Author: "Marco, Brumat" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Marco, Brumat"' showing total 36 results

Start Over Author "Marco, Brumat"

36 results on '"Marco, Brumat"'

1. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Author: Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brüning, Thomas, Buring, Julie E, Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J, Cousminer, Diana L, Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eriksson, Johan G, Fasching, Peter A, Fernández-Rhodes, Lindsay, Ferrucci, Luigi, Flesch-Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Guénel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B, Hartman, Catharina A, Heiss, Gerardo, Hooning, Maartje J, Hopper, John L, Hu, Frank, Hunter, David J, Ikram, M Arfan, Im, Hae Kyung, Järvelin, Marjo-Riitta, Joshi, Peter K, Karasik, David, and Kellis, Manolis
Subjects: LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Humans, Neoplasms, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Ribonucleoproteins, Membrane Proteins, Body Mass Index, Risk Factors, Age Factors, Genomic Imprinting, Puberty, Menarche, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Databases, Genetic, Adolescent, Female, Male, Genome-Wide Association Study, Aging, Breast Cancer, Biotechnology, Cancer, Human Genome, Genetics, Prostate Cancer, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
Published: 2017

2. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author: Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
Subjects: Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract: Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Published: 2023

3. Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Author: Andries Paul Nagtegaal, Linda Broer, Nuno R. Zilhao, Johanna Jakobsdottir, Charles E. Bishop, Marco Brumat, Mark W. Christiansen, Massimiliano Cocca, Yan Gao, Nancy L. Heard-Costa, Daniel S. Evans, Nathan Pankratz, Sheila R. Pratt, T. Ryan Price, Christopher Spankovich, Mary R. Stimson, Karen Valle, Dragana Vuckovic, Helena Wells, Gudny Eiriksdottir, Erik Fransen, Mohammad Arfan Ikram, Chuang-Ming Li, W. T. Longstreth, Claire Steves, Guy Van Camp, Adolfo Correa, Karen J. Cruickshanks, Paolo Gasparini, Giorgia Girotto, Robert C. Kaplan, Michael Nalls, John M. Schweinfurth, Sudha Seshadri, Nona Sotoodehnia, Gregory J. Tranah, André G. Uitterlinden, James G. Wilson, Vilmundur Gudnason, Howard J. Hoffman, Frances M. K. Williams, and André Goedegebure
Subjects: Medicine, Science
Abstract: Abstract Previous research has shown that genes play a substantial role in determining a person’s susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.
Published: 2019
Full Text: View/download PDF

4. Associations of autozygosity with a broad range of human phenotypes

Author: David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson
Subjects: Science
Abstract: Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.
Published: 2019
Full Text: View/download PDF

5. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author: Tuomas O. Kilpeläinen, Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa de las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. Musani, Melissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii-Der Ida Chen, Maria Pina Concas, John Connell, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Lifelines Cohort Study, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau van der Ende, Diana van Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf de Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim van der Harst, Jana V. Van Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. van Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. van Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao, and Ruth J. F. Loos
Subjects: Science
Abstract: GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.
Published: 2019
Full Text: View/download PDF

6. Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway

Author: Anna Rita Fetoni, Veronica Zorzi, Fabiola Paciello, Gaia Ziraldo, Chiara Peres, Marcello Raspa, Ferdinando Scavizzi, Anna Maria Salvatore, Giulia Crispino, Gabriella Tognola, Giulia Gentile, Antonio Gianmaria Spampinato, Denis Cuccaro, Maria Guarnaccia, Giovanna Morello, Guy Van Camp, Erik Fransen, Marco Brumat, Giorgia Girotto, Gaetano Paludetti, Paolo Gasparini, Sebastiano Cavallaro, and Fabio Mammano
Subjects: Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/− mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/− mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/− mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10−2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis. Keywords: Age-related hearing loss, Connexin 26, Mouse models, Genome-wide association study, Hair cells, Spiral ganglion neurons
Published: 2018
Full Text: View/download PDF

7. Next Generation Sequencing and Animal Models Reveal SLC9A3R1 as a New Gene Involved in Human Age-Related Hearing Loss

Author: Giorgia Girotto, Anna Morgan, Navaneethakrishnan Krishnamoorthy, Massimiliano Cocca, Marco Brumat, Sissy Bassani, Martina La Bianca, Mariateresa Di Stazio, and Paolo Gasparini
Subjects: hearing loss, new gene discovery, zebrafish model, CRISPR-Cas9, next-generation sequencing, Genetics, QH426-470
Abstract: Age-related hearing loss (ARHL) is the most common sensory impairment in the elderly affecting millions of people worldwide. To shed light on the genetics of ARHL, a large cohort of 464 Italian patients has been deeply characterized at clinical and molecular level. In particular, 46 candidate genes, selected on the basis of genome-wide association studies (GWAS), animal models and literature updates, were analyzed by targeted re-sequencing. After filtering and prioritization steps, SLC9A3R1 has been identified as a strong candidate and then validated by “in vitro” and “in vivo” studies. Briefly, a rare (MAF: 2.886e-5) missense variant c.539G > A, p.(R180Q) was detected in two unrelated male patients affected by ARHL characterized by a severe to profound high-frequency hearing loss. The variant, predicted as damaging, was not present in healthy matched controls. Protein modeling confirmed the pathogenic effect of p.(R180Q) variant on protein’s structure leading to a change in the total number of hydrogen bonds. In situ hybridization showed slc9a3r1 expression in zebrafish inner ear. A zebrafish knock-in model, generated by CRISPR-Cas9 technology, revealed a reduced auditory response at all frequencies in slc9a3r1R180Q/R180Q mutants compared to slc9a3r1+/+ and slc9a3r1+/R180Q animals. Moreover, a significant reduction (5.8%) in the total volume of the saccular otolith (which is responsible for sound detection) was observed in slc9a3r1R180Q/R180Q compared to slc9a3r1+/+ (P = 0.0014), while the utricular otolith, necessary for balance, was not affected in agreement with the human phenotype. Overall, these data strongly support the role of SLC9A3R1 gene in the pathogenesis of ARHL opening new perspectives in terms of diagnosis, prevention and treatment.
Published: 2019
Full Text: View/download PDF

8. Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations

Author: Anna Morgan, Stefania Lenarduzzi, Stefania Cappellani, Vanna Pecile, Marcello Morgutti, Eva Orzan, Sara Ghiselli, Umberto Ambrosetti, Marco Brumat, Poornima Gajendrarao, Martina La Bianca, Flavio Faletra, Enrico Grosso, Fabio Sirchia, Alberto Sensi, Claudio Graziano, Marco Seri, Paolo Gasparini, and Giorgia Girotto
Subjects: targeted re-sequencing, SNP arrays, hereditary hearing loss, italian families, molecular diagnosis, Genetics, QH426-470
Abstract: Hereditary hearing loss (HHL) is a common disorder characterized by a huge genetic heterogeneity. The definition of a correct molecular diagnosis is essential for proper genetic counseling, recurrence risk estimation, and therapeutic options. From 20 to 40% of patients carry mutations in GJB2 gene, thus, in more than half of cases it is necessary to look for causative variants in the other genes so far identified (~100). In this light, the use of next-generation sequencing technologies has proved to be the best solution for mutational screening, even though it is not always conclusive. Here we describe a combined approach, based on targeted re-sequencing (TRS) of 96 HHL genes followed by high-density SNP arrays, aimed at the identification of the molecular causes of non-syndromic HHL (NSHL). This strategy has been applied to study 103 Italian unrelated cases, negative for mutations in GJB2, and led to the characterization of 31% of them (i.e., 37% of familial and 26.3% of sporadic cases). In particular, TRS revealed TECTA and ACTG1 genes as major players in the Italian population. Furthermore, two de novo missense variants in ACTG1 have been identified and investigated through protein modeling and molecular dynamics simulations, confirming their likely pathogenic effect. Among the selected patients analyzed by SNP arrays (negative to TRS, or with a single variant in a recessive gene) a molecular diagnosis was reached in ~36% of cases, highlighting the importance to look for large insertions/deletions. Moreover, copy number variants analysis led to the identification of the first case of uniparental disomy involving LOXHD1 gene. Overall, taking into account the contribution of GJB2, plus the results from TRS and SNP arrays, it was possible to reach a molecular diagnosis in ~51% of NSHL cases. These data proved the usefulness of a combined approach for the analysis of NSHL and for the definition of the epidemiological picture of HHL in the Italian population.
Published: 2018
Full Text: View/download PDF

9. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Author: Mary F Feitosa, Aldi T Kraja, Daniel I Chasman, Yun J Sung, Thomas W Winkler, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K Musani, Changwei Li, Amy R Bentley, Michael R Brown, Karen Schwander, Melissa A Richard, Raymond Noordam, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Rajkumar Dorajoo, Virginia Fisher, Fernando P Hartwig, Andrea R V R Horimoto, Kurt K Lohman, Alisa K Manning, Tuomo Rankinen, Albert V Smith, Salman M Tajuddin, Mary K Wojczynski, Maris Alver, Mathilde Boissel, Qiuyin Cai, Archie Campbell, Jin Fang Chai, Xu Chen, Jasmin Divers, Chuan Gao, Anuj Goel, Yanick Hagemeijer, Sarah E Harris, Meian He, Fang-Chi Hsu, Anne U Jackson, Mika Kähönen, Anuradhani Kasturiratne, Pirjo Komulainen, Brigitte Kühnel, Federica Laguzzi, Jian'an Luan, Nana Matoba, Ilja M Nolte, Sandosh Padmanabhan, Muhammad Riaz, Rico Rueedi, Antonietta Robino, M Abdullah Said, Robert A Scott, Tamar Sofer, Alena Stančáková, Fumihiko Takeuchi, Bamidele O Tayo, Peter J van der Most, Tibor V Varga, Veronique Vitart, Yajuan Wang, Erin B Ware, Helen R Warren, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Najaf Amin, Marzyeh Amini, Dan E Arking, Tin Aung, Eric Boerwinkle, Ingrid Borecki, Ulrich Broeckel, Morris Brown, Marco Brumat, Gregory L Burke, Mickaël Canouil, Aravinda Chakravarti, Sabanayagam Charumathi, Yii-Der Ida Chen, John M Connell, Adolfo Correa, Lisa de Las Fuentes, Renée de Mutsert, H Janaka de Silva, Xuan Deng, Jingzhong Ding, Qing Duan, Charles B Eaton, Georg Ehret, Ruben N Eppinga, Evangelos Evangelou, Jessica D Faul, Stephan B Felix, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Yechiel Friedlander, Ilaria Gandin, He Gao, Mohsen Ghanbari, Bruna Gigante, C Charles Gu, Dongfeng Gu, Saskia P Hagenaars, Göran Hallmans, Tamara B Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Barbara V Howard, M Arfan Ikram, InterAct Consortium, Ulrich John, Tomohiro Katsuya, Chiea Chuen Khor, Tuomas O Kilpeläinen, Woon-Puay Koh, José E Krieger, Stephen B Kritchevsky, Michiaki Kubo, Johanna Kuusisto, Timo A Lakka, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Benjamin Lehne, Cora E Lewis, Yize Li, Shiow Lin, Jianjun Liu, Jingmin Liu, Marie Loh, Tin Louie, Reedik Mägi, Colin A McKenzie, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Lili Milani, Karen L Mohlke, Yukihide Momozawa, Mike A Nalls, Christopher P Nelson, Nona Sotoodehnia, Jill M Norris, Jeff R O'Connell, Nicholette D Palmer, Thomas Perls, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Neil Poulter, Leslie J Raffel, Olli T Raitakari, Kathryn Roll, Lynda M Rose, Frits R Rosendaal, Jerome I Rotter, Carsten O Schmidt, Pamela J Schreiner, Nicole Schupf, William R Scott, Peter S Sever, Yuan Shi, Stephen Sidney, Mario Sims, Colleen M Sitlani, Jennifer A Smith, Harold Snieder, John M Starr, Konstantin Strauch, Heather M Stringham, Nicholas Y Q Tan, Hua Tang, Kent D Taylor, Yik Ying Teo, Yih Chung Tham, Stephen T Turner, André G Uitterlinden, Peter Vollenweider, Melanie Waldenberger, Lihua Wang, Ya Xing Wang, Wen Bin Wei, Christine Williams, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B Zonderman, Diane M Becker, Michael Boehnke, Donald W Bowden, John C Chambers, Ian J Deary, Tõnu Esko, Martin Farrall, Paul W Franks, Barry I Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Jost Bruno Jonas, Yoichiro Kamatani, Norihiro Kato, Jaspal S Kooner, Zoltán Kutalik, Markku Laakso, Cathy C Laurie, Karin Leander, Terho Lehtimäki, Lifelines Cohort Study, Patrik K E Magnusson, Albertine J Oldehinkel, Brenda W J H Penninx, Ozren Polasek, David J Porteous, Rainer Rauramaa, Nilesh J Samani, James Scott, Xiao-Ou Shu, Pim van der Harst, Lynne E Wagenknecht, Nicholas J Wareham, Hugh Watkins, David R Weir, Ananda R Wickremasinghe, Tangchun Wu, Wei Zheng, Claude Bouchard, Kaare Christensen, Michele K Evans, Vilmundur Gudnason, Bernardo L Horta, Sharon L R Kardia, Yongmei Liu, Alexandre C Pereira, Bruce M Psaty, Paul M Ridker, Rob M van Dam, W James Gauderman, Xiaofeng Zhu, Dennis O Mook-Kanamori, Myriam Fornage, Charles N Rotimi, L Adrienne Cupples, Tanika N Kelly, Ervin R Fox, Caroline Hayward, Cornelia M van Duijn, E Shyong Tai, Tien Yin Wong, Charles Kooperberg, Walter Palmas, Kenneth Rice, Alanna C Morrison, Paul Elliott, Mark J Caulfield, Patricia B Munroe, Dabeeru C Rao, Michael A Province, and Daniel Levy
Subjects: Medicine, Science
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
Published: 2018
Full Text: View/download PDF

10. F cell numbers are associated with an X‐linked genetic polymorphism and correlate with haematological parameters in patients with sickle cell disease

Author: Upendo Masamu, Helen Rooks, Ted Mselle, Florence Urio, Siana Nkya, Stephan Menzel, Julie Makani, Marco Brumat, Bruno Mmbando, Lucio Luzzatto, Raphael Z. Sangeda, and Josephine Mgaya
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Reticulocytes, Adolescent, Cell, Erythrocytes, Abnormal, Single-nucleotide polymorphism, Locus (genetics), Anemia, Sickle Cell, Disease, Biology, 03 medical and health sciences, 0302 clinical medicine, Genes, X-Linked, hemic and lymphatic diseases, Internal medicine, medicine, Humans, SNP, Child, Chromosomes, Human, X, Polymorphism, Genetic, Red Cell, Hematology, Middle Aged, medicine.disease, Lymphoma, Repressor Proteins, medicine.anatomical_structure, Endocrinology, Child, Preschool, 030220 oncology & carcinogenesis, Chromosomal region, Female, 030215 immunology
Abstract: Patients with sickle cell disease (SCD) with high fetal haemoglobin (HbF) tend to have a lower incidence of complications and longer survival due to inhibition of deoxyhaemoglobin S (HbS) polymerisation by HbF. HbF-containing cells, namely F cells, are strongly influenced by genetic factors. We measured the percentage of F cells (Fcells%) in 222 patients with SCD to evaluate the association of (i) Fcells% with genetic HbF-modifier variants and (ii) Fcells% with haematological parameters. There was a different distribution of Fcells% in females compared to males. The association of the B-cell lymphoma/leukaemia 11A (BCL11A) locus with Fcells% (β = 8·238; P < 0·001) and with HbF% (β = 2·490; P < 0·001) was significant. All red cell parameters except for Hb and mean corpuscular Hb concentration levels in males and females were significantly different. The Fcells% was positively associated with mean cell Hb, mean cell volume and reticulocytes. To explain the significant gender difference in Fcells%, we tested for associations with single nucleotide polymorphisms on the X chromosomal region Xp22.2, where a genetic determinant of HbF had been previously hypothesised. We found in males a significant association with a SNP in FERM and PDZ domain-containing protein 4 (FRMPD4) and adjacent to male-specific lethal complex subunit 3 (MSL3). Thus, we have identified an X-linked locus that could account for a significant fraction of the Fcells% variation in patients with SCD.
Published: 2020

11. Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Author: Adolfo Correa, Dragana Vuckovic, Chuang Ming Li, Sheila R. Pratt, Vilmundur Gudnason, Robert C. Kaplan, Massimiliano Cocca, Giorgia Girotto, Frances M K Williams, Nona Sotoodehnia, Christopher Spankovich, T. Ryan Price, Charles E. Bishop, Johanna Jakobsdottir, W. T. Longstreth, Howard J. Hoffman, Karen Valle, Mark W. Christiansen, Erik Fransen, Helena R R Wells, John M. Schweinfurth, André G. Uitterlinden, Mohammad Arfan Ikram, Guy Van Camp, Daniel S. Evans, Paolo Gasparini, Linda Broer, Gregory J. Tranah, Marco Brumat, Andries Paul Nagtegaal, Mike A. Nalls, Mary Rachel Stimson, Sudha Seshadri, Gudny Eiriksdottir, Karen J. Cruickshanks, Yan Gao, Nancy L. Heard-Costa, Nuno R. Zilhão, James G. Wilson, Nathan Pankratz, André Goedegebure, Claire J. Steves, Otorhinolaryngology and Head and Neck Surgery, Internal Medicine, Epidemiology, Nagtegaal, A. P., Broer, L., Zilhao, N. R., Jakobsdottir, J., Bishop, C. E., Brumat, M., Christiansen, M. W., Cocca, M., Gao, Y., Heard-Costa, N. L., Evans, D. S., Pankratz, N., Pratt, S. R., Price, T. R., Spankovich, C., Stimson, M. R., Valle, K., Vuckovic, D., Wells, H., Eiriksdottir, G., Fransen, E., Ikram, M. A., Li, C. -M., Longstreth, W. T., Steves, C., Van Camp, G., Correa, A., Cruickshanks, K. J., Gasparini, P., Girotto, G., Kaplan, R. C., Nalls, M., Schweinfurth, J. M., Seshadri, S., Sotoodehnia, N., Tranah, G. J., Uitterlinden, A. G., Wilson, J. G., Gudnason, V., Hoffman, H. J., Williams, F. M. K., and Goedegebure, A.
Subjects: 0301 basic medicine, Male, Aging, Auditory Pathways, Genome-wide association study, Audiology, Genome-wide association studies, Mice, 0302 clinical medicine, Genetics research, GWAS, age-related hearing lo, Multidisciplinary, Middle Aged, Phenotype, age-related hearing loss, Meta-analysis, Medicine, Female, medicine.symptom, medicine.medical_specialty, Hearing loss, Science, Single-nucleotide polymorphism, Biology, Article, ARHL, 03 medical and health sciences, medicine, otorhinolaryngologic diseases, SNP, Animals, Humans, Genetic Predisposition to Disease, Hearing Loss, Gene, Reproducibility of Results, Molecular Sequence Annotation, Genetic architecture, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Previous research has shown that genes play a substantial role in determining a person’s susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.
Published: 2019

12. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R H J, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J C N, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K, Hopper, John L, Hottenga, Jouke J, Hu, Frank, Hunter, David, Ikram, Mohammad A, Jackson, Rebecca D, Joaquim, Micaella D R, John, Esther M, Joshi, Peter K, Karasik, David, Kardia, Sharon L R, Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M, Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W, Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J, Laven, Joop S E, Lawlor, Deborah A, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K E, Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G, Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E, Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L, Montgomery, Grant W, Mook-Kanamori, Dennis O, Mulas, Antonella, Mulligan, Anna M, Murray, Alison, Nalls, Mike A, Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R, Olshan, Andrew F, Olsson, Håkan, Painter, Jodie N, Patel, Alpa V, Pedersen, Nancy L, Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D P, Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M, Rahman, Iffat, Rennert, Gad, Rennert, Hedy S, Ridker, Paul M, Ring, Susan M, Robino, Antonietta, Rose, Lynda M, Rosendaal, Frits R, Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F, Saloustros, Emmanouil, Sandler, Dale P, Sanna, Serena, Sawyer, Elinor J, Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K, Schoemaker, Minouk J, Schraut, Katharina E, Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V, Smith, Blair H, Smith, Jennifer A, Sorice, Rossella, Southey, Melissa C, Spector, Tim D, Spinelli, John J, Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B J, Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J, Tanaka, Toshiko, Teras, Lauren R, Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J, Toniolo, Daniela, Traglia, Michela, Troester, Melissa A, Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G, Ulivi, Sheila, Vachon, Celine M, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J, Weinberg, Clarice R, Weir, David R, Wilcox, Amber N, van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F, Wolffenbuttel, Bruce H R, Wolk, Alicja, Wood, Andrew R, Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H, Grøndahl, Marie Louise, Andersen, Claus Yding, Pujol, Anna, Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R H J, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J C N, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K, Hopper, John L, Hottenga, Jouke J, Hu, Frank, Hunter, David, Ikram, Mohammad A, Jackson, Rebecca D, Joaquim, Micaella D R, John, Esther M, Joshi, Peter K, Karasik, David, Kardia, Sharon L R, Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M, Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W, Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J, Laven, Joop S E, Lawlor, Deborah A, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K E, Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G, Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E, Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L, Montgomery, Grant W, Mook-Kanamori, Dennis O, Mulas, Antonella, Mulligan, Anna M, Murray, Alison, Nalls, Mike A, Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R, Olshan, Andrew F, Olsson, Håkan, Painter, Jodie N, Patel, Alpa V, Pedersen, Nancy L, Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D P, Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M, Rahman, Iffat, Rennert, Gad, Rennert, Hedy S, Ridker, Paul M, Ring, Susan M, Robino, Antonietta, Rose, Lynda M, Rosendaal, Frits R, Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F, Saloustros, Emmanouil, Sandler, Dale P, Sanna, Serena, Sawyer, Elinor J, Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K, Schoemaker, Minouk J, Schraut, Katharina E, Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V, Smith, Blair H, Smith, Jennifer A, Sorice, Rossella, Southey, Melissa C, Spector, Tim D, Spinelli, John J, Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B J, Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J, Tanaka, Toshiko, Teras, Lauren R, Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J, Toniolo, Daniela, Traglia, Michela, Troester, Melissa A, Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G, Ulivi, Sheila, Vachon, Celine M, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J, Weinberg, Clarice R, Weir, David R, Wilcox, Amber N, van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F, Wolffenbuttel, Bruce H R, Wolk, Alicja, Wood, Andrew R, Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H, Grøndahl, Marie Louise, Andersen, Claus Yding, and Pujol, Anna
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021

13. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, Katherine S., Day, Felix R., Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E., Azad, Ajuna, Thompson, Deborah J., Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L., Martín-González, Javier, Fasching, Peter A., Faul, Jessica D., Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M., Kitahara, Cari M., Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Sawyer, Elinor J., Grøndahl, Marie Louise, Gieger, Christian, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A., Kolcic, Ivana, Håkansson, Niclas, Hall, Per, Andersen, Claus Yding, Lin, Kuang, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W., Kutalik, Zoltan, Claringbould, Annique, Pujol, Anna, La Bianca, Martina, Høffding, Miya K., LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lawlor, Deborah A., Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, López-Contreras, Andrés J., Lindstrom, Sara, Bakker, Olivier B., Sarnowski, Chloé, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Daniel, Jeremy A., Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Schlessinger, David, Sulem, Patrick, Marten, Jonathan, Martin, Nicholas G., Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E., Olsen, Kristina W., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Marjanka K. Schmidt, Milani, Lili, Walters, Robin G., Milne, Roger L., Montgomery, Grant W., Mook-Kanamori, Dennis O., Stefansson, Kari, Mulas, Antonella, Mulligan, Anna M., Murray, Alison, Nalls, Mike A., Newman, Anne, Schoemaker, Minouk J., Noordam, Raymond, Nutile, Teresa, Terao, Chikashi, Nyholt, Dale R., Chang-Claude, Jenny, Olshan, Andrew F., Olsson, Håkan, Painter, Jodie N., Patel, Alpa V., Pedersen, Nancy L., Perjakova, Natalia, Schraut, Katharina E., Peters, Annette, Peters, Ulrike, Pharoah, Paul D. P., Schouw, Yvonne T. van der, Turon, Sandra, Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M., Rahman, Iffat, Rennert, Gad, Rennert, Hedy S., Scott, Christopher, Ridker, Paul M., Ring, Susan M., John, Esther M., Robino, Antonietta, Rose, Lynda M., Horikoshi, Momoko, Rosendaal, Frits R., Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V., Smith, Blair H., Hopper, John L., Onland-Moret, N. Charlotte, Rossouw, Jacques, Smith, Jennifer A., Sorice, Rossella, Southey, Melissa C., Spector, Tim D., Spinelli, John J., Stampfer, Meir, Stöckl, Doris, Meurs, Joyce B. J. van, Strauch, Konstantin, Hottenga, Jouke J., Lunetta, Kathryn L., Styrkarsdottir, Unnur, Sankar, Aditya, Swerdlow, Anthony J., Tanaka, Toshiko, Teras, Lauren R., Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J., Toniolo, Daniela, Traglia, Michela, Chasman, Daniel I., Hu, Frank, Troester, Melissa A., Truong, Thérèse, Thrane Hertz, Emil Peter, Tyrrell, Jessica, Uitterlinden, André G., Ulivi, Sheila, Vachon, Celine M., Vitart, Veronique, Völker, Uwe, Easton, Douglas F., Vollenweider, Peter, Hunter, David, Völzke, Henry, Wang, Qin, Wareham, Nicholas J., Timshel, Pascal N., Weinberg, Clarice R., Weir, David R., Amber N. Wilcox, Dijk, Ko Willems van, Visser, Jenny A., Willemsen, Gonneke, Wilson, James F., Ikram, Mohammad A., Wolffenbuttel, Bruce H. R., Wolk, Alicja, Wood, Andrew R., Zhao, Wei, Shukla, Vallari, Zygmunt, Marek, Biobank-based Integrative Omics Study (BIOS) Consortium, Ozanne, Susan E., eQTLGen Consortium, The Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Jackson, Rebecca D., KConFab Investigators, The LifeLines Cohort Study, The InterAct consortium, Me Research Team, Chen, Zhengming, Borup, Rehannah, Namekawa, Satoshi H., Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Joaquim, Micaella D. R., Pers, Tune H., Solc, Petr, Aguilera, Paula, Murabito, Joanne M., Ong, Ken K., Rudan, Igor, Joshi, Peter K., Hoffmann, Eva R., Murray, Anna, Roig, Ignasi, Perry, John R. B., Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R. H. J., Ahearn, Thomas U., Rueedi, Rico, Alizadeh, Behrooz Z., Fontanillas, Pierre, Naderi, Elnaz, Andrulis, Irene L., Arnold, Alice M., Aronson, Kristan J., Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M., Beaumont, Robin N., Ruggiero, Daniela, Becher, Heiko, Beckmann, Matthias W., Karasik, David, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Boomsma, Dorret I., Sala, Cinzia F., Bowker, Nicholas, Brody, Jennifer A., Broer, Linda, Kardia, Sharon L. R., Buring, Julie E., Campbell, Archie, Campbell, Harry, Castelao, Jose E., Catamo, Eulalia, Chanock, Stephen J., Saloustros, Emmanouil, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J., Kartsonaki, Christiana, Cox, Angela, Crisponi, Laura, Cross, Simon S., Cucca, Francesco, Czene, Kamila, Sandler, Dale P., Smith, George Davey, Geus, Eco J. C. de, Mutsert, Renée de, De Vivo, Immaculata, Demerath, Ellen W., Karlsson, Robert, Dennis, Joe, Dunning, Alison M., Dwek, Miriam, Eriksson, Mikael, Sanna, Serena, Esko, Tonu, Ruth, Katherine S., Day, Felix R., Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E., Azad, Ajuna, Thompson, Deborah J., Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L., Martín-González, Javier, Fasching, Peter A., Faul, Jessica D., Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M., Kitahara, Cari M., Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Sawyer, Elinor J., Grøndahl, Marie Louise, Gieger, Christian, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A., Kolcic, Ivana, Håkansson, Niclas, Hall, Per, Andersen, Claus Yding, Lin, Kuang, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W., Kutalik, Zoltan, Claringbould, Annique, Pujol, Anna, La Bianca, Martina, Høffding, Miya K., LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lawlor, Deborah A., Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, López-Contreras, Andrés J., Lindstrom, Sara, Bakker, Olivier B., Sarnowski, Chloé, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Daniel, Jeremy A., Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Schlessinger, David, Sulem, Patrick, Marten, Jonathan, Martin, Nicholas G., Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E., Olsen, Kristina W., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Marjanka K. Schmidt, Milani, Lili, Walters, Robin G., Milne, Roger L., Montgomery, Grant W., Mook-Kanamori, Dennis O., Stefansson, Kari, Mulas, Antonella, Mulligan, Anna M., Murray, Alison, Nalls, Mike A., Newman, Anne, Schoemaker, Minouk J., Noordam, Raymond, Nutile, Teresa, Terao, Chikashi, Nyholt, Dale R., Chang-Claude, Jenny, Olshan, Andrew F., Olsson, Håkan, Painter, Jodie N., Patel, Alpa V., Pedersen, Nancy L., Perjakova, Natalia, Schraut, Katharina E., Peters, Annette, Peters, Ulrike, Pharoah, Paul D. P., Schouw, Yvonne T. van der, Turon, Sandra, Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M., Rahman, Iffat, Rennert, Gad, Rennert, Hedy S., Scott, Christopher, Ridker, Paul M., Ring, Susan M., John, Esther M., Robino, Antonietta, Rose, Lynda M., Horikoshi, Momoko, Rosendaal, Frits R., Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V., Smith, Blair H., Hopper, John L., Onland-Moret, N. Charlotte, Rossouw, Jacques, Smith, Jennifer A., Sorice, Rossella, Southey, Melissa C., Spector, Tim D., Spinelli, John J., Stampfer, Meir, Stöckl, Doris, Meurs, Joyce B. J. van, Strauch, Konstantin, Hottenga, Jouke J., Lunetta, Kathryn L., Styrkarsdottir, Unnur, Sankar, Aditya, Swerdlow, Anthony J., Tanaka, Toshiko, Teras, Lauren R., Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J., Toniolo, Daniela, Traglia, Michela, Chasman, Daniel I., Hu, Frank, Troester, Melissa A., Truong, Thérèse, Thrane Hertz, Emil Peter, Tyrrell, Jessica, Uitterlinden, André G., Ulivi, Sheila, Vachon, Celine M., Vitart, Veronique, Völker, Uwe, Easton, Douglas F., Vollenweider, Peter, Hunter, David, Völzke, Henry, Wang, Qin, Wareham, Nicholas J., Timshel, Pascal N., Weinberg, Clarice R., Weir, David R., Amber N. Wilcox, Dijk, Ko Willems van, Visser, Jenny A., Willemsen, Gonneke, Wilson, James F., Ikram, Mohammad A., Wolffenbuttel, Bruce H. R., Wolk, Alicja, Wood, Andrew R., Zhao, Wei, Shukla, Vallari, Zygmunt, Marek, Biobank-based Integrative Omics Study (BIOS) Consortium, Ozanne, Susan E., eQTLGen Consortium, The Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Jackson, Rebecca D., KConFab Investigators, The LifeLines Cohort Study, The InterAct consortium, Me Research Team, Chen, Zhengming, Borup, Rehannah, Namekawa, Satoshi H., Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Joaquim, Micaella D. R., Pers, Tune H., Solc, Petr, Aguilera, Paula, Murabito, Joanne M., Ong, Ken K., Rudan, Igor, Joshi, Peter K., Hoffmann, Eva R., Murray, Anna, Roig, Ignasi, Perry, John R. B., Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R. H. J., Ahearn, Thomas U., Rueedi, Rico, Alizadeh, Behrooz Z., Fontanillas, Pierre, Naderi, Elnaz, Andrulis, Irene L., Arnold, Alice M., Aronson, Kristan J., Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M., Beaumont, Robin N., Ruggiero, Daniela, Becher, Heiko, Beckmann, Matthias W., Karasik, David, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Boomsma, Dorret I., Sala, Cinzia F., Bowker, Nicholas, Brody, Jennifer A., Broer, Linda, Kardia, Sharon L. R., Buring, Julie E., Campbell, Archie, Campbell, Harry, Castelao, Jose E., Catamo, Eulalia, Chanock, Stephen J., Saloustros, Emmanouil, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J., Kartsonaki, Christiana, Cox, Angela, Crisponi, Laura, Cross, Simon S., Cucca, Francesco, Czene, Kamila, Sandler, Dale P., Smith, George Davey, Geus, Eco J. C. de, Mutsert, Renée de, De Vivo, Immaculata, Demerath, Ellen W., Karlsson, Robert, Dennis, Joe, Dunning, Alison M., Dwek, Miriam, Eriksson, Mikael, Sanna, Serena, and Esko, Tonu
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021

14. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: Yongmei Liu, Tuomas O. Kilpeläinen, Kenneth Rice, Ching-Ti Liu, Jin-Fang Chai, Donna K. Arnett, Dhananjay Vaidya, Nicholette D. Palmer, Lili Milani, Yuri Milaneschi, Leo-Pekka Lyytikäinen, Colleen M. Sitlani, Richard S. Cooper, Gudny Eiriksdottir, Daniel Levy, Jerome I. Rotter, Lihua Wang, Sven Bergmann, Yih Chung Tham, Thomas Meitinger, Lynne E. Wagenknecht, Virginia Fisher, Babatunde L. Salako, Vilmundur Gudnason, Bamidele O. Tayo, Caizheng Yu, Barry I. Freedman, Muhammad Riaz, Kaare Christensen, Ulrich Broeckel, W. James Gauderman, Massimiliano Cocca, Eric Boerwinkle, Meian He, Rob M. van Dam, M. Arfan Ikram, Lisa de las Fuentes, Jiang He, Aldi T. Kraja, Nancy L. Pedersen, Albert V. Smith, Woon-Puay Koh, Bernardo L. Horta, He Gao, Traci M. Bartz, Mike A. Nalls, Federica Laguzzi, Raymond Noordam, Paul M. Ridker, Tien Yin Wong, Patricia B. Munroe, Paul S. de Vries, Adolfo Correa, Maris Alver, Dan E. Arking, Colin A. McKenzie, John M. Starr, Chi Charles Gu, Dongfeng Gu, Stefan Weiss, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Jill M. Norris, Patrik K. E. Magnusson, Tamar Sofer, Ioanna Ntalla, Xiuqing Guo, Paul Elliott, Lawrence F. Bielak, Konstantin Strauch, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Ilja M. Nolte, Steven C. Hunt, Mario Sims, Giorgia Girotto, Chuan Gao, Pamela J. Schreiner, Philippe Froguel, Archie Campbell, Xiao-Ou Shu, Claude Bouchard, Kurt Lohman, David R. Weir, José Eduardo Krieger, Yii-Der Ida Chen, Rainer Rauramaa, Walter Palmas, Cornelia M. van Duijn, James M. Shikany, Michael M. Province, Jennifer A. Smith, Wei Zheng, Xiaofeng Zhu, Jianjun Liu, Ozren Polasek, Alexandre C. Pereira, Diane M. Becker, Kari E. North, Salman M. Tajuddin, Deng Xuan, Leslie J. Raffel, Jie Yao, Astrid Petersmann, Ervin F. Fox, Mark J. Caulfield, Daniel I. Chasman, Jasmin Divers, Claudia P. Cabrera, Rico Rueedi, M. Yldau van der Ende, Carl D. Langefeld, Mika Kähönen, Terrence Forrester, Tangchun Wu, Harold Snieder, Caroline Hayward, Tamara B. Harris, Fang-Chi Hsu, Helen R. Warren, Brenda W.J.H. Penninx, Chiea Chuen Khor, Ruifang Li-Gao, Changwei Li, Sami Heikkinen, Jeffrey R. O'Connell, Christian Gieger, Michele K. Evans, Ching-Yu Cheng, Jingjing Liang, Stephen B. Kritchevsky, Gregory L. Burke, Donald W. Bowden, Alexander Teumer, Marcus Dörr, Alanna C. Morrison, Jian-Min Yuan, Annette Peters, Dennis O. Mook-Kanamori, Pedro Marques-Vidal, Pirjo Komulainen, Lisa R. Yanek, Melanie Waldenberger, Alisa K. Manning, Charles N. Rotimi, Chew-Kiat Heng, Tõnu Esko, Franco Giulianini, Miao Li Chee, Treva Rice, David J. Porteous, Yechiel Friedlander, Bing Yu, Myriam Fornage, Karin Leander, Dina Vojinovic, Sharon L.R. Kardia, Xiaoyin Li, Najaf Amin, Karen Schwander, Thomas T. Perls, Oscar Leonel Rueda-Ochoa, Erin B. Ware, Ya Xing Wang, Sandosh Padmanabhan, H. Janaka de Silva, André G. Uitterlinden, Rajkumar Dorajoo, Bruna Gigante, Jennifer A. Brody, Paolo Gasparini, Maryam Kavousi, Wanqing Wen, Stephen Sidney, Alan B. Zonderman, Michael R. Brown, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Alaitz Poveda, Bruce M. Psaty, Terho Lehtimäki, Tanika N. Kelly, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, John M. C. Connell, Mickaël Canouil, Niek Verweij, Thomas W. Winkler, Ian J. Deary, Marco Brumat, Yize Li, Fumihiko Takeuchi, Wei Zhao, Andres Metspalu, Marguerite R. Irvin, David C. Liewald, Pim van der Harst, Hugues Aschard, Candace M. Kammerer, Melissa A. Richard, Adesola Ogunniyi, Wen Bin Wei, Morris A. Swertz, Fernando Pires Hartwig, Dabeeru C. Rao, Reedik Mägi, Solomon K. Musani, Mathilde Boissel, Jonathan Marten, Nilesh J. Samani, Amy R. Bentley, Sarah E. Harris, Charumathi Sabanayagam, Mary F. Feitosa, Jost B. Jonas, Andrea R. V. R. Horimoto, Paul W. Franks, E. Shyong Tai, Medical Research Council (MRC), de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., Bentley, A. R., Brown, M. R., Guo, X., Manning, A., Chasman, D. I., Aschard, H., Bartz, T. M., Bielak, L. F., Campbell, A., Cheng, C. -Y., Dorajoo, R., Hartwig, F. P., Horimoto, A. R. V. R., Li, C., Li-Gao, R., Liu, Y., Marten, J., Musani, S. K., Ntalla, I., Rankinen, T., Richard, M., Sim, X., Smith, A. V., Tajuddin, S. M., Tayo, B. O., Vojinovic, D., Warren, H. R., Xuan, D., Alver, M., Boissel, M., Chai, J. -F., Chen, X., Christensen, K., Divers, J., Evangelou, E., Gao, C., Girotto, G., Harris, S. E., He, M., Hsu, F. -C., Kuhnel, B., Laguzzi, F., Li, X., Lyytikainen, L. -P., Nolte, I. M., Poveda, A., Rauramaa, R., Riaz, M., Rueedi, R., Shu, X. -O., Snieder, H., Sofer, T., Takeuchi, F., Verweij, N., Ware, E. B., Weiss, S., Yanek, L. R., Amin, N., Arking, D. E., Arnett, D. K., Bergmann, S., Boerwinkle, E., Brody, J. A., Broeckel, U., Brumat, M., Burke, G., Cabrera, C. P., Canouil, M., Chee, M. L., Chen, Y. -D. I., Cocca, M., Connell, J., de Silva, H. J., de Vries, P. S., Eiriksdottir, G., Faul, J. D., Fisher, V., Forrester, T., Fox, E. F., Friedlander, Y., Gao, H., Gigante, B., Giulianini, F., Gu, C. C., Gu, D., Harris, T. B., He, J., Heikkinen, S., Heng, C. -K., Hunt, S., Ikram, M. A., Irvin, M. R., Kahonen, M., Kavousi, M., Khor, C. C., Kilpelainen, T. O., Koh, W. -P., Komulainen, P., Kraja, A. T., Krieger, J. E., Langefeld, C. D., Li, Y., Liang, J., Liewald, D. C. M., Liu, C. -T., Liu, J., Lohman, K. K., Magi, R., Mckenzie, C. A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mook-Kanamori, D. O., Nalls, M. A., Nelson, C. P., Norris, J. M., O'Connell, J., Ogunniyi, A., Padmanabhan, S., Palmer, N. D., Pedersen, N. L., Perls, T., Peters, A., Petersmann, A., Peyser, P. A., Polasek, O., Porteous, D. J., Raffel, L. J., Rice, T. K., Rotter, J. I., Rudan, I., Rueda-Ochoa, O. -L., Sabanayagam, C., Salako, B. L., Schreiner, P. J., Shikany, J. M., Sidney, S. S., Sims, M., Sitlani, C. M., Smith, J. A., Starr, J. M., Strauch, K., Swertz, M. A., Teumer, A., Tham, Y. C., Uitterlinden, A. G., Vaidya, D., van der Ende, M. Y., Waldenberger, M., Wang, L., Wang, Y. -X., Wei, W. -B., Weir, D. R., Wen, W., Yao, J., Yu, B., Yu, C., Yuan, J. -M., Zhao, W., Zonderman, A. B., Becker, D. M., Bowden, D. W., Deary, I. J., Dorr, M., Esko, T., Freedman, B. I., Froguel, P., Gasparini, P., Gieger, C., Jonas, J. B., Kammerer, C. M., Kato, N., Lakka, T. A., Leander, K., Lehtimaki, T., Magnusson, P. K. E., Marques-Vidal, P., Penninx, B. W. J. H., Samani, N. J., van der Harst, P., Wagenknecht, L. E., Wu, T., Zheng, W., Zhu, X., Bouchard, C., Cooper, R. S., Correa, A., Evans, M. K., Gudnason, V., Hayward, C., Horta, B. L., Kelly, T. N., Kritchevsky, S. B., Levy, D., Palmas, W. R., Pereira, A. C., Province, M. M., Psaty, B. M., Ridker, P. M., Rotimi, C. N., Tai, E. S., van Dam, R. M., van Duijn, C. M., Wong, T. Y., Rice, K., Gauderman, W. J., Morrison, A. C., North, K. E., Kardia, S. L. R., Caulfield, M. J., Elliott, P., Munroe, P. B., Franks, P. W., Rao, D. C., Fornage, M., Washington University in Saint Louis (WUSTL), Leiden University Medical Center (LUMC), University of Regensburg, Washington University School of Medicine in St. Louis, National Institutes of Health [Bethesda] (NIH), Harbor UCLA Medical Center [Torrance, Ca.], Massachusetts General Hospital [Boston], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Lifelines Cohort Study, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Cardiovascular Centre (CVC)
Subjects: 0301 basic medicine, CORONARY-HEART-DISEASE, SOCIOECONOMIC-STATUS, RISK-FACTORS, CARDIOVASCULAR-DISEASE, ESSENTIAL-HYPERTENSION, C825T POLYMORPHISM, SOCIAL-CLASS, ASSOCIATION, EXPRESSION, VARIANTS, Blood Pressure, Genome, 0302 clinical medicine, 11 Medical and Health Sciences, Genetics, Psychiatry, [STAT.AP]Statistics [stat]/Applications [stat.AP], 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Meta-analysis, Hypertension, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, GNB3, Biochemistry & Molecular Biology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Humans, Risk factor, Molecular Biology, Gene, Science & Technology, Neurosciences, Epistasis, Genetic, 06 Biological Sciences, Genetic architecture, Educational attainment, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Blood Pressure/genetics, Genome-Wide Association Study, Hypertension/genetics, 030217 neurology & neurosurgery
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2020

15. COVID-19 experience: first Italian survey on healthcare staff members from a Mother-Child Research hospital using combined molecular and rapid immunoassays test

Author: Marco Brumat, Agnese Feresin, Massimo Del Pin, Livia Bicego, Anna Morgan, Annamonica Rosaria Bianco, Stefano Russian, Fulvia Vascotto, Roberta Bottega, Paola Toscani, Giorgia Argentini, Mariateresa Di Stazio, Marianela Urriza, Eulalia Catamo, Vincenzo Petix, Martina La Bianca, Maria Pina Concas, Manola Comar, Sarah Suergiu, Giulia Pelliccione, Andrea Cassone, Sara Morassut, Beatrice Spedicati, Petra Carli, Antonietta Robino, Giorgia Girotto, Paolo Gasparini, Giulia Ragusa, and Massimiliano Cocca
Subjects: medicine.medical_specialty, education.field_of_study, Coronavirus disease 2019 (COVID-19), business.industry, Population, Outbreak, Test (assessment), Family medicine, Epidemiology, Cohort, Health care, medicine, Medium Risk, business, education
Abstract: The fast spread of the novel coronavirus (SARS-CoV-2) has become a global threat hitting the worldwide fragile health care system. In Italy, there is a continued COVID-19 growth of cases and deaths that requires control measures for the correct management of the epidemiological emergency. To contribute to increasing the overall knowledge of COVID-19, systematic tests in the general population are required.Here, we describe the first Italian survey performed in 727 employees belonging to a Mother-Child Research hospital tested for both viral (nasopharyngeal and oropharyngeal swabs) and antibody presence. Individuals were divided into three risk categories (high, medium and low) according to their job activity. Only one subject was positive at the swab test while 17.2% of the cohort was positive for the presence of antibodies. Results highlighted that the presence of Positive antibodies is significantly associated with high and medium risk exposure occupation (p-value=0.026) as well as cold and conjunctivitis symptoms (p-value=0.016 and 0.042 respectively). Moreover, among healthcare professionals, the category of medical doctors showed a significant association with the presence of antibodies against SARS-CoV-2 (p-value=0.0127). Finally, we detected a rapid decrease in antibody intensity between two assessments performed within a very short period (p-value=0.009). Overall, the present study increases our knowledge of the epidemiological data of COVID-19 infection in Italy, suggesting a high prevalence of immune individuals (i.e. at least among at-risk categories) and the efficacy of the combined diagnostic protocol to monitor the possible outbreak.
Published: 2020
Full Text: View/download PDF

16. COVID-19 Experience: First Italian Survey on Healthcare Staff Members from a Mother-Child Research Hospital Using Combined Molecular and Rapid Immunoassay Tests

Author: Roberta Bottega, Anna Morgan, Martina La Bianca, Vincenzo Petix, Mariateresa Di Stazio, Giorgia Girotto, Maria Pina Concas, Sarah Suergiu, Giulia Pelliccione, Annamonica Rosaria Bianco, Fulvia Vascotto, Stefano Russian, Livia Bicego, Eulalia Catamo, Andrea Cassone, Manola Comar, Paolo Gasparini, Massimo Del Pin, Massimiliano Cocca, Giorgia Argentini, Marianela Urriza, Petra Carli, Sara Morassut, Beatrice Spedicati, Giulia Ragusa, Marco Brumat, Agnese Feresin, Paola Toscani, and Antonietta Robino
Subjects: 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, viruses, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), fungi, virus diseases, medicine.disease_cause, Viral test, Test (assessment), body regions, Family medicine, Health care, Medicine, skin and connective tissue diseases, business, Coronavirus
Abstract: Background: The fast spread of the novel coronavirus (SARS-CoV-2) has become a global threat hitting the worldwide fragile health care system In Italy, there i
Published: 2020

17. Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway

Author: Fabio Mammano, Veronica Zorzi, Gaia Ziraldo, Giovanna Morello, Anna Maria Salvatore, Maria Guarnaccia, Anna Rita Fetoni, Gaetano Paludetti, Denis Cuccaro, Guy Van Camp, Giulia Gentile, Fabiola Paciello, Marco Brumat, Antonio Gianmaria Spampinato, Erik Fransen, Giulia Crispino, Chiara Peres, Sebastiano Cavallaro, Ferdinando Scavizzi, Gabriella Tognola, Marcello Raspa, Paolo Gasparini, Giorgia Girotto, Fetoni, Anna Rita, Zorzi, Veronica, Paciello, Fabiola, Ziraldo, Gaia, Peres, Chiara, Raspa, Marcello, Scavizzi, Ferdinando, Salvatore, Anna Maria, Crispino, Giulia, Tognola, Gabriella, Gentile, Giulia, Spampinato, Antonio Gianmaria, Cuccaro, Deni, Guarnaccia, Maria, Morello, Giovanna, Van Camp, Guy, Fransen, Erik, Brumat, Marco, Girotto, Giorgia, Paludetti, Gaetano, Gasparini, Paolo, Cavallaro, Sebastiano, Mammano, Fabio, Fetoni, Ar, Zorzi, V, Paciello, F, Ziraldo, G, Peres, C, Raspa, M, Scavizzi, F, Salvatore, Alba Maria Rita, Crispino, G, Tognola, G, Gentile, Giuseppe, Spampinato, Ag, Cuccaro, D, Guarnaccia, M, Morello, G, Van Camp, G, Fransen, E, Brumat, M, Girotto, G, Paludetti, G, Gasparini, P, Cavallaro, S, and Mammano, F.
Subjects: Male, 0301 basic medicine, Clinical Biochemistry, Connexin, Presbycusis, Apoptosis, Cochlear duct, Inbred C57BL, Hair cells, Mouse models, medicine.disease_cause, Biochemistry, Mice, lcsh:QH301-705.5, Regulation of gene expression, lcsh:R5-920, Chemistry, Cell biology, Connexin 26, medicine.anatomical_structure, Age-related hearing lo, Settore MED/32 - AUDIOLOGIA, Female, Hair cell, medicine.symptom, Signal transduction, lcsh:Medicine (General), Spiral ganglion neurons, Oxidation-Reduction, Research Paper, Signal Transduction, Age-related hearing loss, Genome-wide association study, Animals, Gene Deletion, Mice, Inbred C57BL, NF-E2-Related Factor 2, Organic Chemistry, Hearing loss, Settore BIO/09 - FISIOLOGIA, Mouse model, PRKCE Gene, 03 medical and health sciences, otorhinolaryngologic diseases, medicine, Biology, medicine.disease, 030104 developmental biology, lcsh:Biology (General), Oxidative stress
Abstract: Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2+/− mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2+/− mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2+/− mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10−2) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis., Graphical abstract fx1, Highlights • Partial loss of Cx26 accelerates hearing impairment progression in Gjb2+/- mice. • The auditory organ is affected by increased apoptosis due to redox imbalance. • The expression of several genes controlled by the Nrf2/ARE pathway is deregulated. • Genome-wide association detected two of these genes in humans with presbycusis. • This work sheds new light on the etiopathogenesis of presbycusis and its prevention.
Published: 2018

18. Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author: Seyhan Yazar, M. Arfan Ikram, Gonneke Willemsen, Maria Pina Concas, Manfred Kayser, Tim D. Spector, David M. Evans, Nicholas G. Martin, David L. Duffy, Changqing Zeng, Bochao D. Lin, Daniela Toniolo, Pirro G. Hysi, Gibran Hemani, Jouke-Jan Hottenga, Paolo Gasparini, Gu Zhu, Sarah E. Medland, Cornelia M. van Duijn, Mario Falchi, Marco Brumat, Nicholas A. Furlotte, Alessia Visconti, André G. Uitterlinden, Cinzia Sala, George McMahon, David A. Hinds, Dorret I. Boomsma, Ilaria Gandin, Ana M. Valdes, Dragana Vuckovic, Giorgia Girotto, Veronique Bataille, Massimiliano Cocca, David A. Mackey, Susan M. Ring, Fan Liu, Tamar Nijsten, Scott D. Gordon, Yan Chen, George Davey Smith, Merel A. Hamer, Antonietta Robino, Alex W. Hewitt, Genetic Identification, Erasmus MC other, Epidemiology, Internal Medicine, Dermatology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, Hysi, Pirro G., Valdes, A. M., Liu, Fan, Furlotte, Nicholas A., Evans, David M., Bataille, Veronique, Visconti, Alessia, Hemani, Gibran, Mcmahon, George, Ring, Susan M., Smith, George Davey, Duffy, David L., Zhu, Gu, Gordon, Scott D., Medland, Sarah E., Lin, Bochao D., Willemsen, Gonneke, Jan Hottenga, Jouke, Vuckovic, Dragana, Girotto, Giorgia, Gandin, Ilaria, Sala, Cinzia, Concas, Maria Pina, Brumat, Marco, Gasparini, Paolo, Toniolo, Daniela, Cocca, Massimiliano, Robino, Antonietta, Yazar, Seyhan, Hewitt, Alex W., Chen, Yan, Zeng, Changqing, Uitterlinden, Andre G., Ikram, M. Arfan, Hamer, Merel A., van Duijn, Cornelia M., Nijsten, Tamar, Mackey, David A., Falchi, Mario, Boomsma, Dorret I., Martin, Nicholas G., Hinds, David A., Kayser, Manfred, and Spector, Timothy D.
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, 0302 clinical medicine, Black hair, Genetic variation, Genotype, Genetics, Eye color, otorhinolaryngologic diseases, Journal Article, Humans, Hair Color, Aged, Chromosomes, Human, X, Autosome, integumentary system, Heritability, Middle Aged, 030104 developmental biology, Phenotype, Evolutionary biology, Genetic Loci, Female, sense organs, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.
Published: 2018

19. Associations of autozygosity with a broad range of human phenotypes

Author: Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics
Subjects: 0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract: Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.
Published: 2019

20. Effects of Calcium, Magnesium, and Potassium concentrations on ventricular repolarization in unselected individuals

Author: Pedro Guatimosim Vidigal, Yongmei Liu, Alice Stanton, Kent D. Taylor, Thomas Meitinger, Vilmundur Gudnason, Massimo Mangino, Mario Pirastu, Nilesh J. Samani, Christopher Newton-Cheh, Xiuqing Guo, Bruno H. Stricker, Mortiz F. Sinner, Steven R. Cummings, Jennifer A. Brody, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Bryan Kestenbaum, Dennis O. Mook-Kanamori, Jørgen K. Kanters, Kirill V. Tarasov, Martina Müller-Nurasyid, Luana Giatti, Elsayed Z. Soliman, Christian R. Juhl, Nuno R. Zilhão, Harold Snieder, Eric Campana, Mika Kähönen, Ginevra Biino, Raymond Noordam, Jun Ding, Chris H. L. Thio, Jerome I. Rotter, Torben Hansen, M. Abdullah Said, Francesco Cucca, Allan Linneberg, Nona Sotoodehnia, Niels Grarup, Peter S. Sever, James F. Wilson, André G. Uitterlinden, Xia Shen, Luisa Foco, Yong Qian, Christina Ellervik, Diana van Heemst, Antonietta Robino, Henry J. Lin, Konstantin Strauch, Patricia B. Munroe, Nabi Shah, Claus Graff, Daniel S. Evans, Peter J. van der Most, Stefan Weiss, Maria Pina Concas, Reem Salman, Hao Mei, Linda Repetto, Helen R. Warren, Peter K. Joshi, Susan R. Heckbert, Tim D. Spector, Sandhi Maria Barreto, Jie Yao, Marcus Dörr, Eulalia Catamo, Anna F. Dominiczak, Leo-Pekka Lyytikäinen, Giorgia Girotto, Peter P. Pramstaller, Gudny Eiriksdottir, J. Wouter Jukema, Paulo A. Lotufo, Colin N. A. Palmer, Andrew Tinker, James G. Wilson, Mary L. Biggs, Astrid Petersmann, Arie C. Maan, Peter S. Braund, Maria Fernanda Lima-Costa, Paraskevi Christofidou, Sandosh Padmanabhan, Adolfo Correa, Melanie Waldenberger, Alessandro De Grandi, Stefan Kääb, Cristian Pattaro, Annette Peters, William J Young, Alex S. F. Doney, Katharina Schramm, Terho Lehtimäki, Christopher P. Nelson, Martin Gögele, Marten E. van den Berg, Marco Brumat, Pim van der Harst, Niek Verweij, Simona Vaccargiu, Noordam, R, Young, Wj, Salman, R, Kanters, Jk, van den Berg, Me, van Heemst, D, Lin, Hj, Barreto, Sm, Biggs, Ml, Biino, G, Catamo, E, Concas, Mp, Ding, J, Evans, D, Foco, L, Grarup, N, Lyytikäinen, Lp, Mangino, M, Mei, H, van der Most, Pj, Müller-Nurasyid, M, Nelson, Cp, Qian, Y, Repetto, L, Said, Ma, Shah, N, Schramm, K, Vidigal, Pg, Weiss, S, Yao, J, Zilhao, Nr, Brody, Ja, Braund, P, Brumat, M, Campana, E, Christofidou, P, Caulfield, Mj, De Grandi, A, Dominiczak, Af, Doney, Asf, Eiriksdottir, G, Ellervik, C, Giatti, L, Gögele, M, Graff, C, Guo, X, van der Harst, P, Joshi, Pk, Kähönen, M, Kestenbaum, B, Lima-Costa, Mf, Linneberg, A, Maan, Ac, Meitinger, T, Padmanabhan, S, Pattaro, C, Peters, A, Petersmann, A, Sever, P, Sinner, Mf, Shen, X, Stanton, A, Strauch, K, Soliman, Ez, Tarasov, Kv, Taylor, Kd, Thio, Chl, Uitterlinden, Ag, Vaccargiu, S, Waldenberger, M, Robino, A, Correa, A, Cucca, F, Cummings, Sr, Dörr, M, Girotto, G, Gudnason, V, Hansen, T, Heckbert, Sr, Juhl, Cr, Kääb, S, Lehtimäki, T, Liu, Y, Lotufo, Pa, Palmer, Cna, Pirastu, M, Pramstaller, Pp, Ribeiro, Alp, Rotter, Ji, Samani, Nj, Snieder, H, Spector, Td, Stricker, Bh, Verweij, N, Wilson, Jf, Wilson, Jg, Jukema, Jw, Tinker, A, Newton-Cheh, Ch, Sotoodehnia, N, Mook-Kanamori, Do, Munroe, Pb, Warren, Hr., Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), and Epidemiology
Subjects: Male, Cardiac & Cardiovascular Systems, 030204 cardiovascular system & hematology, ELECTROCARDIOGRAM, Electrocardiography, 0302 clinical medicine, cohort studies, Risk Factors, Medicine, Magnesium, 030212 general & internal medicine, Correlation of Data, 1102 Cardiorespiratory Medicine and Haematology, RISK, education.field_of_study, medicine.diagnostic_test, ACTION-POTENTIAL DURATION, ASSOCIATION, Middle Aged, COUNCIL, electrocardiographic intervals, Cardiovascular Diseases, Cardiology, Female, epidemiology, Electrical conduction system of the heart, Cardiology and Cardiovascular Medicine, Electrophysiologic Techniques, Cardiac, Life Sciences & Biomedicine, medicine.medical_specialty, Population, electrolytes epidemiology, meta-analysis, chemistry.chemical_element, electrolytes, Calcium, QT interval, 1117 Public Health and Health Services, 03 medical and health sciences, QRS complex, DISPERSION, Heart Conduction System, Internal medicine, Humans, PR interval, education, Science & Technology, Cohort Studies, Electrocardiographic Intervals, Electrolytes, Epidemiology, Meta-analysis, business.industry, QT INTERVAL, RESTING HEART-RATE, Confidence interval, REDUCTION, chemistry, Cardiovascular System & Hematology, CONDUCTION, Asymptomatic Diseases, Potassium, Cardiovascular System & Cardiology, electrocardiographic interval, business, cohort studie
Abstract: BACKGROUND Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.OBJECTIVES This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.METHODS Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 +/- 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.RESULTS Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.CONCLUSIONS The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms. (C) 2019 by the American College of Cardiology Foundation.
Published: 2019

21. A bird’s-eye view of Italian genomic variation through whole-genome sequencing

Author: Massimiliano Cocca, Giuseppe Matullo, Massimo Mezzavilla, Caterina Barbieri, Maria Pina Concas, Matteo Trudu, Dragana Vuckovic, Cinzia Sala, Ozren Polasek, Ivana Kolcic, Antonietta Robino, Giorgia Girotto, Marco Brumat, Daniela Toniolo, Ilaria Gandin, Paolo Gasparini, Nicole Soranzo, Cocca, M., Barbieri, C., Concas, M. P., Robino, A., Brumat, M., Gandin, I., Trudu, M., Sala, C. F., Vuckovic, D., Girotto, G., Matullo, G., Polasek, O., Kolcic, I., Gasparini, P., Soranzo, N., Toniolo, D., and Mezzavilla, M.
Subjects: Male, Population, Population structure, genomic variation, whole genome sequencing, Genome-wide association study, Biology, Genome, Article, 03 medical and health sciences, Gene Frequency, Databases, Genetic, Genetic variation, Genetics, Humans, WIDE ASSOCIATION, GENOTYPE IMPUTATION, LOW-FREQUENCY, POPULATION, VARIANTS, RARE, METAANALYSIS, Selection, Genetic, 1000 Genomes Project, Genetics (clinical), 030304 developmental biology, Whole genome sequencing, 0303 health sciences, Polymorphism, Genetic, Natural selection, Genome, Human, 030305 genetics & heredity, Rare variants, Reference Standards, Italy, Evolutionary biology, Next-generation sequencing, Female, Imputation (genetics), Genome-Wide Association Study
Abstract: The genomic variation of the Italian peninsula populations is currently under characterised: the only Italian whole-genome reference is represented by the Tuscans from the 1000 Genome Project. To address this issue, we sequenced a total of 947 Italian samples from three different geographical areas. First, we defined a new Italian Genome Reference Panel (IGRP1.0) for imputation, which improved imputation accuracy, especially for rare variants, and we tested it by GWAS analysis on red blood traits. Furthermore, we extended the catalogue of genetic variation investigating the level of population structure, the pattern of natural selection, the distribution of deleterious variants and occurrence of human knockouts (HKOs). Overall the results demonstrate a high level of genomic differentiation between cohorts, different signatures of natural selection and a distinctive distribution of deleterious variants and HKOs, confirming the necessity of distinct genome references for the Italian population.
Published: 2019

22. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author: Michael R. Brown, Christian Gieger, André G. Uitterlinden, Diana van Heemst, Alison D. Murray, Stephen B. Kritchevsky, Timo A. Lakka, Karen Schwander, Federica Laguzzi, Stephen S. Rich, Rajkumar Dorajoo, Yun Ju Sung, Xiaofeng Zhu, Hugues Aschard, Jing Hua Zhao, Gregory P. Wilson, Kenneth Rice, Barbara Sternfeld, Kent D. Taylor, Paul Elliott, Ei-Ei Khaing Nang, Ilja M. Nolte, Heather M. Stringham, Bruce M. Psaty, Heming Wang, Tangchun Wu, Caroline Hayward, Vilmundur Gudnason, Fernando Pires Hartwig, Paolo Gasparini, Jingjing Liang, Neil Risch, Albertine J. Oldehinkel, Ani Manichaikul, Tibor V. Varga, Michael Y. Tsai, Niek Verweij, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Xiuqing Guo, Traci M. Bartz, Nicholette D. Palmer, Woon-Puay Koh, Rozenn N. Lemaitre, Caizheng Yu, Mike A. Nalls, Mariaelisa Graff, Eric Boerwinkle, Dabeeru C. Rao, Thomas Meitinger, Virginia Fisher, Mario Sims, Charles Kooperberg, Carl D. Langefeld, Jaakko Tuomilehto, Reedik Mägi, Wei Zhao, Wanqing Wen, Donna K. Arnett, Ervin R. Fox, Lynda M. Rose, Maris Alver, Ayse Demirkan, Solomon K. Musani, Dennis O. Mook-Kanamori, Andres Metspalu, Jerome I. Rotter, Barry I. Freedman, Jiang He, Hermina Jakupović, Steven C. Hunt, Marco Brumat, Maria Pina Concas, Rob M. van Dam, Rico Rueedi, Jonathan Marten, Chi Charles Gu, Tõnu Esko, Peter Vollenweider, Zoltán Kutalik, Olli T. Raitakari, Ya X. Wang, Yong-Bing Xiang, Pamela J. Schreiner, Antonietta Robino, Tanika N. Kelly, Igor Rudan, Mathilde Boissel, Claudia Langenberg, Yii-Der Ida Chen, Anne U. Jackson, Lawrence F. Bielak, Brenda W.J.H. Penninx, Brigitte Kühnel, Christopher P. Nelson, Konstantin Strauch, Albert V. Smith, Daniel I. Chasman, Jasmin Divers, Lisa R. Yanek, M. Arfan Ikram, Melissa A. Richard, Nilesh J. Samani, Lisa de las Fuentes, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Yongmei Liu, Peter J. van der Most, Fang-Chi Hsu, Jeffrey R. O'Connell, Alexandre C. Pereira, Raymond Noordam, Changwei Li, Jie Yao, Trudy Voortman, Zhe Wang, Thomas H. Mosley, Diane M. Becker, Charles N. Rotimi, Sami Heikkinen, Archie Campbell, John M. C. Connell, Lenore J. Launer, Hua Tang, Rainer Rauramaa, Ruth J. F. Loos, Pirjo Komulainen, Amy R. Bentley, Patrik Wennberg, Chew-Kiat Heng, Kari E. North, Salman M. Tajuddin, Renée de Mutsert, David J. Porteous, Susan Redline, Sarah E. Harris, Tamara B. Harris, Raha Pazoki, Mickaël Canouil, Robert A. Scott, Jingzhong Ding, Mary F. Feitosa, Jost B. Jonas, José Eduardo Krieger, John M. Starr, Karin Leander, Jennifer A. Smith, Paul W. Franks, Charles B. Eaton, Sharon L.R. Kardia, E. Shyong Tai, Jill M. Norris, Annette Peters, Chiamaka Vivian Nwuba, Jianjun Liu, Stella Aslibekyan, Nora Franceschini, Kurt Lohman, Myriam Fornage, Dina Vojinovic, Erin B. Ware, Xiaoyin Li, Najaf Amin, Johanna Kuusisto, M. Yldau van der Ende, Cora E. Lewis, Lynne E. Wagenknecht, Jennifer G. Robinson, Franco Giulianini, Ulf de Faire, Yechiel Friedlander, Nicholas J. Wareham, Meian He, George J. Papanicolau, Nancy L. Pedersen, Bernardo L. Horta, Karen L. Mohlke, Kelley Pettee Gabriel, Minjung Kho, Michele K. Evans, Ozren Polasek, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Ioanna Ntalla, Cornelia M. van Duijn, L. Adrienne Cupples, Yuri Milaneschi, Stephen Sidney, Alan B. Zonderman, Leo-Pekka Lyytikäinen, Mohsen Ghanbari, Harold Snieder, Donald W. Bowden, Aldi T. Kraja, Alaitz Poveda, Terho Lehtimäki, Paul S. de Vries, Dongfeng Gu, Sotoodehnia Nona, Thomas W. Winkler, Muhammad Riaz, Ian J. Deary, Fumihiko Takeuchi, Pim van der Harst, Alisa K. Manning, Michael A. Province, Andrea R. V. R. Horimoto, David R. Weir, Wei Zheng, Alanna C. Morrison, Marzyeh Amini, Jian-Min Yuan, W. James Gauderman, Paul M. Ridker, Melanie Waldenberger, Chuan Gao, Xiao-Ou Shu, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, Tamar Sofer, Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, UK DRI Ltd, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Digital Health, IT University of Copenhagen, Icahn School of Medicine at Mount Sinai [New York] (MSSM), National Institutes of Health [Bethesda] (NIH), Leiden University Medical Center (LUMC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Regensburg, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], Queen Mary University of London (QMUL), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), University of Washington [Seattle], The present work was largely supported by a grant from the US National Heart, Lung,and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305)., Kilpeläinen, Tuomas O., Bentley, Amy R., Noordam, Raymond, Sung, Yun Ju, Schwander, Karen, Winkler, Thomas W., Jakupović, Hermina, Chasman, Daniel I., Manning, Alisa, Ntalla, Ioanna, Aschard, Hugue, Brown, Michael R., de las Fuentes, Lisa, Franceschini, Nora, Guo, Xiuqing, Vojinovic, Dina, Aslibekyan, Stella, Feitosa, Mary F., Kho, Minjung, Musani, Solomon K., Richard, Melissa, Wang, Heming, Wang, Zhe, Bartz, Traci M., Bielak, Lawrence F., Campbell, Archie, Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Li, Changwei, Lohman, Kurt K., Marten, Jonathan, Sim, Xueling, Smith, Albert V., Tajuddin, Salman M., Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Evangelou, Evangelo, Gao, Chuan, Graff, Mariaelisa, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Zhao, Jing Hua, Kraja, Aldi T., Kühnel, Brigitte, Laguzzi, Federica, Lyytikäinen, Leo-Pekka, Nolte, Ilja M., Rauramaa, Rainer, Riaz, Muhammad, Robino, Antonietta, Rueedi, Rico, Stringham, Heather M., Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Verweij, Niek, Ware, Erin B., Wen, Wanqing, Li, Xiaoyin, Yanek, Lisa R., Amin, Najaf, Arnett, Donna K., Boerwinkle, Eric, Brumat, Marco, Cade, Brian, Canouil, Mickaël, Chen, Yii-Der Ida, Concas, Maria Pina, Connell, John, de Mutsert, Renée, de Silva, H. Janaka, de Vries, Paul S., Demirkan, Ayşe, Ding, Jingzhong, Eaton, Charles B., Faul, Jessica D., Friedlander, Yechiel, Gabriel, Kelley P., Ghanbari, Mohsen, Giulianini, Franco, Gu, Chi Charle, Gu, Dongfeng, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hunt, Steven C., Ikram, M. Arfan, Jonas, Jost B., Koh, Woon-Puay, Komulainen, Pirjo, Krieger, Jose E., Kritchevsky, Stephen B., Kutalik, Zoltán, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Leander, Karin, Lemaitre, Rozenn N., Lewis, Cora E., Liang, Jingjing, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Navis, Gerjan, Rots, Marianne, Swertz, Morri, Wolffenbuttel, Bruce H. R., Wijmenga, Cisca, Liu, Jianjun, Mägi, Reedik, Manichaikul, Ani, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Mohlke, Karen L., Mosley, Thomas H., Murray, Alison D., Nalls, Mike A., Nang, Ei-Ei Khaing, Nelson, Christopher P., Nona, Sotoodehnia, Norris, Jill M., Nwuba, Chiamaka Vivian, O’Connell, Jeff, Palmer, Nicholette D., Papanicolau, George J., Pazoki, Raha, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Porteous, David J., Poveda, Alaitz, Raitakari, Olli T., Rich, Stephen S., Risch, Neil, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Schreiner, Pamela J., Scott, Robert A., Sidney, Stephen S., Sims, Mario, Smith, Jennifer A., Snieder, Harold, Sofer, Tamar, Starr, John M., Sternfeld, Barbara, Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Tsai, Michael Y., Tuomilehto, Jaakko, Uitterlinden, André G., van der Ende, M. Yldau, van Heemst, Diana, Voortman, Trudy, Waldenberger, Melanie, Wennberg, Patrik, Wilson, Gregory, Xiang, Yong-Bing, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., de Faire, Ulf, Deary, Ian J., Elliott, Paul, Esko, Tõnu, Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Kato, Norihiro, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Samani, Nilesh J., Shu, Xiao-Ou, van der Harst, Pim, Van Vliet-Ostaptchouk, Jana V., Vollenweider, Peter, Wagenknecht, Lynne E., Wang, Ya X., Wareham, Nicholas J., Weir, David R., Wu, Tangchun, Zheng, Wei, Zhu, Xiaofeng, Evans, Michele K., Franks, Paul W., Gudnason, Vilmundur, Hayward, Caroline, Horta, Bernardo L., Kelly, Tanika N., Liu, Yongmei, North, Kari E., Pereira, Alexandre C., Ridker, Paul M., Tai, E. Shyong, van Dam, Rob M., Fox, Ervin R., Kardia, Sharon L. R., Liu, Ching-Ti, Mook-Kanamori, Dennis O., Province, Michael A., Redline, Susan, van Duijn, Cornelia M., Rotter, Jerome I., Kooperberg, Charles B., Gauderman, W. Jame, Psaty, Bruce M., Rice, Kenneth, Munroe, Patricia B., Fornage, Myriam, Cupples, L. Adrienne, Rotimi, Charles N., Morrison, Alanna C., Rao, Dabeeru C., Loos, Ruth J. F., Bentley, Amy R [0000-0002-0827-9101], Jakupović, Hermina [0000-0001-9667-9406], Manning, Alisa [0000-0003-0247-902X], Aschard, Hugues [0000-0003-0907-2548], de Las Fuentes, Lisa [0000-0002-4689-325X], Richard, Melissa [0000-0003-0129-9860], Liu, Ching-Ti [0000-0002-0703-0742], Rice, Kenneth [0000-0002-3071-7278], Munroe, Patricia B [0000-0002-4176-2947], Loos, Ruth JF [0000-0002-8532-5087], Apollo - University of Cambridge Repository, Epidemiology, Radiology & Nuclear Medicine, Erasmus MC other, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, IT University of Copenhagen (ITU), Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Value, Affordability and Sustainability (VALUE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Navis, G., Rots, M., Swertz, M., Wolffenbuttel, BHR, and Wijmenga, C.
Subjects: Genetics and Molecular Biology (all), Male, Genome-wide association study, 02 engineering and technology, Biochemistry, MESH: Genotype, MESH: Nerve Tissue Proteins, lcsh:Science, MESH: Lipid Metabolism, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, MESH: Asian Continental Ancestry Group, Kólesteról, Hispanic or Latino, MESH: Transcription Factors, MESH: European Continental Ancestry Group, Lipids, ddc, 3. Good health, REVEAL, Cholesterol, MESH: Young Adult, Science & Technology - Other Topics, MESH: Membrane Proteins, MESH: Cholesterol, HDL, Hispanic Americans, 0210 nano-technology, Erfðarannsóknir, MESH: Cholesterol, LDL, MESH: Triglycerides, Genotype, Genetic Loci, Lipid Metabolism, Science, European Continental Ancestry Group, LIM-Homeodomain Proteins, Locus (genetics), EXERCISE, Adolescent, Adult, African Continental Ancestry Group/genetics, Aged, Asian Continental Ancestry Group/genetics, Brazil, Calcium-Binding Proteins/genetics, Cholesterol/blood, Cholesterol, HDL/blood, Cholesterol, HDL/genetics, Cholesterol, LDL/blood, Cholesterol, LDL/genetics, European Continental Ancestry Group/genetics, Exercise, Female, Genetic Loci/genetics, Genome-Wide Association Study, Hispanic Americans/genetics, Humans, LIM-Homeodomain Proteins/genetics, Lipid Metabolism/genetics, Lipids/blood, Lipids/genetics, Membrane Proteins/genetics, Microtubule-Associated Proteins/genetics, Middle Aged, Muscle Proteins/genetics, Nerve Tissue Proteins/genetics, Transcription Factors/genetics, Triglycerides/blood, Triglycerides/genetics, Young Adult, General Biochemistry, Genetics and Molecular Biology, Article, White People, CARBOXYLASE, 03 medical and health sciences, Physics and Astronomy (all), MESH: Muscle Proteins, Asian People, Lifelines Cohort Study, SNP, METAANALYSIS, Ancestry, MESH: Adolescent, Biochemistry, Genetics and Molecular Biology (all), MESH: Humans, Science & Technology, Calcium-Binding Proteins, MESH: Adult, MESH: Microtubule-Associated Proteins, 030104 developmental biology, chemistry, MESH: Genome-Wide Association Study, lcsh:Q, MESH: African Continental Ancestry Group, Chemistry (all), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Brazil, MESH: Female, Transcription Factors, 0301 basic medicine, General Physics and Astronomy, Blood lipids, Muscle Proteins, MESH: Calcium-Binding Proteins, chemistry.chemical_compound, MESH: Aged, 80 and over, MESH: Cholesterol, WIDE ASSOCIATION, African Continental Ancestry Group, Genetics, MESH: Aged, Multidisciplinary, Public Health, Global Health, Social Medicine and Epidemiology, 021001 nanoscience & nanotechnology, Multidisciplinary Sciences, lipids (amino acids, peptides, and proteins), Medical Genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Microtubule-Associated Proteins, Asian Continental Ancestry Group, Black People, Nerve Tissue Proteins, Biology, MESH: Genetic Loci, MD Multidisciplinary, Triglycerides, Medicinsk genetik, MESH: LIM-Homeodomain Proteins, Triglyceride, MESH: Hispanic Americans, Cholesterol, HDL, Genome-wide analyses, Membrane Proteins, Lipid metabolism, General Chemistry, Cholesterol, LDL, Arfgengi, MESH: Lipids, MESH: Male, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, INDIVIDUALS, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Exercise, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: Publisher's version (útgefin grein), Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels., The present work was largely supported by a grant from the US National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (R01HL118305). The full list of acknowledgments appears in the Supplementary Notes 3 and 4.
Published: 2018

