania %A Mirza, Saira S %A Benton, Miles C %A Broeckel, Ulrich %A Medland, Sarah E %A Lind, Penelope A %A Malerba, Giovanni %A Drong, Alexander %A Yengo, Loic %A Bielak, Lawrence F %A Zhi, Degui %A van der Most, Peter J %A Shriner, Daniel %A Mägi, Reedik %A Hemani, Gibran %A Karaderi, Tugce %A Wang, Zhaoming %A Liu, Tian %A Demuth, Ilja %A Zhao, Jing Hua %A Meng, Weihua %A Lataniotis, Lazaros %A van der Laan, Sander W %A Bradfield, Jonathan P %A Wood, Andrew R %A Bonnefond, Amelie %A Ahluwalia, Tarunveer S %A Hall, Leanne M %A Salvi, Erika %A Yazar, Seyhan %A Carstensen, Lisbeth %A de Haan, Hugoline G %A Abney, Mark %A Afzal, Uzma %A Allison, Matthew A %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Barr, R Graham %A Baumeister, Sebastian E %A Benjamin, Daniel J %A Bergmann, Sven %A Boerwinkle, Eric %A Bottinger, Erwin P %A Campbell, Archie %A Chakravarti, Aravinda %A Chan, Yingleong %A Chanock, Stephen J %A Chen, Constance %A Chen, Y-D Ida %A Collins, Francis S %A Connell, John %A Correa, Adolfo %A Cupples, L Adrienne %A Smith, George Davey %A Davies, Gail %A Dörr, Marcus %A Ehret, Georg %A Ellis, Stephen B %A Feenstra, Bjarke %A Feitosa, Mary F %A Ford, Ian %A Fox, Caroline S %A Frayling, Timothy M %A Friedrich, Nele %A Geller, Frank %A Scotland, Generation %A Gillham-Nasenya, Irina %A Gottesman, Omri %A Graff, Misa %A Grodstein, Francine %A Gu, Charles %A Haley, Chris %A Hammond, Christopher J %A Harris, Sarah E %A Harris, Tamara B %A Hastie, Nicholas D %A Heard-Costa, Nancy L %A Heikkilä, Kauko %A Hocking, Lynne J %A Homuth, Georg %A Hottenga, Jouke-Jan %A Huang, Jinyan %A Huffman, Jennifer E %A Hysi, Pirro G %A Ikram, M Arfan %A Ingelsson, Erik %A Joensuu, Anni %A Johansson, Åsa %A Jousilahti, Pekka %A Jukema, J Wouter %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanoni, Stavroula %A Kerr, Shona M %A Khan, Nazir M %A Koellinger, Philipp %A Koistinen, Heikki A %A Kooner, Manraj K %A Kubo, Michiaki %A Kuusisto, Johanna %A Lahti, Jari %A Launer, Lenore J %A Lea, Rodney A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lind, Lars %A Loh, Marie %A Lokki, Marja-Liisa %A London, Stephanie J %A Loomis, Stephanie J %A Loukola, Anu %A Lu, Yingchang %A Lumley, Thomas %A Lundqvist, Annamari %A Männistö, Satu %A Marques-Vidal, Pedro %A Masciullo, Corrado %A Matchan, Angela %A Mathias, Rasika A %A Matsuda, Koichi %A Meigs, James B %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Mentch, Frank D %A Mihailov, Evelin %A Milani, Lili %A Montasser, May E %A Montgomery, Grant W %A Morrison, Alanna %A Myers, Richard H %A Nadukuru, Rajiv %A Navarro, Pau %A Nelis, Mari %A Nieminen, Markku S %A Nolte, Ilja M %A O'Connor, George T %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Pankow, James S %A Patarcic, Inga %A Pavani, Francesca %A Peyser, Patricia A %A Pietilainen, Kirsi %A Poulter, Neil %A Prokopenko, Inga %A Ralhan, Sarju %A Redmond, Paul %A Rich, Stephen S %A Rissanen, Harri %A Robino, Antonietta %A Rose, Lynda M %A Rose, Richard %A Sala, Cinzia %A Salako, Babatunde %A Salomaa, Veikko %A Sarin, Antti-Pekka %A Saxena, Richa %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sennblad, Bengt %A Seshadri, Sudha %A Sever, Peter %A Shrestha, Smeeta %A Smith, Blair H %A Smith, Jennifer A %A Soranzo, Nicole %A Sotoodehnia, Nona %A Southam, Lorraine %A Stanton, Alice V %A Stathopoulou, Maria G %A Strauch, Konstantin %A Strawbridge, Rona J %A Suderman, Matthew J %A Tandon, Nikhil %A Tang, Sian-Tsun %A Taylor, Kent D %A Tayo, Bamidele O %A Töglhofer, Anna Maria %A Tomaszewski, Maciej %A Tšernikova, Natalia %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Vaidya, Dhananjay %A van Hylckama Vlieg, Astrid %A van Setten, Jessica %A Vasankari, Tuula %A Vedantam, Sailaja %A Vlachopoulou, Efthymia %A Vozzi, Diego %A Vuoksimaa, Eero %A Waldenberger, Melanie %A Ware, Erin B %A Wentworth-Shields, William %A Whitfield, John B %A Wild, Sarah %A Willemsen, Gonneke %A Yajnik, Chittaranjan S %A Yao, Jie %A Zaza, Gianluigi %A Zhu, Xiaofeng %A Salem, Rany M %A Melbye, Mads %A Bisgaard, Hans %A Samani, Nilesh J %A Cusi, Daniele %A Mackey, David A %A Cooper, Richard S %A Froguel, Philippe %A Pasterkamp, Gerard %A Grant, Struan F A %A Hakonarson, Hakon %A Ferrucci, Luigi %A Scott, Robert A %A Morris, Andrew D %A Palmer, Colin N A %A Dedoussis, George %A Deloukas, Panos %A Bertram, Lars %A Lindenberger, Ulman %A Berndt, Sonja I %A Lindgren, Cecilia M %A Timpson, Nicholas J %A Tönjes, Anke %A Munroe, Patricia B %A Sørensen, Thorkild I A %A Rotimi, Charles N %A Arnett, Donna K %A Oldehinkel, Albertine J %A Kardia, Sharon L R %A Balkau, Beverley %A Gambaro, Giovanni %A Morris, Andrew P %A Eriksson, Johan G %A Wright, Margie J %A Martin, Nicholas G %A Hunt, Steven C %A Starr, John M %A Deary, Ian J %A Griffiths, Lyn R %A Tiemeier, Henning %A Pirastu, Nicola %A Kaprio, Jaakko %A Wareham, Nicholas J %A Pérusse, Louis %A Wilson, James G %A Girotto, Giorgia %A Caulfield, Mark J %A Raitakari, Olli %A Boomsma, Dorret I %A Gieger, Christian %A van der