23. New age-related hearing loss candidate genes in humans: an ongoing challenge

Author: Valerio Marino, S. Bassani, Giorgia Girotto, Daniele Dell'Orco, Paolo Gasparini, Anna Morgan, M. Di Stazio, Marco Brumat, P. Garagnani, C. Giuliani, Di Stazio M., Morgan A., Brumat M., Bassani S., Dell'Orco D., Marino V., Garagnani P., Giuliani C., Gasparini P., Girotto G., Di Stazio, M., Morgan, A., Brumat, M., Bassani, S., Dell'Orco, D., Marino, V., Garagnani, P., Giuliani, C., Gasparini, P., and Girotto, G.
Subjects: Male, 0301 basic medicine, Candidate gene, Membrane Transport Protein, Cell Cycle Proteins, Age-related hearing loss gene discovery, Genome-wide association study, Protein-Serine-Threonine Kinase, Severity of Illness Index, Cohort Studies, Mice, Doublecortin-Like Kinases, 0302 clinical medicine, HEK293 Cell, Cell Cycle Protein, Zebrafish, Aged, 80 and over, in vitro studies, biology, Intracellular Signaling Peptides and Proteins, Protein modelling, General Medicine, Presbycusis, Middle Aged, Cadherins, Italy, 030220 oncology & carcinogenesis, Models, Animal, Cohort, Female, medicine.symptom, Case-Control Studie, In vitro studie, Human, Hearing loss, In silico, Presbycusi, Nerve Tissue Proteins, Computational biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, 03 medical and health sciences, Audiometry, Hair Cells, Auditory, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene, Allele frequency, gene expression, protein modelling, Aged, Whole Genome Sequencing, Animal, Gene Expression Profiling, Membrane Transport Proteins, biology.organism_classification, Protocadherins, HEK293 Cells, 030104 developmental biology, Intracellular Signaling Peptides and Protein, Case-Control Studies, Mutation, Nerve Tissue Protein, Cadherin, Gene expression, Cohort Studie
Abstract: Age-related hearing loss (ARHL) is the most frequent sensory disorder in the elderly, affecting approximately one-third of people aged more than 65 years. Despite a large number of people affected, ARHL is still an area of unmet clinical needs, and only a few ARHL susceptibility genes have been detected so far. In order to further investigate the genetics of ARHL, we analyzed a series of 46 ARHL candidate genes, selected according to previous Genome Wide Association Studies (GWAS) data, literature updates and animal models, in a large cohort of 464 Italian ARHL patients. We have filtered the variants according to a) pathogenicity prediction, b) allele frequency in public databases, c) allele frequency in an internal cohort of 113 healthy matched controls, and 81 healthy semi-supercentenarians. After data analysis, all the variants of interest have been tested by functional “in silico” or “in vitro” experiments (i.e., molecular dynamics simulations and protein translation analysis) to assess their pathogenic role, and the expression of the mutated genes have been checked in mouse or zebrafish inner ear. This multi-step approach led to the characterization of a series of ultra-rare likely pathogenic variants in DCLK1, SLC28A3, CEP104, and PCDH20 genes, contributing to describe the first association of these genes with ARHL in humans. These results provide essential insights on the understanding of the molecular bases of such a complex, heterogeneous and frequent disorder, unveiling new possible targets for the future development of innovative therapeutic and preventive approaches that could improve the quality of life of the millions of people affected worldwide.
Published: 2020

24. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Alison Pattie, Ailith Pirie, Francis S. Collins, Charles Kooperberg, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Lisa Bastarache, Allan Linneberg, Peter T. Campbell, Helena Kuivaniemi, Struan F.A. Grant, Sascha Fauser, Sekar Kathiresan, Lars Lind, Erin B. Ware, Olli T. Raitakari, Dawn M. Waterworth, James G. Wilson, Markus Perola, Chris J. Packard, Michelle L. O'Donoghue, Fredrik Karpe, Roel A. Ophoff, Sailaja Vedantam, Artitaya Lophatananon, Uwe Völker, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Craig E. Pennell, Xueling Sim, Jennifer E. Huffman, Sandosh Padmanabhan, Digna R. Velez Edwards, Michiel L. Bots, Ayush Giri, Renée de Mutsert, Emanuele Di Angelantonio, Nicholas J. Wareham, Jin Li, Gail P. Jarvik, Evangelos Evangelou, Anne Tybjærg-Hansen, Patricia B. Munroe, Penny Gordon-Larsen, Lia E. Bang, Ivan Brandslund, Hester M. den Ruijter, Jussi Hernesniemi, Nancy L. Heard-Costa, Angela L. Mazul, Jonathan Tyrer, Danish Saleheen, Mark J. Caulfield, John Andrew Pospisilik, Annette Peters, Caroline Hayward, Iris M. Heid, J. Wouter Jukema, Valérie Turcot, Matt Neville, Rudolf Uher, Patricia A. Peyser, Jessica D. Faul, Asif Rasheed, Shuai Wang, John C. Chambers, Jordi Corominas Galbany, Murray H. Brilliant, Yucheng Jia, Torben Hansen, Veikko Salomaa, Mary F. Feitosa, Mathias Gorski, Li-An Lin, George Dedoussis, Honghuang Lin, Ethan M. Lange, Veronique Vitart, Bratati Kahali, Alexander Teumer, Jerome I. Rotter, Wayne H-H Sheu, Vilmantas Giedraitis, Aliki-Eleni Farmaki, Lorraine Southam, Ele Ferrannini, Anette P. Gjesing, Krina T. Zondervan, Stavroula Kanoni, David J. Roberts, Rebecca S. Fine, Svati H. Shah, Tugce Karaderi, Claudia Langenberg, Stefan Johansson, Elizabeth K. Speliotes, Alexander P. Reiner, Ching-Ti Liu, Yiqin Wang, Pål R. Njølstad, Gabriel Cuellar-Partida, Amanda J. Cox, Tim D. Spector, Paul W. Franks, Anke Tönjes, John D. Rioux, Jeffrey Haessler, Paul L. Auer, Ingrid B. Borecki, Deborah J. Thompson, Weihua Zhang, John R. B. Perry, Paul Elliott, Folkert W. Asselbergs, Myriam Fornage, Ken Sin Lo, Marie Moitry, Paul Mitchell, Martin den Heijer, Zoltán Kutalik, Tune H. Pers, Kari Stefansson, Kari Kuulasmaa, Robert E. Schoen, Mark C.H. De Groot, Laura M. Yerges-Armstrong, Jing Hua Zhao, Beverley Balkau, Peggy L. Peissig, Michael Boehnke, Janie Corley, Katharine R. Owen, Unnur Thorsteinsdottir, Naveed Sattar, Sita H. Vermeulen, Thomas N. Person, Mark I. McCarthy, Paul I.W. de Bakker, David Lamparter, Poorva Mudgal, Nicholette D. Palmer, Maria Karaleftheri, Jan-Håkan Jansson, Ozren Polasek, Ruth J. F. Loos, Daniel R. Witte, Dermot F. Reilly, Anubha Mahajan, Stella Trompet, James A. Perry, Yingchang Lu, Claudia Schurmann, Yii-Der Ida Chen, Hidetoshi Kitajima, Dale R. Nyholt, John Danesh, Pamela J. Schreiner, Narisu Narisu, Jose C. Florez, Adelheid Lempradl, Gerome Breen, Torben Jørgensen, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Vilmundur Gudnason, Timo A. Lakka, Heather M. Highland, Sven Bergmann, Marie-Pierre Dubé, Giovanni Veronesi, Martina Müller-Nurasyid, Jaakko Tuomilehto, Nele Friedrich, Joel N. Hirschhorn, Pia R. Kamstrup, Nilesh J. Samani, Josh C. Denny, Mika Kähönen, Massimiliano Cocca, Liang Sun, Karina Meidtner, Carsten A. Böger, Sara M. Willems, Marcelo P. Segura-Lepe, Johanna Kuusisto, Hanieh Yaghootkar, Konstantin Strauch, Ruth Frikke-Schmidt, Jane Gibson, Matti Uusitupa, Oscar H. Franco, Yongmei Liu, Heather M. Stringham, Rohit Varma, Grant W. Montgomery, Dennis O. Mook-Kanamori, Stefania Cappellani, Paul L. Huang, Albert V. Smith, Eric Kim, Anke R. Hammerschlag, Katherine S. Ruth, Carolina Medina-Gomez, Gerard Pasterkamp, Cristen J. Willer, Alisa K. Manning, Frida Renström, René S. Kahn, Lili Milani, Feijie Wang, Tessel E. Galesloot, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Adam S. Butterworth, Tamara B. Harris, Matthew A. Allison, Paul M. Ridker, David J. Carey, Todd L. Edwards, Panos Deloukas, Xiuqing Guo, Lawrence F. Bielak, Leena Moilanen, Heiner Boeing, Peter Kovacs, Karen L. Mohlke, Myriam Rheinberger, Cramer Christensen, Betina H. Thuesen, Mike A. Nalls, Erik Ingelsson, Nicholas G. D. Masca, Colin N. A. Palmer, Audrey E. Hendricks, Linda Broer, Vanisha Mistry, Praveen Surendran, Audrey Y. Chu, Rainer Rauramaa, Angela D'Eustacchio, Helen Griffiths, Satu Männistö, Patrick T. Ellinor, Terho Lehtimäki, Katherine E. Tansey, I. Sadaf Farooqi, Gaëlle Marenne, Anneke I. den Hollander, Jessica van Setten, Hannu Puolijoki, Tinca J. C. Polderman, Timothy M. Frayling, Niels Grarup, Eric Boerwinkle, Gonçalo R. Abecasis, Adam E. Locke, Mengmeng Du, Manuel A. Rivas, Philippe Amouyel, Jaakko Kaprio, Leslie A. Lange, Loes M. Olde Loohuis, Trevor A. Mori, Lambertus A. Kiemeney, Wei Zhao, Eva Rb Petersen, Huaixing Li, Thomas W. Winkler, Tellervo Korhonen, Kathleen Stirrups, Jean Ferrières, Wei Zhou, Ian J. Deary, Guillaume Lettre, M. Arfan Ikram, Alex W. Hewitt, Marit E. Jørgensen, Ian Ford, Liang He, Mark Walker, Stefan Gustafsson, Andre Franke, Yao Hu, Jaana Lindström, Jonathan P. Bradfield, Anne E. Justice, Kristin L. Young, Sander W. van der Laan, Shuang Feng, Yadav Sapkota, Douglas F. Easton, Cornelia M. van Duijn, Amy J. Swift, Kjell Nikus, Helen R. Warren, Christian Theil Have, Wei Gan, Steven A. Lubitz, Harvey D. White, Pirjo Komulainen, John M. Starr, Jeffrey R. O'Connel, Anette Varbo, Daniel I. Chasman, Ruifang Li-Gao, Lynne E. Wagenknecht, Matthias Blüher, Xiaowei Zhan, Thomas F. Vogt, Eleftheria Zeggini, Tamuno Alfred, Katja K.H. Aben, Lars Wallentin, Joanna M. M. Howson, Jie Yao, Eulalia Catamo, Henrik Vestergaard, Gina M. Peloso, Markku Laakso, Matthias B. Schulze, Hayato Tada, Jennifer Wessel, Andrew R. Wood, Erwin P. Bottinger, Cora E. Lewis, Robin Young, Carol A. Wang, Oddgeir L. Holmen, Andrew J. Slater, Jean-Claude Tardif, Xu Lin, Inês Barroso, Gail Davies, Tibor V. Varga, Andrew J. Lotery, Igor Rudan, Andrew T. Hattersley, Michael Stumvoll, David Ellinghaus, Andrew C. Heath, Frank Kee, Christopher P. Nelson, Donald W. Bowden, Alison M. Dunning, Marianne Benn, Oluf Pedersen, Amber A. Burt, Aniruddh P. Patel, G. Kees Hovingh, David S. Crosslin, Gorm B. Jensen, Keng-Hung Lin, Dewan S. Alam, Jian'an Luan, Ying Wu, Tõnu Esko, Kathleen Mullan Harris, Antonietta Robino, Anne U. Jackson, Eirini Marouli, Robert A. Scott, Jette Bork-Jensen, Olov Rolandsson, Nanette R. Lee, Gerard Tromp, Megan L. Grove, Suthesh Sivapalaratnam, Sameer E. Al-Harthi, Roberta McKean-Cowdin, Paolo Gasparini, Ellen W. Demerath, Marco Brumat, Maggie C.Y. Ng, Børge G. Nordestgaard, Kari E. North, Rajiv Chowdhury, Mauno Vanhala, Andrew P. Morris, Sarah E. Medland, Sune F. Nielsen, Ilaria Gandin, Øyvind Helgeland, James P. Cook, Kent D. Taylor, Andrew D. Morris, Gudmar Thorleifsson, André G. Uitterlinden, Pang Yao, Valgerdur Steinthorsdottir, Eric B. Larson, Kerrin S. Small, Cecilia M. Lindgren, Dragana Vuckovic, Mariaelisa Graff, Fotios Drenos, Jaspal S. Kooner, Schurmann, Claudia [0000-0003-4158-9192], Justice, Anne E [0000-0002-8903-8712], Giri, Ayush [0000-0002-7786-4670], Locke, Adam E [0000-0001-6227-198X], Young, Kristin L [0000-0003-0070-6145], Medina-Gomez, Carolina [0000-0001-7999-5538], Winkler, Thomas W [0000-0003-0292-5421], Zeggini, Eleftheria [0000-0003-4238-659X], Zhao, Wei [0000-0002-8301-9297], Zondervan, Krina T [0000-0002-0275-9905], Pospisilik, John A [0000-0002-9745-0977], Rivadeneira, Fernando [0000-0001-9435-9441], Deloukas, Panos [0000-0001-9251-070X], Apollo - University of Cambridge Repository, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Radiology & Nuclear Medicine, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), National Institute for Health Research, Home Office, National Institutes of Health, Imperial College Healthcare NHS Trust- BRC Funding, Turcot, Valérie, Lu, Yingchang, Highland, Heather M., Schurmann, Claudia, Justice, Anne E., Fine, Rebecca S., Bradfield, Jonathan P., Esko, Tõnu, Giri, Ayush, Graff, Mariaelisa, Guo, Xiuqing, Hendricks, Audrey E., Karaderi, Tugce, Lempradl, Adelheid, Locke, Adam E., Mahajan, Anubha, Marouli, Eirini, Sivapalaratnam, Suthesh, Young, Kristin L., Alfred, Tamuno, Feitosa, Mary F., Masca, Nicholas G. D., Manning, Alisa K., Medina-Gomez, Carolina, Mudgal, Poorva, Ng, Maggie C. Y., Reiner, Alex P., Vedantam, Sailaja, Willems, Sara M., Winkler, Thomas W., Abecasis, Gonçalo, Aben, Katja K., Alam, Dewan S., Alharthi, Sameer E., Allison, Matthew, Amouyel, Philippe, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Bang, Lia E., Barroso, Inê, Bastarache, Lisa, Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blüher, Matthia, Boehnke, Michael, Boeing, Heiner, Boerwinkle, Eric, Böger, Carsten A., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Brumat, Marco, Burt, Amber A., Butterworth, Adam S., Campbell, Peter T., Cappellani, Stefania, Carey, David J., Catamo, Eulalia, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der I., Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Corominas Galbany, Jordi, Cox, Amanda J., Crosslin, David S., Cuellar-Partida, Gabriel, D'Eustacchio, Angela, Danesh, John, Davies, Gail, Bakker, Paul I. W., Groot, Mark C. H., Mutsert, Renée, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., Heijer, Martin, Hollander, Anneke I., Ruijter, Hester M., Dennis, Joe G., Denny, Josh C., Angelantonio, Emanuele, Drenos, Fotio, Du, Mengmeng, Dubé, Marie-Pierre, Dunning, Alison M., Easton, Douglas F., Edwards, Todd L., Ellinghaus, David, Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelo, Farmaki, Aliki-Eleni, Farooqi, I. Sadaf, Faul, Jessica D., Fauser, Sascha, Feng, Shuang, Ferrannini, Ele, Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franco, Oscar H., Franke, Andre, Franks, Paul W., Friedrich, Nele, Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Gibson, Jane, Giedraitis, Vilmanta, Gjesing, Anette P., Gordon-Larsen, Penny, Gorski, Mathia, Grabe, Hans-Jörgen, Grant, Struan F. A., Grarup, Niel, Griffiths, Helen L., Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeff, Hakonarson, Hakon, Hammerschlag, Anke R., Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Have, Christian T., Hayward, Caroline, He, Liang, Heard-Costa, Nancy L., Heath, Andrew C., Heid, Iris M., Helgeland, Øyvind, Hernesniemi, Jussi, Hewitt, Alex W., Holmen, Oddgeir L., Hovingh, G. Kee, Howson, Joanna M. M., Hu, Yao, Huang, Paul L., Huffman, Jennifer E., Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Håkan, Jarvik, Gail P., Jensen, Gorm B., Jia, Yucheng, Johansson, Stefan, Jørgensen, Marit E., Jørgensen, Torben, Jukema, J. Wouter, Kahali, Bratati, Kahn, René S., Kähönen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kathiresan, Sekar, Kee, Frank, Kiemeney, Lambertus A., Kim, Eric, Kitajima, Hidetoshi, Komulainen, Pirjo, Kooner, Jaspal S., Kooperberg, Charle, Korhonen, Tellervo, Kovacs, Peter, Kuivaniemi, Helena, Kutalik, Zoltán, Kuulasmaa, Kari, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lamparter, David, Lange, Ethan M., Lange, Leslie A., Langenberg, Claudia, Larson, Eric B., Lee, Nanette R., Lehtimäki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Keng-Hung, Lin, Li-An, Lin, Xu, Lind, Lar, Lindström, Jaana, Linneberg, Allan, Liu, Ching-Ti, Liu, Dajiang J., Liu, Yongmei, Lo, Ken S., Lophatananon, Artitaya, Lotery, Andrew J., Loukola, Anu, Luan, Jian'An, Lubitz, Steven A., Lyytikäinen, Leo-Pekka, Männistö, Satu, Marenne, Gaëlle, Mazul, Angela L., Mccarthy, Mark I., McKean-Cowdin, Roberta, Medland, Sarah E., Meidtner, Karina, Milani, Lili, Mistry, Vanisha, Mitchell, Paul, Mohlke, Karen L., Moilanen, Leena, Moitry, Marie, Montgomery, Grant W., Mook-Kanamori, Dennis O., Moore, Carmel, Mori, Trevor A., Morris, Andrew D., Morris, Andrew P., Müller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Narisu, Narisu, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njølstad, Pål R., Nordestgaard, Børge G., Nyholt, Dale R., O'Connel, Jeffrey R., O'Donoghue, Michelle L., Olde Loohuis, Loes M., Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Palmer, Nicholette D., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Marku, Perry, James A., Perry, John R. B., Pers, Tune H., Person, Thomas N., Peters, Annette, Petersen, Eva R. B., Peyser, Patricia A., Pirie, Ailith, Polasek, Ozren, Polderman, Tinca J., Puolijoki, Hannu, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Renström, Frida, Rheinberger, Myriam, Ridker, Paul M., Rioux, John D., Rivas, Manuel A., Roberts, David J., Robertson, Neil R., Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sapkota, Yadav, Sattar, Naveed, Schoen, Robert E., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati H., Sheu, Wayne H. -H., Sim, Xueling, Slater, Andrew J., Small, Kerrin S., Smith, Albert V., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Stefansson, Kari, Steinthorsdottir, Valgerdur, Stirrups, Kathleen E., Strauch, Konstantin, Stringham, Heather M., Stumvoll, Michael, Sun, Liang, Surendran, Praveen, Swift, Amy J., Tada, Hayato, Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Thuesen, Betina H., Tönjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, André G., Uusitupa, Matti, Laan, Sander W., Duijn, Cornelia M., Leeuwen, Nienke, Van Setten, Jessica, Vanhala, Mauno, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Velez Edwards, Digna R., Vermeulen, Sita H., Veronesi, Giovanni, Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Völker, Uwe, Vuckovic, Dragana, Wagenknecht, Lynne E., Walker, Mark, Wallentin, Lar, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Ware, Erin B., Wareham, Nicholas J., Warren, Helen R., Waterworth, Dawn M., Wessel, Jennifer, White, Harvey D., Willer, Cristen J., Wilson, James G., Witte, Daniel R., Wood, Andrew R., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zhou, Wei, Zondervan, Krina T, Rotter, Jerome I., Pospisilik, John A., Rivadeneira, Fernando, Borecki, Ingrid B., Deloukas, Pano, Frayling, Timothy M., Lettre, Guillaume, North, Kari E., Lindgren, Cecilia M., Hirschhorn, Joel N., Loos, Ruth J. F., Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Physiology, and VU University medical center
Subjects: 0301 basic medicine, Male, ReproGen Consortium, MathematicsofComputing_GENERAL, Genome-wide association study, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Body Mass Index, genetics [Obesity], 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Adult, Animals, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Genetic Variation, Humans, Obesity/genetics, Proteins/genetics, Syndrome, 11 Medical and Health Sciences, 2. Zero hunger, Genetics, Genetics & Heredity, Mutation, CHD Exome+ Consortium, body mass index, TheoryofComputation_GENERAL, T2D-Genes Consortium, GENOME-WIDE ASSOCIATION, MELANOCORTIN-4 RECEPTOR GENE, DONEPEZIL 23 MG, FRAMESHIFT MUTATION, GLUCOSE-HOMEOSTASIS, HYPOTHALAMIC AMPK, CODING VARIANTS, BLOOD-PRESSURE, RARE, LOCI, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Drosophila, ExomeBP Consortium, Life Sciences & Biomedicine, INTERVAL Study, Understanding Society Scientific Group, EPIC InterAct Consortium, genetics [Energy Metabolism], Biology, EPIC-CVD Consortium, Frameshift mutation, 03 medical and health sciences, MAGIC Investigators, All institutes and research themes of the Radboud University Medical Center, Genetic, SDG 3 - Good Health and Well-being, ddc:570, genetics [Drosophila], medicine, Journal Article, Global Lipids Genetic Consortium, Obesity, Gene, Allele frequency, Genetic association, Science & Technology, Proteins, 06 Biological Sciences, genetics [Proteins], Minor allele frequency, 030104 developmental biology, GoT2D Genes Consortium, Energy Intake, Energy Metabolism, genetics [Energy Intake], 030217 neurology & neurosurgery, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Published: 2018

25. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract: 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. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
Published: 2018

26. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Author: Rico Rueedi, Yuri Milaneschi, Brenda W.J.H. Penninx, Neil Poulter, Karen Schwander, Marco Brumat, Kenneth Rice, Yize Li, Veronique Vitart, Ioanna Ntalla, Michele K. Evans, Jeffrey R. O'Connell, Nilesh J. Samani, Colleen M. Sitlani, W. James Gauderman, Xuan Deng, Paul M. Ridker, Yun J. Sung, Yukihide Momozawa, Archie Campbell, Tin Louie, Nona Sotoodehnia, Yii-Der Ida Chen, Cornelia M. van Duijn, Tanika N. Kelly, Peter S. Sever, André G. Uitterlinden, Brigitte Kühnel, John M. Starr, Lawrence F. Bielak, Christopher P. Nelson, Wanqing Wen, Stephan B. Felix, Stefan Weiss, Daniel Levy, Nicholette D. Palmer, Alisa K. Manning, Salman M. Tajuddin, Jill M. Norris, Marie Loh, M. Abdullah Said, Alena Stančáková, Anuradhani Kasturiratne, John M. C. Connell, Jian'an Luan, Tuomas O. Kilpeläinen, Amy R. Bentley, Stephen Sidney, Alan B. Zonderman, Karin Leander, David J. Porteous, Jianjun Liu, Tin Aung, Charles B. Eaton, Sharon L.R. Kardia, Rajkumar Dorajoo, Stephen Turner, Michael Boehnke, Diane M. Becker, Cora E. Lewis, Ozren Polasek, Mickaël Canouil, Kurt Lohman, Georg Ehret, Sarah E. Harris, Robert A. Scott, Claude Bouchard, Lynne E. Wagenknecht, Mohsen Ghanbari, Stephen B. Kritchevsky, Jin-Fang Chai, Gregory L. Burke, Jiang He, Federica Laguzzi, Michael R. Brown, Walter Palmas, Lili Milani, Thomas T. Perls, Tibor V. Varga, José Eduardo Krieger, Erin B. Ware, Tamara B. Harris, Tomohiro Katsuya, Nicole Schupf, Mika Kähönen, Nana Matoba, Hugues Aschard, Ilaria Gandin, Jennifer A. Smith, Traci M. Bartz, James Scott, Tuomo Rankinen, Yuan Shi, Meian He, Timo A. Lakka, Helen R. Warren, Mike A. Nalls, Kent D. Taylor, Woon-Puay Koh, Ya Xing Wang, Muhammad Riaz, Sandosh Padmanabhan, Mary F. Feitosa, Jost B. Jonas, Paul Elliott, Christian Gieger, Terho Lehtimäki, Kaare Christensen, Maris Alver, Pirjo Komulainen, Pamela J. Schreiner, M. Arfan Ikram, David R. Weir, Charles Kooperberg, Oscar H. Franco, Yongmei Liu, Lisa de las Fuentes, Nancy L. Pedersen, Thomas W. Winkler, Bruna Gigante, Göran Hallmans, Ingrid B. Borecki, Shiow Lin, Ian J. Deary, Wei Zheng, Yajuan Wang, Bernardo L. Horta, Heather M. Stringham, Bruce M. Psaty, Paul W. Franks, Weihua Zhang, Nora Franceschini, Adolfo Correa, Nita G. Forouhi, Xiuqing Guo, Fumihiko Takeuchi, L. Adrienne Cupples, William R. Scott, Zoltán Kutalik, He Gao, Nicholas J. Wareham, E. Shyong Tai, Aravinda Chakravarti, C. Charles Gu, Paolo Gasparini, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Colin A. McKenzie, Qing Duan, Aldi T. Kraja, Carsten Oliver Schmidt, Bamidele O. Tayo, Xiaofeng Zhu, Thomas Meitinger, Mary K. Wojczynski, Markku Laakso, Mark J. Caulfield, Carl D. Langefeld, Jingzhong Ding, Yechiel Friedlander, Tien Yin Wong, Virginia Fisher, Raymond Noordam, Caizheng Yu, Pim van der Harst, Yik Ying Teo, Ervin R. Fox, Sabanayagam Charumathi, Jonathan Marten, Nicholas Y.Q. Tan, Jerome I. Rotter, Harold Snieder, Karen L. Mohlke, Christine Williams, Olli T. Raitakari, Renée de Mutsert, Lihua Wang, Kathryn Roll, Jingmin Liu, Dongfeng Gu, Wei Zhao, Lynda M. Rose, Michael A. Province, Fernando Pires Hartwig, Rob M. van Dam, Barry I. Freedman, Andres Metspalu, Donald W. Bowden, Andrea R. V. R. Horimoto, Martin Farrall, Frits R. Rosendaal, Rainer Rauramaa, Konstantin Strauch, Albert V. Smith, Yanick Hagemeijer, Michiaki Kubo, Ilja M. Nolte, Tõnu Esko, Yih Chung Tham, Cathy C. Laurie, Antonietta Robino, Anne U. Jackson, Chuan Gao, Dabeeru C. Rao, Xiao-Ou Shu, H. Janaka de Silva, Morris J. Brown, Alanna C. Morrison, Peter J. van der Most, Jian-Min Yuan, Melanie Waldenberger, Leslie J. Raffel, Ulrich John, Fang-Chi Hsu, Reedik Mägi, Solomon K. Musani, Chiea Chuen Khor, Mario Sims, Ruben N. Eppinga, Melissa A. Richard, Yoichiro Kamatani, Changwei Li, Qiuyin Cai, Daniel I. Chasman, Mathilde Boissel, Claudia Langenberg, Sami Heikkinen, Jasmin Divers, Saima Afaq, Wen Bin Wei, Jaspal S. Kooner, Terrence Forrester, Hua Tang, Charles N. Rotimi, Anuj Goel, Annette Peters, Tangchun Wu, Dennis O. Mook-Kanamori, Caroline Hayward, Ching-Yu Cheng, Lisa R. Yanek, Ananda R. Wickremasinghe, Chew-Kiat Heng, Myriam Fornage, Dina Vojinovic, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Jing Hua Zhao, Barbara V. Howard, Vilmundur Gudnason, Ulrich Broeckel, Eric Boerwinkle, Saskia P. Hagenaars, Dan E. Arking, Peter Vollenweider, Alexandre C. Pereira, Jie Yao, Makoto Hirata, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, Epidemiology, Erasmus MC other, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), University of Regensburg, Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Northwestern Polytechnical University [Xi'an] (NPU), Centre for Molecular Epidemiology, National University of Singapore (NUS), Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), National Institutes of Health [Bethesda] (NIH), The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., AGES (Age Gene/Environment Susceptibility Reykjavik Study) is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC (Atherosclerosis Risk in Communities): The authors thank the staff and participants of the ARIC study for their important contributions. CARDIA (Coronary Artery Risk Development in Young Adults): This manuscript has been reviewed and approved by CARDIA for scientific content. CHS (Cardiovascular Health Study): A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. IGMM (Institute of Genetics and Molecular Medicine): CROATIA-Korcula: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and the Croatian Institute for Public Health. We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the participants. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. GS:SFHS: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland. ERF (Erasmus Rucphen Family study): We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work, P. Snijders for his help in data collection and E.M. van Leeuwen for genetic imputation. GENOA (Genetic Epidemiology Network of Arteriopathy): Genotyping was performed at the Mayo Clinic (Stephen T. Turner, MD, Mariza de Andrade PhD, Julie Cunningham, PhD). We thank Eric Boerwinkle, PhD and Megan L. Grove from the Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, Texas, USA for their help with genotyping. We would also like to thank the families that participated in the GENOA study. HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span): Data analyses for the HANDLS study utilized the high-performance computational resources of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. http://hpc.nih.gov HUFS (Howard University Family Study): We thank the participants of the study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. HyperGEN (Hypertension Genetic Epidemiology Network): The study involves: University of Utah: (Network Coordinating Center, Field Center, and Molecular Genetics Lab), Univ. of Alabama at Birmingham: (Field Center and Echo Coordinating and Analysis Center), Medical College of Wisconsin: (Echo Genotyping Lab), Boston University: (Field Center), University of Minnesota: (Field Center and Biochemistry Lab), University of North Carolina: (Field Center), Washington University: (Data Coordinating Center), Weil Cornell Medical College: (Echo Reading Center), National Heart, Lung, & Blood Institute. For a complete list of HyperGEN Investigators: http://www.biostat.wustl.edu/hypergen/Acknowledge.html JHS (Jackson Heart Study): The authors wish to thank the staffs and participants of the JHS. MESA (Multi-Ethnic Study of Atherosclerosis): MESA and the MESA SHARe project are conducted in collaboration with MESA investigators. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. NEO (The Netherlands Epidemiology of Obesity study): The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Petra Noordijk, Pat van Beelen and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. RS (Rotterdam Study) was funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters and Carolina Medina-Gomez for their help in creating the GWAS database, and Karol Estrada, Yurii Aulchenko and Carolina Medina-Gomez for the creation and analysis of imputed data. WHI (Women’s Health Initiative): The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf Replication: AA-DHS (African American Diabetes Heart Study): The investigators acknowledge the cooperation of our Diabetes Heart Study (DHS) and AA-DHS participants. ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial): We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular, we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome chip array. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. BBJ (Biobank Japan Project): We thank all the participants, medical coordinators of the cooperating hospitals for collecting samples and clinical information in the project. BRIGHT (British Genetics of Hypertension): The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. CoLaus (Cohorte Lausannoise Study): The authors would like to thank all the people who participated in the recruitment of the participants, data collection and validation, particularly Nicole Bonvin, Yolande Barreau, Mathieu Firmann, François Bastardot, Julien Vaucher, Panagiotis Antiochos and Cédric Gubelmann. DESIR (Data from an Epidemiological Study on the Insulin Resistance): The DESIR Study Group is composed of Inserm-U1018 (Paris: B. Balkau, P. Ducimetière, E. Eschwège), Inserm-U367 (Paris: F. Alhenc-Gelas), CHU d’Angers (A. Girault), Bichat Hospital (Paris: F. Fumeron, M. Marre, R. Roussel), CHU de Rennes (F. Bonnet), CNRS UMR-8199 (Lille: A. Bonnefond, P. Froguel), Medical Examination Services (Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, LeMans, Orléans and Tours), Research Institute for General Medicine (J. Cogneau), the general practitioners of the region and the Cross- Regional Institute for Health (C. Born, E. Caces, M. Cailleau, N. Copin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol). DHS (Diabetes Heart Study): The authors thank the investigators, staff, and participants of the DHS for their valuable contributions. EGCUT Estonian Genome Center—University of Tartu (Estonian Biobank): Data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk: We thank all EPIC participants and staff for their contribution to the study. FENLAND (The Fenland Study): We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support from the Medical research council (MC_UU_12015/1). GeneSTAR (Genetic Studies of Atherosclerosis Risk): We are very grateful to all of our participants for their long-term involvement. GLACIER (Gene x Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk): We thank the participants, health professionals and data managers involved in the Västerbottens Intervention Project. We are also grateful to the staff of the Northern Sweden Biobank for preparing materials and to K Enqvist and T Johansson (Västerbottens County Council, Umeå, Sweden) for DNA preparation. HCHS/SOL (Hispanic Community Health Study/Study of Latinos): We thank the participants and staff of the HCHS/SOL study for their contributions to this study. HRS (Health & Retirement Study): Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. HyperGEN-AXIOM (Hypertension Genetic Epidemiology Network—Axiom Chip GWAS): We thank the study investigators, staff and participants for their value contributions. INGI (Italian Network Genetic Isolate): We thank all the inhabitants who participated to the projects. InterAct (The EPIC-InterAct Case-Cohort Study): We thank all EPIC participants and staff for their contribution to the study. IRAS (Insulin Resistance Atherosclerosis Study): The authors thank study investigators, staff, and participants for their valuable contributions. KORA (Cooperative Health Research in the Augsburg Region): We thank all KORA participants and staff for their contribution to the study. LBC1921 (Lothian Birth Cohort 1921): We thank the LBC1921 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LBC1936 (Lothian Birth Cohort 1936): We thank the LBC1936 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LifeLines (Lifelines Cohort Study): The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. Also, Lifelines acknowledges the contributions from Behrooz Z Alizadeh (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), H Marike Boezen (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Lude Franke (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Pim van der Harst (Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands), Gerjan Navis (Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands), Marianne Rots (Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands), Harold Snieder (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Morris Swertz (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Bruce HR Wolffenbuttel (Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands), Cisca Wijmenga (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands). LLFS (Long Life Family Study): The LLFS would like to thank the participants and research staff who make the study possible. LOLIPOP (London Life Sciences Prospective Population Study): We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. PROCARDIS (Precocious Coronary Artery Disease): The PROCARDIS researchers thank the patients for their selfless participation in this project. RHS (Ragama Health Study): The RHS was supported by the Grant of National Center for Global Health and Medicine (NCGM), Japan. SWHS/SMHS (Shanghai Women's Health Study/ Shanghai Men's Health Study): We thank all the individuals who took part in these studies and all the researchers who have enabled this work to be carried out. TRAILS (TRacking Adolescents’ Individual Lives Survey): TRAILS is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. We are grateful to all adolescents who participated in this research and to everyone who worked on this project and made it possible. UKB (United Kingdom Biobank, www.ukbiobank.ac.uk): This research has been conducted using the UK Biobank Resource. The UK Biobank data were analyzed from the data set corresponding to UK Biobank access application no. 236, application title 'Genome-wide association study of blood pressure', with Paul Elliott as the PI/applicant. This work was supported by the UK-CMC and the BP working group., InterAct Consortium, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Feitosa, Mary F., Kraja, Aldi T., Chasman, Daniel I., Sung, Yun J., Winkler, Thomas W., Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Bentley, Amy R., Brown, Michael R., Schwander, Karen, Richard, Melissa A., Noordam, Raymond, Aschard, Hugue, Bartz, Traci M., Bielak, Lawrence F., Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Lohman, Kurt K., Manning, Alisa K., Rankinen, Tuomo, Smith, Albert V., Tajuddin, Salman M., Wojczynski, Mary K., Alver, Mari, Boissel, Mathilde, Cai, Qiuyin, Campbell, Archie, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Luan, Jian'An, Matoba, Nana, Nolte, Ilja M., Padmanabhan, Sandosh, Riaz, Muhammad, Rueedi, Rico, Robino, Antonietta, Said, M. Abdullah, Scott, Robert A., Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O., Van Der Most, Peter J., Varga, Tibor V., Vitart, Veronique, Wang, Yajuan, Ware, Erin B., Warren, Helen R., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E., Aung, Tin, Boerwinkle, Eric, Borecki, Ingrid, Broeckel, Ulrich, Brown, Morri, Brumat, Marco, Burke, Gregory L., Canouil, Mickaël, Chakravarti, Aravinda, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M., Correa, Adolfo, De Las Fuentes, Lisa, De Mutsert, Renée, De Silva, H. Janaka, Deng, Xuan, Ding, Jingzhong, Duan, Qing, Eaton, Charles B., Ehret, Georg, Eppinga, Ruben N., Evangelou, Evangelo, Faul, Jessica D., Felix, Stephan B., Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Friedlander, Yechiel, Gandin, Ilaria, Gao, He, Ghanbari, Mohsen, Gigante, Bruna, Gu, C. Charle, Gu, Dongfeng, Hagenaars, Saskia P., Hallmans, Göran, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Howard, Barbara V., Ikram, M. Arfan, John, Ulrich, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Krieger, José E., Kritchevsky, Stephen B., Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lin, Shiow, Liu, Jianjun, Liu, Jingmin, Loh, Marie, Louie, Tin, Mägi, Reedik, Mckenzie, Colin A., Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L., Momozawa, Yukihide, Nalls, Mike A., Nelson, Christopher P., Sotoodehnia, Nona, Norris, Jill M., O'Connell, Jeff R., Palmer, Nicholette D., Perls, Thoma, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Poulter, Neil, Raffel, Leslie J., Raitakari, Olli T., Roll, Kathryn, Rose, Lynda M., Rosendaal, Frits R., Rotter, Jerome I., Schmidt, Carsten O., Schreiner, Pamela J., Schupf, Nicole, Scott, William R., Sever, Peter S., Shi, Yuan, Sidney, Stephen, Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Stringham, Heather M., Tan, Nicholas Y. Q., Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Turner, Stephen T., Uitterlinden, André G., Vollenweider, Peter, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Williams, Christine, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Deary, Ian J., Esko, Tõnu, Farrall, Martin, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S., Kutalik, Zoltán, Laakso, Markku, Laurie, Cathy C., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Polasek, Ozren, Porteous, David J., Rauramaa, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, Van Der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Bouchard, Claude, Christensen, Kaare, Evans, Michele K., Gudnason, Vilmundur, Horta, Bernardo L., Kardia, Sharon L. R., Liu, Yongmei, Pereira, Alexandre C., Psaty, Bruce M., Ridker, Paul M., Van Dam, Rob M., Gauderman, W. Jame, Zhu, Xiaofeng, Mook-Kanamori, Dennis O., Fornage, Myriam, Rotimi, Charles N., Cupples, L. Adrienne, Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Kooperberg, Charle, Palmas, Walter, Rice, Kenneth, Morrison, Alanna C., Elliott, Paul, Caulfield, Mark J., Munroe, Patricia B., Rao, Dabeeru C., Province, Michael A., Levy, Daniel, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Surgery, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, and Ehret, Georg Benedikt
Subjects: Genetics and Molecular Biology (all), Male, Erfðagreining, Áfengissýki, LOCI, Social Sciences, Blood Pressure, Genome-wide association study, Biochemistry, Vascular Medicine, TRANSCRIPTION FACTOR GATA4, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), DEPENDENCE, HEPATOCELLULAR-CARCINOMA, 80 and over, Psychology, Public and Occupational Health, Alcohol consumption, Cardiac and Cardiovascular Systems, Gene–environment interaction, ddc:616, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, Kardiologi, MESH: Polymorphism, Single Nucleotide, Áfengisneysla, MESH: Gene-Environment Interaction, COMMON VARIANTS, Genomics, MESH: Blood Pressure, Pedigree, 3. Good health, Näringslära, MESH: Young Adult, Physical Sciences, Medicine, Medical genetics, Erfðarannsóknir, Statistics (Mathematics), medicine.medical_specialty, Blood Pressure/genetics, Alcohol Drinking, MESH: Pedigree, Science, Genetic loci, ta3111, Genome Complexity, 03 medical and health sciences, Gene mapping, Genetics, Humans, Polymorphism, Statistical Methods, GENOME-WIDE ASSOCIATION, Molecular Biology Techniques, Molecular Biology, Alleles, Aged, MESH: Adolescent, MESH: Humans, Adolescent, Adult, Alcohol Drinking/epidemiology, Alcohol Drinking/genetics, Cohort Studies, Continental Population Groups/genetics, Continental Population Groups/statistics & numerical data, Female, Gene-Environment Interaction, Genetic Predisposition to Disease/epidemiology, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Hypertension/epidemiology, Hypertension/genetics, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Gene Mapping, Racial Groups, ta1182, Biology and Life Sciences, Computational Biology, MESH: Adult, Meta-analysis, 030104 developmental biology, Genetic Loci, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, Mathematics, MESH: Alcohol Drinking, Meta-Analysis, 0301 basic medicine, MESH: Continental Population Groups, MESH: Hypertension, Mathematical and Statistical Techniques, MESH: Aged, 80 and over, Polymorphism (computer science), Medicine and Health Sciences, FUNCTIONAL VARIATION, MESH: Cohort Studies, MESH: Aged, Alcohol Consumption, Multidisciplinary, Nutrition and Dietetics, MESH: Genetic Predisposition to Disease, Genetic Predisposition to Disease/epidemiology/genetics, Single Nucleotide, Blóðþrýstingur, ENVIRONMENT INTERACTION, PTP4A1-PHF3-EYS VARIANTS, Alcoholism, ANCESTRAIS, Háþrýstingur, Hypertension, Blood pressure, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Medical Genetics, Research Article, Substance-Related Disorders, Addiction, RISK, METAANALYSIS, Research and Analysis Methods, Mental Health and Psychiatry, medicine, Medicine [Science], Genetic Predisposition to Disease, Allele, Hypertension/epidemiology/genetics, Nutrition, Medicinsk genetik, Continental Population Groups/genetics/statistics & numerical data, business.industry, Alcohol Drinking/epidemiology/genetics, Genetic architecture, MESH: Male, Introns, Diet, BODY-MASS INDEX, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2018