Harst, Pim %A Hicks, Andrew A %A Kraft, Peter %A Sinisalo, Juha %A Knekt, Paul %A Johannesson, Magnus %A Magnusson, Patrik K E %A Hamsten, Anders %A Schmidt, Reinhold %A Borecki, Ingrid B %A Vartiainen, Erkki %A Becker, Diane M %A Bharadwaj, Dwaipayan %A Mohlke, Karen L %A Boehnke, Michael %A van Duijn, Cornelia M %A Sanghera, Dharambir K %A Teumer, Alexander %A Zeggini, Eleftheria %A Metspalu, Andres %A Gasparini, Paolo %A Ulivi, Sheila %A Ober, Carole %A Toniolo, Daniela %A Rudan, Igor %A Porteous, David J %A Ciullo, Marina %A Spector, Tim D %A Hayward, Caroline %A Dupuis, Josée %A Loos, Ruth J F %A Wright, Alan F %A Chandak, Giriraj R %A Vollenweider, Peter %A Shuldiner, Alan R %A Ridker, Paul M %A Rotter, Jerome I %A Sattar, Naveed %A Gyllensten, Ulf %A North, Kari E %A Pirastu, Mario %A Psaty, Bruce M %A Weir, David R %A Laakso, Markku %A Gudnason, Vilmundur %A Takahashi, Atsushi %A Chambers, John C %A Kooner, Jaspal S %A Strachan, David P %A Campbell, Harry %A Hirschhorn, Joel N %A Perola, Markus %A Polasek, Ozren %A Wilson, James F %K Biological Evolution %K Blood Pressure %K Body Height %K Cholesterol, LDL %K Cognition %K Cohort Studies %K Educational Status %K Female %K Forced Expiratory Volume %K Genome, Human %K Homozygote %K Humans %K Lung Volume Measurements %K Male %K Phenotype %X

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

%B Nature %V 523 %P 459-62 %8 2015 Jul 23 %G eng %N 7561 %1 http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract %R 10.1038/nature14618 %0 Journal Article %J Nature %D 2015 %T Genetic studies of body mass index yield new insights for obesity biology. %A Locke, Adam E %A Kahali, Bratati %A Berndt, Sonja I %A Justice, Anne E %A Pers, Tune H %A Day, Felix R %A Powell, Corey %A Vedantam, Sailaja %A Buchkovich, Martin L %A Yang, Jian %A Croteau-Chonka, Damien C %A Esko, Tõnu %A Fall, Tove %A Ferreira, Teresa %A Gustafsson, Stefan %A Kutalik, Zoltán %A Luan, Jian'an %A Mägi, Reedik %A Randall, Joshua C %A Winkler, Thomas W %A Wood, Andrew R %A Workalemahu, Tsegaselassie %A Faul, Jessica D %A Smith, Jennifer A %A Hua Zhao, Jing %A Zhao, Wei %A Chen, Jin %A Fehrmann, Rudolf %A Hedman, Åsa K %A Karjalainen, Juha %A Schmidt, Ellen M %A Absher, Devin %A Amin, Najaf %A Anderson, Denise %A Beekman, Marian %A Bolton, Jennifer L %A Bragg-Gresham, Jennifer L %A Buyske, Steven %A Demirkan, Ayse %A Deng, Guohong %A Ehret, Georg B %A Feenstra, Bjarke %A Feitosa, Mary F %A Fischer, Krista %A Goel, Anuj %A Gong, Jian %A Jackson, Anne U %A Kanoni, Stavroula %A Kleber, Marcus E %A Kristiansson, Kati %A Lim, Unhee %A Lotay, Vaneet %A Mangino, Massimo %A Mateo Leach, Irene %A Medina-Gomez, Carolina %A Medland, Sarah E %A Nalls, Michael A %A Palmer, Cameron D %A Pasko, Dorota %A Pechlivanis, Sonali %A Peters, Marjolein J %A Prokopenko, Inga %A Shungin, Dmitry %A Stančáková, Alena %A Strawbridge, Rona J %A Ju Sung, Yun %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A van der Laan, Sander W %A van Setten, Jessica %A Van Vliet-Ostaptchouk, Jana V %A Wang, Zhaoming %A Yengo, Loic %A Zhang, Weihua %A Isaacs, Aaron %A Albrecht, Eva %A Arnlöv, Johan %A Arscott, Gillian M %A Attwood, Antony P %A Bandinelli, Stefania %A Barrett, Amy %A Bas, Isabelita N %A Bellis, Claire %A Bennett, Amanda J %A Berne, Christian %A Blagieva, Roza %A Blüher, Matthias %A Böhringer, Stefan %A Bonnycastle, Lori L %A Böttcher, Yvonne %A Boyd, Heather A %A Bruinenberg, Marcel %A Caspersen, Ida H %A Ida Chen, Yii-Der %A Clarke, Robert %A Daw, E Warwick %A de Craen, Anton J M %A Delgado, Graciela %A Dimitriou, Maria %A Doney, Alex S F %A Eklund, Niina %A Estrada, Karol %A Eury, Elodie %A Folkersen, Lasse %A Fraser, Ross M %A Garcia, Melissa E %A Geller, Frank %A Giedraitis, Vilmantas %A Gigante, Bruna %A Go, Alan S %A Golay, Alain %A Goodall, Alison H %A Gordon, Scott D %A Gorski, Mathias %A Grabe, Hans-Jörgen %A Grallert, Harald %A Grammer, Tanja B %A Gräßler, Jürgen %A Grönberg, Henrik %A Groves, Christopher J %A Gusto, Gaëlle %A Haessler, Jeffrey %A Hall, Per %A Haller, Toomas %A Hallmans, Goran %A Hartman, Catharina A %A Hassinen, Maija %A Hayward, Caroline %A Heard-Costa, Nancy L %A Helmer, Quinta %A Hengstenberg, Christian %A Holmen, Oddgeir %A Hottenga, Jouke-Jan %A James, Alan L %A Jeff, Janina M %A Johansson, Åsa %A Jolley, Jennifer %A Juliusdottir, Thorhildur %A Kinnunen, Leena %A Koenig, Wolfgang %A Koskenvuo, Markku %A Kratzer, Wolfgang %A Laitinen, Jaana %A Lamina, Claudia %A Leander, Karin %A Lee, Nanette R %A Lichtner, Peter %A Lind, Lars %A Lindström, Jaana %A Sin Lo, Ken %A Lobbens, Stéphane %A Lorbeer, Roberto %A Lu, Yingchang %A Mach, François %A Magnusson, Patrik K E %A Mahajan, Anubha %A McArdle, Wendy L %A McLachlan, Stela %A Menni, Cristina %A Merger, Sigrun %A Mihailov, Evelin %A Milani, Lili %A Moayyeri, Alireza %A Monda, Keri L %A Morken, Mario A %A Mulas, Antonella %A Müller, Gabriele %A Müller-Nurasyid, Martina %A Musk, Arthur W %A Nagaraja, Ramaiah %A Nöthen, Markus M %A Nolte, Ilja M %A Pilz, Stefan %A Rayner, Nigel W %A Renstrom, Frida %A Rettig, Rainer %A Ried, Janina S %A Ripke, Stephan %A Robertson, Neil R %A Rose, Lynda M %A Sanna, Serena %A Scharnagl, Hubert %A Scholtens, Salome %A Schumacher, Fredrick R %A Scott, William R %A Seufferlein, Thomas %A Shi, Jianxin %A Vernon Smith, Albert %A Smolonska, Joanna %A Stanton, Alice V %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen %A Stringham, Heather M %A Sundström, Johan %A Swertz, Morris A %A Swift, Amy J %A Syvänen, Ann-Christine %A Tan, Sian-Tsung %A Tayo, Bamidele O %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tyrer, Jonathan P %A Uh, Hae-Won %A Vandenput, Liesbeth %A Verhulst, Frank C %A Vermeulen, Sita H %A Verweij, Niek %A Vonk, Judith M %A Waite, Lindsay L %A Warren, Helen R %A Waterworth, Dawn %A Weedon, Michael N %A Wilkens, Lynne R %A Willenborg, Christina %A Wilsgaard, Tom %A Wojczynski, Mary K %A Wong, Andrew %A Wright, Alan F %A Zhang, Qunyuan %A Brennan, Eoin P %A Choi, Murim %A Dastani, Zari %A Drong, Alexander W %A Eriksson, Per %A Franco-Cereceda, Anders %A Gådin, Jesper R %A Gharavi, Ali G %A Goddard, Michael E %A Handsaker, Robert E %A Huang, Jinyan %A Karpe, Fredrik %A Kathiresan, Sekar %A Keildson, Sarah %A Kiryluk, Krzysztof %A Kubo, Michiaki %A Lee, Jong-Young %A Liang, Liming %A Lifton, Richard P %A Ma, Baoshan %A McCarroll, Steven A %A McKnight, Amy J %A Min, Josine L %A Moffatt, Miriam F %A Montgomery, Grant W %A Murabito, Joanne M %A Nicholson, George %A Nyholt, Dale R %A Okada, Yukinori %A Perry, John R B %A Dorajoo, Rajkumar %A Reinmaa, Eva %A Salem, Rany M %A Sandholm, Niina %A Scott, Robert A %A Stolk, Lisette %A Takahashi, Atsushi %A Tanaka, Toshihiro %A Van't Hooft, Ferdinand M %A Vinkhuyzen, Anna A E %A Westra, Harm-Jan %A Zheng, Wei %A Zondervan, Krina T %A Heath, Andrew C %A Arveiler, Dominique %A Bakker, Stephan J L %A Beilby, John %A Bergman, Richard N %A Blangero, John %A Bovet, Pascal %A Campbell, Harry %A Caulfield, Mark J %A Cesana, Giancarlo %A Chakravarti, Aravinda %A Chasman, Daniel I %A Chines, Peter S %A Collins, Francis S %A Crawford, Dana C %A Cupples, L Adrienne %A Cusi, Daniele %A Danesh, John %A de Faire, Ulf %A den Ruijter, Hester M %A Dominiczak, Anna F %A Erbel, Raimund %A Erdmann, Jeanette %A Eriksson, Johan G %A Farrall, Martin %A Felix, Stephan B %A Ferrannini, Ele %A Ferrières, Jean %A Ford, Ian %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Gansevoort, Ron T %A Gejman, Pablo V %A Gieger, Christian %A Gottesman, Omri %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hall, Alistair S %A Harris, Tamara B %A Hattersley, Andrew T %A Hicks, Andrew A %A Hindorff, Lucia A %A Hingorani, Aroon D %A Hofman, Albert %A Homuth, Georg %A Hovingh, G Kees %A Humphries, Steve E %A Hunt, Steven C %A Hyppönen, Elina %A Illig, Thomas %A Jacobs, Kevin B %A Järvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Johansen, Berit %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti M %A Kaprio, Jaakko %A Kastelein, John J P %A Keinanen-Kiukaanniemi, Sirkka M %A Kiemeney, Lambertus A %A Knekt, Paul %A Kooner, Jaspal S %A Kooperberg, Charles %A Kovacs, Peter %A Kraja, Aldi T %A Kumari, Meena %A Kuusisto, Johanna %A Lakka, Timo A %A Langenberg, Claudia %A Le Marchand, Loic %A Lehtimäki, Terho %A Lyssenko, Valeriya %A Männistö, Satu %A Marette, André %A Matise, Tara C %A McKenzie, Colin A %A McKnight, Barbara %A Moll, Frans L %A Morris, Andrew D %A Morris, Andrew P %A Murray, Jeffrey C %A Nelis, Mari %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Ong, Ken K %A Madden, Pamela A F %A Pasterkamp, Gerard %A Peden, John F %A Peters, Annette %A Postma, Dirkje S %A Pramstaller, Peter P %A Price, Jackie F %A Qi, Lu %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rice, Treva K %A Ridker, Paul M %A Rioux, John D %A Ritchie, Marylyn D %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Saramies, Jouko %A Sarzynski, Mark A %A Schunkert, Heribert %A Schwarz, Peter E H %A Sever, Peter %A Shuldiner, Alan R %A Sinisalo, Juha %A Stolk, Ronald P %A Strauch, Konstantin %A Tönjes, Anke %A Trégouët, David-Alexandre %A Tremblay, Angelo %A Tremoli, Elena %A Virtamo, Jarmo %A Vohl, Marie-Claude %A Völker, Uwe %A Waeber, Gerard %A Willemsen, Gonneke %A Witteman, Jacqueline C %A Zillikens, M Carola %A Adair, Linda S %A Amouyel, Philippe %A Asselbergs, Folkert W %A Assimes, Themistocles L %A Bochud, Murielle %A Boehm, Bernhard O %A Boerwinkle, Eric %A Bornstein, Stefan R %A Bottinger, Erwin P %A Bouchard, Claude %A Cauchi, Stéphane %A Chambers, John C %A Chanock, Stephen J %A Cooper, Richard S %A de Bakker, Paul I W %A Dedoussis, George %A Ferrucci, Luigi %A Franks, Paul W %A Froguel, Philippe %A Groop, Leif C %A Haiman, Christopher A %A Hamsten, Anders %A Hui, Jennie %A Hunter, David J %A Hveem, Kristian %A Kaplan, Robert C %A Kivimaki, Mika %A Kuh, Diana %A Laakso, Markku %A Liu, Yongmei %A Martin, Nicholas G %A März, Winfried %A Melbye, Mads %A Metspalu, Andres %A Moebus, Susanne %A Munroe, Patricia B %A Njølstad, Inger %A Oostra, Ben A %A Palmer, Colin N A %A Pedersen, Nancy L %A Perola, Markus %A Pérusse, Louis %A Peters, Ulrike %A Power, Chris %A Quertermous, Thomas %A Rauramaa, Rainer %A Rivadeneira, Fernando %A Saaristo, Timo E %A Saleheen, Danish %A Sattar, Naveed %A Schadt, Eric E %A Schlessinger, David %A Slagboom, P Eline %A Snieder, Harold %A Spector, Tim D %A Thorsteinsdottir, Unnur %A Stumvoll, Michael %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van der Harst, Pim %A Walker, Mark %A Wallaschofski, Henri %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wichmann, H-Erich %A Wilson, James F %A Zanen, Pieter %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Heid, Iris M %A O'Connell, Jeffrey R %A Strachan, David P %A Stefansson, Kari %A van Duijn, Cornelia M %A Abecasis, Goncalo R %A Franke, Lude %A Frayling, Timothy M %A McCarthy, Mark I %A Visscher, Peter M %A Scherag, André %A Willer, Cristen J %A Boehnke, Michael %A Mohlke, Karen L %A Lindgren, Cecilia M %A Beckmann, Jacques S %A Barroso, Inês %A North, Kari E %A Ingelsson, Erik %A Hirschhorn, Joel N %A Loos, Ruth J F %A Speliotes, Elizabeth K %K Adipogenesis %K Adiposity %K Age Factors %K Body Mass Index %K Continental Population Groups %K Energy Metabolism %K Europe %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glutamic Acid %K Humans %K Insulin %K Male %K Obesity %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Synapses %X

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

%B Nature %V 518 %P 197-206 %8 2015 Feb 12 %G eng %N 7538 %1 http://www.ncbi.nlm.nih.gov/pubmed/25673413?dopt=Abstract %R 10.1038/nature14177 %0 Journal Article %J PLoS One %D 2015 %T Modulation of genetic associations with serum urate levels by body-mass-index in humans. %A Huffman, Jennifer E %A Albrecht, Eva %A Teumer, Alexander %A Mangino, Massimo %A Kapur, Karen %A Johnson, Toby %A Kutalik, Zoltán %A Pirastu, Nicola %A Pistis, Giorgio %A Lopez, Lorna M %A Haller, Toomas %A Salo, Perttu %A Goel, Anuj %A Li, Man %A Tanaka, Toshiko %A Dehghan, Abbas %A Ruggiero, Daniela %A Malerba, Giovanni %A Smith, Albert V %A Nolte, Ilja M %A Portas, Laura %A Phipps-Green, Amanda %A Boteva, Lora %A Navarro, Pau %A Johansson, Åsa %A Hicks, Andrew A %A Polasek, Ozren %A Esko, Tõnu %A Peden, John F %A Harris, Sarah E %A Murgia, Federico %A Wild, Sarah H %A Tenesa, Albert %A Tin, Adrienne %A Mihailov, Evelin %A Grotevendt, Anne %A Gislason, Gauti K %A Coresh, Josef %A d'Adamo, Pio %A Ulivi, Sheila %A Vollenweider, Peter %A Waeber, Gerard %A Campbell, Susan %A Kolcic, Ivana %A Fisher, Krista %A Viigimaa, Margus %A Metter, Jeffrey E %A Masciullo, Corrado %A Trabetti, Elisabetta %A Bombieri, Cristina %A Sorice, Rossella %A Döring, Angela %A Reischl, Eva %A Strauch, Konstantin %A Hofman, Albert %A Uitterlinden, André G %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Dalbeth, Nicola %A Stamp, Lisa %A Smit, Johannes H %A Kirin, Mirna %A Nagaraja, Ramaiah %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Farrington, Susan M %A Theodoratou, Evropi %A Jula, Antti %A Salomaa, Veikko %A Sala, Cinzia %A Hengstenberg, Christian %A Burnier, Michel %A Mägi, Reedik %A Klopp, Norman %A Kloiber, Stefan %A Schipf, Sabine %A Ripatti, Samuli %A Cabras, Stefano %A Soranzo, Nicole %A Homuth, Georg %A Nutile, Teresa %A Munroe, Patricia B %A Hastie, Nicholas %A Campbell, Harry %A Rudan, Igor %A Cabrera, Claudia %A Haley, Chris %A Franco, Oscar H %A Merriman, Tony R %A Gudnason, Vilmundur %A Pirastu, Mario %A Penninx, Brenda W %A Snieder, Harold %A Metspalu, Andres %A Ciullo, Marina %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Dunlop, Malcolm G %A Wilson, James F %A Gasparini, Paolo %A Gyllensten, Ulf %A Spector, Tim D %A Wright, Alan F %A Hayward, Caroline %A Watkins, Hugh %A Perola, Markus %A Bochud, Murielle %A Kao, W H Linda %A Caulfield, Mark %A Toniolo, Daniela %A Völzke, Henry %A Gieger, Christian %A Köttgen, Anna %A Vitart, Veronique %X

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

%B PLoS One %V 10 %P e0119752 %8 2015 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25811787?dopt=Abstract %R 10.1371/journal.pone.0119752 %0 Journal Article %J Nature %D 2015 %T New genetic loci link adipose and insulin biology to body fat distribution. %A Shungin, Dmitry %A Winkler, Thomas W %A Croteau-Chonka, Damien C %A Ferreira, Teresa %A Locke, Adam E %A Mägi, Reedik %A Strawbridge, Rona J %A Pers, Tune H %A Fischer, Krista %A Justice, Anne E %A Workalemahu, Tsegaselassie %A Wu, Joseph M W %A Buchkovich, Martin L %A Heard-Costa, Nancy L %A Roman, Tamara S %A Drong, Alexander W %A Song, Ci %A Gustafsson, Stefan %A Day, Felix R %A Esko, Tõnu %A Fall, Tove %A Kutalik, Zoltán %A Luan, Jian'an %A Randall, Joshua C %A Scherag, André %A Vedantam, Sailaja %A Wood, Andrew R %A Chen, Jin %A Fehrmann, Rudolf %A Karjalainen, Juha %A Kahali, Bratati %A Liu, Ching-Ti %A Schmidt, Ellen M %A Absher, Devin %A Amin, Najaf %A Anderson, Denise %A Beekman, Marian %A Bragg-Gresham, Jennifer L %A Buyske, Steven %A Demirkan, Ayse %A Ehret, Georg B %A Feitosa, Mary F %A Goel, Anuj %A Jackson, Anne U %A Johnson, Toby %A Kleber, Marcus E %A Kristiansson, Kati %A Mangino, Massimo %A Mateo Leach, Irene %A Medina-Gomez, Carolina %A Palmer, Cameron D %A Pasko, Dorota %A Pechlivanis, Sonali %A Peters, Marjolein J %A Prokopenko, Inga %A Stančáková, Alena %A Ju Sung, Yun %A Tanaka, Toshiko %A Teumer, Alexander %A Van Vliet-Ostaptchouk, Jana V %A Yengo, Loic %A Zhang, Weihua %A Albrecht, Eva %A Arnlöv, Johan %A Arscott, Gillian M %A Bandinelli, Stefania %A Barrett, Amy %A Bellis, Claire %A Bennett, Amanda J %A Berne, Christian %A Blüher, Matthias %A Böhringer, Stefan %A Bonnet, Fabrice %A Böttcher, Yvonne %A Bruinenberg, Marcel %A Carba, Delia B %A Caspersen, Ida H %A Clarke, Robert %A Daw, E Warwick %A Deelen, Joris %A Deelman, Ewa %A Delgado, Graciela %A Doney, Alex S F %A Eklund, Niina %A Erdos, Michael R %A Estrada, Karol %A Eury, Elodie %A Friedrich, Nele %A Garcia, Melissa E %A Giedraitis, Vilmantas %A Gigante, Bruna %A Go, Alan S %A Golay, Alain %A Grallert, Harald %A Grammer, Tanja B %A Gräßler, Jürgen %A Grewal, Jagvir %A Groves, Christopher J %A Haller, Toomas %A Hallmans, Goran %A Hartman, Catharina A %A Hassinen, Maija %A Hayward, Caroline %A Heikkilä, Kauko %A Herzig, Karl-Heinz %A Helmer, Quinta %A Hillege, Hans L %A Holmen, Oddgeir %A Hunt, Steven C %A Isaacs, Aaron %A Ittermann, Till %A James, Alan L %A Johansson, Ingegerd %A Juliusdottir, Thorhildur %A Kalafati, Ioanna-Panagiota %A Kinnunen, Leena %A Koenig, Wolfgang %A Kooner, Ishminder K %A Kratzer, Wolfgang %A Lamina, Claudia %A Leander, Karin %A Lee, Nanette R %A Lichtner, Peter %A Lind, Lars %A Lindström, Jaana %A Lobbens, Stéphane %A Lorentzon, Mattias %A Mach, François %A Magnusson, Patrik K E %A Mahajan, Anubha %A McArdle, Wendy L %A Menni, Cristina %A Merger, Sigrun %A Mihailov, Evelin %A Milani, Lili %A Mills, Rebecca %A Moayyeri, Alireza %A Monda, Keri L %A Mooijaart, Simon P %A Mühleisen, Thomas W %A Mulas, Antonella %A Müller, Gabriele %A Müller-Nurasyid, Martina %A Nagaraja, Ramaiah %A Nalls, Michael A %A Narisu, Narisu %A Glorioso, Nicola %A Nolte, Ilja M %A Olden, Matthias %A Rayner, Nigel W %A Renstrom, Frida %A Ried, Janina S %A Robertson, Neil R %A Rose, Lynda M %A Sanna, Serena %A Scharnagl, Hubert %A Scholtens, Salome %A Sennblad, Bengt %A Seufferlein, Thomas %A Sitlani, Colleen M %A Vernon Smith, Albert %A Stirrups, Kathleen %A Stringham, Heather M %A Sundström, Johan %A Swertz, Morris A %A Swift, Amy J %A Syvänen, Ann-Christine %A Tayo, Bamidele O %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tomaschitz, Andreas %A Troffa, Chiara %A van Oort, Floor V A %A Verweij, Niek %A Vonk, Judith M %A Waite, Lindsay L %A Wennauer, Roman %A Wilsgaard, Tom %A Wojczynski, Mary K %A Wong, Andrew %A Zhang, Qunyuan %A Hua Zhao, Jing %A Brennan, Eoin P %A Choi, Murim %A Eriksson, Per %A Folkersen, Lasse %A Franco-Cereceda, Anders %A Gharavi, Ali G %A Hedman, Åsa K %A Hivert, Marie-France %A Huang, Jinyan %A Kanoni, Stavroula %A Karpe, Fredrik %A Keildson, Sarah %A Kiryluk, Krzysztof %A Liang, Liming %A Lifton, Richard P %A Ma, Baoshan %A McKnight, Amy J %A McPherson, Ruth %A Metspalu, Andres %A Min, Josine L %A Moffatt, Miriam F %A Montgomery, Grant W %A Murabito, Joanne M %A Nicholson, George %A Nyholt, Dale R %A Olsson, Christian %A Perry, John R B %A Reinmaa, Eva %A Salem, Rany M %A Sandholm, Niina %A Schadt, Eric E %A Scott, Robert A %A Stolk, Lisette %A Vallejo, Edgar E %A Westra, Harm-Jan %A Zondervan, Krina T %A Amouyel, Philippe %A Arveiler, Dominique %A Bakker, Stephan J L %A Beilby, John %A Bergman, Richard N %A Blangero, John %A Brown, Morris J %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chines, Peter S %A Claudi-Boehm, Simone %A Collins, Francis S %A Crawford, Dana C %A Danesh, John %A de Faire, Ulf %A de Geus, Eco J C %A Dörr, Marcus %A Erbel, Raimund %A Eriksson, Johan G %A Farrall, Martin %A Ferrannini, Ele %A Ferrières, Jean %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Gansevoort, Ron T %A Gieger, Christian %A Gudnason, Vilmundur %A Haiman, Christopher A %A Harris, Tamara B %A Hattersley, Andrew T %A Heliövaara, Markku %A Hicks, Andrew A %A Hingorani, Aroon D %A Hoffmann, Wolfgang %A Hofman, Albert %A Homuth, Georg %A Humphries, Steve E %A Hyppönen, Elina %A Illig, Thomas %A Järvelin, Marjo-Riitta %A Johansen, Berit %A Jousilahti, Pekka %A Jula, Antti M %A Kaprio, Jaakko %A Kee, Frank %A Keinanen-Kiukaanniemi, Sirkka M %A Kooner, Jaspal S %A Kooperberg, Charles %A Kovacs, Peter %A Kraja, Aldi T %A Kumari, Meena %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Lakka, Timo A %A Langenberg, Claudia %A Le Marchand, Loic %A Lehtimäki, Terho %A Lyssenko, Valeriya %A Männistö, Satu %A Marette, André %A Matise, Tara C %A McKenzie, Colin A %A McKnight, Barbara %A Musk, Arthur W %A Möhlenkamp, Stefan %A Morris, Andrew D %A Nelis, Mari %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Ong, Ken K %A Palmer, Lyle J %A Penninx, Brenda W %A Peters, Annette %A Pramstaller, Peter P %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rice, Treva K %A Ridker, Paul M %A Ritchie, Marylyn D %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Saramies, Jouko %A Sarzynski, Mark A %A Schwarz, Peter E H %A Shuldiner, Alan R %A Staessen, Jan A %A Steinthorsdottir, Valgerdur %A Stolk, Ronald P %A Strauch, Konstantin %A Tönjes, Anke %A Tremblay, Angelo %A Tremoli, Elena %A Vohl, Marie-Claude %A Völker, Uwe %A Vollenweider, Peter %A Wilson, James F %A Witteman, Jacqueline C %A Adair, Linda S %A Bochud, Murielle %A Boehm, Bernhard O %A Bornstein, Stefan R %A Bouchard, Claude %A Cauchi, Stéphane %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Cooper, Richard S %A Dedoussis, George %A Ferrucci, Luigi %A Froguel, Philippe %A Grabe, Hans-Jörgen %A Hamsten, Anders %A Hui, Jennie %A Hveem, Kristian %A Jöckel, Karl-Heinz %A Kivimaki, Mika %A Kuh, Diana %A Laakso, Markku %A Liu, Yongmei %A März, Winfried %A Munroe, Patricia B %A Njølstad, Inger %A Oostra, Ben A %A Palmer, Colin N A %A Pedersen, Nancy L %A Perola, Markus %A Pérusse, Louis %A Peters, Ulrike %A Power, Chris %A Quertermous, Thomas %A Rauramaa, Rainer %A Rivadeneira, Fernando %A Saaristo, Timo E %A Saleheen, Danish %A Sinisalo, Juha %A Slagboom, P Eline %A Snieder, Harold %A Spector, Tim D %A Thorsteinsdottir, Unnur %A Stumvoll, Michael %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van der Harst, Pim %A Veronesi, Giovanni %A Walker, Mark %A Wareham, Nicholas J %A Watkins, Hugh %A Wichmann, H-Erich %A Abecasis, Goncalo R %A Assimes, Themistocles L %A Berndt, Sonja I %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Franke, Lude %A Frayling, Timothy M %A Groop, Leif C %A Hunter, David J %A Kaplan, Robert C %A O'Connell, Jeffrey R %A Qi, Lu %A Schlessinger, David %A Strachan, David P %A Stefansson, Kari %A van Duijn, Cornelia M %A Willer, Cristen J %A Visscher, Peter M %A Yang, Jian %A Hirschhorn, Joel N %A Zillikens, M Carola %A McCarthy, Mark I %A Speliotes, Elizabeth K %A North, Kari E %A Fox, Caroline S %A Barroso, Inês %A Franks, Paul W %A Ingelsson, Erik %A Heid, Iris M %A Loos, Ruth J F %A Cupples, L Adrienne %A Morris, Andrew P %A Lindgren, Cecilia M %A Mohlke, Karen L %K Adipocytes %K Adipogenesis %K Adipose Tissue %K Age Factors %K Body Fat Distribution %K Body Mass Index %K Continental Population Groups %K Epigenesis, Genetic %K Europe %K Female %K Genome, Human %K Genome-Wide Association Study %K Humans %K Insulin %K Insulin Resistance %K Male %K Models, Biological %K Neovascularization, Physiologic %K Obesity %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Sex Characteristics %K Transcription, Genetic %K Waist-Hip Ratio %X

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

%B Nature %V 518 %P 187-96 %8 2015 Feb 12 %G eng %N 7538 %1 http://www.ncbi.nlm.nih.gov/pubmed/25673412?dopt=Abstract %R 10.1038/nature14132 %0 Journal Article %J Nat Genet %D 2014 %T Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. %A Arking, Dan E %A Pulit, Sara L %A Crotti, Lia %A van der Harst, Pim %A Munroe, Patricia B %A Koopmann, Tamara T %A Sotoodehnia, Nona %A Rossin, Elizabeth J %A Morley, Michael %A Wang, Xinchen %A Johnson, Andrew D %A Lundby, Alicia %A Gudbjartsson, Daniel F %A Noseworthy, Peter A %A Eijgelsheim, Mark %A Bradford, Yuki %A Tarasov, Kirill V %A Dörr, Marcus %A Müller-Nurasyid, Martina %A Lahtinen, Annukka M %A Nolte, Ilja M %A Smith, Albert Vernon %A Bis, Joshua C %A Isaacs, Aaron %A Newhouse, Stephen J %A Evans, Daniel S %A Post, Wendy S %A Waggott, Daryl %A Lyytikäinen, Leo-Pekka %A Hicks, Andrew A %A Eisele, Lewin %A Ellinghaus, David %A Hayward, Caroline %A Navarro, Pau %A Ulivi, Sheila %A Tanaka, Toshiko %A Tester, David J %A Chatel, Stéphanie %A Gustafsson, Stefan %A Kumari, Meena %A Morris, Richard W %A Naluai, Åsa T %A Padmanabhan, Sandosh %A Kluttig, Alexander %A Strohmer, Bernhard %A Panayiotou, Andrie G %A Torres, Maria %A Knoflach, Michael %A Hubacek, Jaroslav A %A Slowikowski, Kamil %A Raychaudhuri, Soumya %A Kumar, Runjun D %A Harris, Tamara B %A Launer, Lenore J %A Shuldiner, Alan R %A Alonso, Alvaro %A Bader, Joel S %A Ehret, Georg %A Huang, Hailiang %A Kao, W H Linda %A Strait, James B %A Macfarlane, Peter W %A Brown, Morris %A Caulfield, Mark J %A Samani, Nilesh J %A Kronenberg, Florian %A Willeit, Johann %A Smith, J Gustav %A Greiser, Karin H %A Meyer Zu Schwabedissen, Henriette %A Werdan, Karl %A Carella, Massimo %A Zelante, Leopoldo %A Heckbert, Susan R %A Psaty, Bruce M %A Rotter, Jerome I %A Kolcic, Ivana %A Polasek, Ozren %A Wright, Alan F %A Griffin, Maura %A Daly, Mark J %A Arnar, David O %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Denny, Joshua C %A Roden, Dan M %A Zuvich, Rebecca L %A Emilsson, Valur %A Plump, Andrew S %A Larson, Martin G %A O'Donnell, Christopher J %A Yin, Xiaoyan %A Bobbo, Marco %A d'Adamo, Adamo P %A Iorio, Annamaria %A Sinagra, Gianfranco %A Carracedo, Angel %A Cummings, Steven R %A Nalls, Michael A %A Jula, Antti %A Kontula, Kimmo K %A Marjamaa, Annukka %A Oikarinen, Lasse %A Perola, Markus %A Porthan, Kimmo %A Erbel, Raimund %A Hoffmann, Per %A Jöckel, Karl-Heinz %A Kälsch, Hagen %A Nöthen, Markus M %A den Hoed, Marcel %A Loos, Ruth J F %A Thelle, Dag S %A Gieger, Christian %A Meitinger, Thomas %A Perz, Siegfried %A Peters, Annette %A Prucha, Hanna %A Sinner, Moritz F %A Waldenberger, Melanie %A de Boer, Rudolf A %A Franke, Lude %A van der Vleuten, Pieter A %A Beckmann, Britt Maria %A Martens, Eimo %A Bardai, Abdennasser %A Hofman, Nynke %A Wilde, Arthur A M %A Behr, Elijah R %A Dalageorgou, Chrysoula %A Giudicessi, John R %A Medeiros-Domingo, Argelia %A Barc, Julien %A Kyndt, Florence %A Probst, Vincent %A Ghidoni, Alice %A Insolia, Roberto %A Hamilton, Robert M %A Scherer, Stephen W %A Brandimarto, Jeffrey %A Margulies, Kenneth %A Moravec, Christine E %A del Greco M, Fabiola %A Fuchsberger, Christian %A O'Connell, Jeffrey R %A Lee, Wai K %A Watt, Graham C M %A Campbell, Harry %A Wild, Sarah H %A El Mokhtari, Nour E %A Frey, Norbert %A Asselbergs, Folkert W %A Mateo Leach, Irene %A Navis, Gerjan %A van den Berg, Maarten P %A van Veldhuisen, Dirk J %A Kellis, Manolis %A Krijthe, Bouwe P %A Franco, Oscar H %A Hofman, Albert %A Kors, Jan A %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Kedenko, Lyudmyla %A Lamina, Claudia %A Oostra, Ben A %A Abecasis, Goncalo R %A Lakatta, Edward G %A Mulas, Antonella %A Orru, Marco %A Schlessinger, David %A Uda, Manuela %A Markus, Marcello R P %A Völker, Uwe %A Snieder, Harold %A Spector, Timothy D %A Arnlöv, Johan %A Lind, Lars %A Sundström, Johan %A Syvänen, Ann-Christine %A Kivimaki, Mika %A Kähönen, Mika %A Mononen, Nina %A Raitakari, Olli T %A Viikari, Jorma S %A Adamkova, Vera %A Kiechl, Stefan %A Brion, Maria %A Nicolaides, Andrew N %A Paulweber, Bernhard %A Haerting, Johannes %A Dominiczak, Anna F %A Nyberg, Fredrik %A Whincup, Peter H %A Hingorani, Aroon D %A Schott, Jean-Jacques %A Bezzina, Connie R %A Ingelsson, Erik %A Ferrucci, Luigi %A Gasparini, Paolo %A Wilson, James F %A Rudan, Igor %A Franke, Andre %A Mühleisen, Thomas W %A Pramstaller, Peter P %A Lehtimäki, Terho J %A Paterson, Andrew D %A Parsa, Afshin %A Liu, Yongmei %A van Duijn, Cornelia M %A Siscovick, David S %A Gudnason, Vilmundur %A Jamshidi, Yalda %A Salomaa, Veikko %A Felix, Stephan B %A Sanna, Serena %A Ritchie, Marylyn D %A Stricker, Bruno H %A Stefansson, Kari %A Boyer, Laurie A %A Cappola, Thomas P %A Olsen, Jesper V %A Lage, Kasper %A Schwartz, Peter J %A Kääb, Stefan %A Chakravarti, Aravinda %A Ackerman, Michael J %A Pfeufer, Arne %A de Bakker, Paul I W %A Newton-Cheh, Christopher %K Adult %K Aged %K Arrhythmias, Cardiac %K Calcium Signaling %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Ventricles %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Myocardium %K Polymorphism, Single Nucleotide %X

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

%B Nat Genet %V 46 %P 826-36 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract %R 10.1038/ng.3014 %0 Journal Article %J Nat Genet %D 2013 %T Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. %A Köttgen, Anna %A Albrecht, Eva %A Teumer, Alexander %A Vitart, Veronique %A Krumsiek, Jan %A Hundertmark, Claudia %A Pistis, Giorgio %A Ruggiero, Daniela %A O'Seaghdha, Conall M %A Haller, Toomas %A Yang, Qiong %A Tanaka, Toshiko %A Johnson, Andrew D %A Kutalik, Zoltán %A Smith, Albert V %A Shi, Julia %A Struchalin, Maksim %A Middelberg, Rita P S %A Brown, Morris J %A Gaffo, Angelo L %A Pirastu, Nicola %A Li, Guo %A Hayward, Caroline %A Zemunik, Tatijana %A Huffman, Jennifer %A Yengo, Loic %A Zhao, Jing Hua %A Demirkan, Ayse %A Feitosa, Mary F %A Liu, Xuan %A Malerba, Giovanni %A Lopez, Lorna M %A van der Harst, Pim %A Li, Xinzhong %A Kleber, Marcus E %A Hicks, Andrew A %A Nolte, Ilja M %A Johansson, Åsa %A Murgia, Federico %A Wild, Sarah H %A Bakker, Stephan J L %A Peden, John F %A Dehghan, Abbas %A Steri, Maristella %A Tenesa, Albert %A Lagou, Vasiliki %A Salo, Perttu %A Mangino, Massimo %A Rose, Lynda M %A Lehtimäki, Terho %A Woodward, Owen M %A Okada, Yukinori %A Tin, Adrienne %A Müller, Christian %A Oldmeadow, Christopher %A Putku, Margus %A Czamara, Darina %A Kraft, Peter %A Frogheri, Laura %A Thun, Gian Andri %A Grotevendt, Anne %A Gislason, Gauti Kjartan %A Harris, Tamara B %A Launer, Lenore J %A McArdle, Patrick %A Shuldiner, Alan R %A Boerwinkle, Eric %A Coresh, Josef %A Schmidt, Helena %A Schallert, Michael %A Martin, Nicholas G %A Montgomery, Grant W %A Kubo, Michiaki %A Nakamura, Yusuke %A Tanaka, Toshihiro %A Munroe, Patricia B %A Samani, Nilesh J %A Jacobs, David R %A Liu, Kiang %A d'Adamo, Pio %A Ulivi, Sheila %A Rotter, Jerome I %A Psaty, Bruce M %A Vollenweider, Peter %A Waeber, Gerard %A Campbell, Susan %A Devuyst, Olivier %A Navarro, Pau %A Kolcic, Ivana %A Hastie, Nicholas %A Balkau, Beverley %A Froguel, Philippe %A Esko, Tõnu %A Salumets, Andres %A Khaw, Kay Tee %A Langenberg, Claudia %A Wareham, Nicholas J %A Isaacs, Aaron %A Kraja, Aldi %A Zhang, Qunyuan %A Wild, Philipp S %A Scott, Rodney J %A Holliday, Elizabeth G %A Org, Elin %A Viigimaa, Margus %A Bandinelli, Stefania %A Metter, Jeffrey E %A Lupo, Antonio %A Trabetti, Elisabetta %A Sorice, Rossella %A Döring, Angela %A Lattka, Eva %A Strauch, Konstantin %A Theis, Fabian %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Bruinenberg, Marcel %A Stolk, Ronald P %A Kooner, Jaspal S %A Zhang, Weihua %A Winkelmann, Bernhard R %A Boehm, Bernhard O %A Lucae, Susanne %A Penninx, Brenda W %A Smit, Johannes H %A Curhan, Gary %A Mudgal, Poorva %A Plenge, Robert M %A Portas, Laura %A Persico, Ivana %A Kirin, Mirna %A Wilson, James F %A Mateo Leach, Irene %A van Gilst, Wiek H %A Goel, Anuj %A Ongen, Halit %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Imboden, Medea %A von Eckardstein, Arnold %A Cucca, Francesco %A Nagaraja, Ramaiah %A Piras, Maria Grazia %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Ernst, Florian %A Farrington, Susan M %A Theodoratou, Evropi %A Prokopenko, Inga %A Stumvoll, Michael %A Jula, Antti %A Perola, Markus %A Salomaa, Veikko %A Shin, So-Youn %A Spector, Tim D %A Sala, Cinzia %A Ridker, Paul M %A Kähönen, Mika %A Viikari, Jorma %A Hengstenberg, Christian %A Nelson, Christopher P %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Singleton, Andrew B %A Kamatani, Naoyuki %A Zeller, Tanja %A Burnier, Michel %A Attia, John %A Laan, Maris %A Klopp, Norman %A Hillege, Hans L %A Kloiber, Stefan %A Choi, Hyon %A Pirastu, Mario %A Tore, Silvia %A Probst-Hensch, Nicole M %A Völzke, Henry %A Gudnason, Vilmundur %A Parsa, Afshin %A Schmidt, Reinhold %A Whitfield, John B %A Fornage, Myriam %A Gasparini, Paolo %A Siscovick, David S %A Polasek, Ozren %A Campbell, Harry %A Rudan, Igor %A Bouatia-Naji, Nabila %A Metspalu, Andres %A Loos, Ruth J F %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Wolffenbuttel, Bruce H R %A Chambers, John C %A März, Winfried %A Pramstaller, Peter P %A Snieder, Harold %A Gyllensten, Ulf %A Wright, Alan F %A Navis, Gerjan %A Watkins, Hugh %A Witteman, Jacqueline C M %A Sanna, Serena %A Schipf, Sabine %A Dunlop, Malcolm G %A Tönjes, Anke %A Ripatti, Samuli %A Soranzo, Nicole %A Toniolo, Daniela %A Chasman, Daniel I %A Raitakari, Olli %A Kao, W H Linda %A Ciullo, Marina %A Fox, Caroline S %A Caulfield, Mark %A Bochud, Murielle %A Gieger, Christian %K Analysis of Variance %K European Continental Ancestry Group %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Glucose %K Gout %K Humans %K Inhibins %K Polymorphism, Single Nucleotide %K Signal Transduction %K Uric Acid %X

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

%B Nat Genet %V 45 %P 145-54 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract %R 10.1038/ng.2500 %0 Journal Article %J PLoS Genet %D 2012 %T Evidence of inbreeding depression on human height. %A McQuillan, Ruth %A Eklund, Niina %A Pirastu, Nicola %A Kuningas, Maris %A McEvoy, Brian P %A Esko, Tõnu %A Corre, Tanguy %A Davies, Gail %A Kaakinen, Marika %A Lyytikäinen, Leo-Pekka %A Kristiansson, Kati %A Havulinna, Aki S %A Gögele, Martin %A Vitart, Veronique %A Tenesa, Albert %A Aulchenko, Yurii %A Hayward, Caroline %A Johansson, Åsa %A Boban, Mladen %A Ulivi, Sheila %A Robino, Antonietta %A Boraska, Vesna %A Igl, Wilmar %A Wild, Sarah H %A Zgaga, Lina %A Amin, Najaf %A Theodoratou, Evropi %A Polasek, Ozren %A Girotto, Giorgia %A Lopez, Lorna M %A Sala, Cinzia %A Lahti, Jari %A Laatikainen, Tiina %A Prokopenko, Inga %A Kals, Mart %A Viikari, Jorma %A Yang, Jian %A Pouta, Anneli %A Estrada, Karol %A Hofman, Albert %A Freimer, Nelson %A Martin, Nicholas G %A Kähönen, Mika %A Milani, Lili %A Heliövaara, Markku %A Vartiainen, Erkki %A Räikkönen, Katri %A Masciullo, Corrado %A Starr, John M %A Hicks, Andrew A %A Esposito, Laura %A Kolcic, Ivana %A Farrington, Susan M %A Oostra, Ben %A Zemunik, Tatijana %A Campbell, Harry %A Kirin, Mirna %A Pehlic, Marina %A Faletra, Flavio %A Porteous, David %A Pistis, Giorgio %A Widen, Elisabeth %A Salomaa, Veikko %A Koskinen, Seppo %A Fischer, Krista %A Lehtimäki, Terho %A Heath, Andrew %A McCarthy, Mark I %A Rivadeneira, Fernando %A Montgomery, Grant W %A Tiemeier, Henning %A Hartikainen, Anna-Liisa %A Madden, Pamela A F %A d'Adamo, Pio %A Hastie, Nicholas D %A Gyllensten, Ulf %A Wright, Alan F %A van Duijn, Cornelia M %A Dunlop, Malcolm %A Rudan, Igor %A Gasparini, Paolo %A Pramstaller, Peter P %A Deary, Ian J %A Toniolo, Daniela %A Eriksson, Johan G %A Jula, Antti %A Raitakari, Olli T %A Metspalu, Andres %A Perola, Markus %A Järvelin, Marjo-Riitta %A Uitterlinden, André %A Visscher, Peter M %A Wilson, James F %K Adult %K Aged %K Body Height %K Consanguinity %K Databases, Genetic %K Family %K Female %K Genes, Recessive %K Genetic Heterogeneity %K Genome-Wide Association Study %K Homozygote %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait, Heritable %X

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

%B PLoS Genet %V 8 %P e1002655 %8 2012 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22829771?dopt=Abstract %R 10.1371/journal.pgen.1002655