27. Genomic studies in a large cohort of hearing impaired italian patients revealed several new alleles, a rare case of uniparental disomy (Upd) and the importance to search for copy number variations

Author: Marco Seri, Vanna Pecile, Flavio Faletra, Alberto Sensi, Anna Morgan, Poornima Gajendrarao, Fabio Sirchia, Sara Ghiselli, Stefania Lenarduzzi, Martina La Bianca, Stefania Cappellani, Enrico Grosso, Claudio Graziano, Marco Brumat, Eva Orzan, Marcello Morgutti, Umberto Ambrosetti, Giorgia Girotto, Paolo Gasparini, Morgan, Anna, Lenarduzzi, Stefania, Cappellani, Stefania, Pecile, Vanna, Morgutti, Marcello, Orzan, Eva, Ghiselli, Sara, Ambrosetti, Umberto, Brumat, Marco, Gajendrarao, Poornima, La Bianca, Martina, Faletra, Flavio, Grosso, Enrico, Sirchia, Fabio, Sensi, Alberto, Graziano, Claudio, Seri, Marco, Gasparini, Paolo, and Girotto, Giorgia
Subjects: 0301 basic medicine, Hereditary hearing loss, Italian families, Molecular diagnosis, SNP arrays, Targeted re-sequencing, lcsh:QH426-470, Genetic counseling, Biology, 03 medical and health sciences, Genetics, medicine, SNP, hereditary hearing loss, italian families, molecular diagnosis, targeted re-sequencing, Copy-number variation, TECTA, Allele, Genetics (clinical), molecular diagnosi, Original Research, ACTG1, Genetic heterogeneity, hereditary hearing lo, medicine.disease, Uniparental disomy, italian familie, lcsh:Genetics, 030104 developmental biology, Molecular Medicine, SNP array
Abstract: Hereditary hearing loss (HHL) is a common disorder characterized by a huge genetic heterogeneity. The definition of a correct molecular diagnosis is essential for proper genetic counseling, recurrence risk estimation, and therapeutic options. From 20 to 40% of patients carry mutations in GJB2 gene, thus, in more than half of cases it is necessary to look for causative variants in the other genes so far identified (~100). In this light, the use of next-generation sequencing technologies has proved to be the best solution for mutational screening, even though it is not always conclusive. Here we describe a combined approach, based on targeted re-sequencing (TRS) of 96 HHL genes followed by high-density SNP arrays, aimed at the identification of the molecular causes of non-syndromic HHL (NSHL). This strategy has been applied to study 103 Italian unrelated cases, negative for mutations in GJB2, and led to the characterization of 31% of them (i.e., 37% of familial and 26.3% of sporadic cases). In particular, TRS revealed TECTA and ACTG1 genes as major players in the Italian population. Furthermore, two de novo missense variants in ACTG1 have been identified and investigated through protein modeling and molecular dynamics simulations, confirming their likely pathogenic effect. Among the selected patients analyzed by SNP arrays (negative to TRS, or with a single variant in a recessive gene) a molecular diagnosis was reached in ~36% of cases, highlighting the importance to look for large insertions/deletions. Moreover, copy number variants analysis led to the identification of the first case of uniparental disomy involving LOXHD1 gene. Overall, taking into account the contribution of GJB2, plus the results from TRS and SNP arrays, it was possible to reach a molecular diagnosis in ~51% of NSHL cases. These data proved the usefulness of a combined approach for the analysis of NSHL and for the definition of the epidemiological picture of HHL in the Italian population.
Published: 2018

28. Genetic analysis of over one million people identifies 535 novel loci for blood pressure

Author: Lorenz Risch, Anne-Claire Vergnaud, Nguyen Quang Tri, Rona J. Strawbridge, Alan F. Wright, Francesco Cucca, Evan Tzanis, Caterina Barbieri, Jaakko Tuomilehto, Louise V. Wain, Jonathan Marten, James F. Wilson, Christopher Newton-Cheh, Reedik Mägi, Olli T. Raitakari, Peter W.F. Wilson, Joris Deelen, Morris Brown, Anna Morgan, Nabi Shah, Weihua Zhang, Ganesh Chauhan, Gail Davies, Peter S. Braund, Bram P. Prins, Alison Pattie, Marcus Dörr, Zoltán Kutalik, Marco Brumat, Franco Giulianini, Rainer Rettig, Uwe Völker, Georgios Ntritsos, Teresa Nutile, Todd L. Edwards, Albertine J. Oldehinkel, Christopher J. O'Donnell, Jaume Marrugat, Evangelos Evangelou, Nilesh J. Samani, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Francis S. Collins, Tim D. Spector, Simon Thom, Sarah E. Harris, Heather J. Cordell, Helen R. Warren, Cinzia Sala, Peter P. Pramstaller, Seppo Koskinen, Paul F. O'Reilly, Aravinda Chakravarti, Joshua C. Bis, Archie Campbell, Bernard Keavney, Sébastien Thériault, Gonneke Willemsen, Lynda M. Rose, Massimiliano Cocca, Jennifer E. Huffman, Meixia Ren, Massimo Mangino, Markus Perola, Joanna M. M. Howson, David Mosen-Ansorena, Harriëtte Riese, Martin Farrall, Albert V. Smith, Lenore J. Launer, Marina Ciullo, Antti-Pekka Sarin, Veikko Salomaa, Ilaria Gandin, Kent D. Taylor, Peter S. Sever, Markku Laakso, André G. Uitterlinden, Yan V. Sun, Raymond Noordam, Renée de Mutsert, Alan L. James, Jing Hua Zhao, Stefan Enroth, Andrew D. Morris, David S. Siscovick, Andrew D. Johnson, Igor Rudan, Tõnu Esko, Jun Ding, David P. Strachan, Martin D. Tobin, Christopher P. Nelson, Daniela Toniolo, J. Wouter Jukema, Vilmundur Gudnason, Borbala Mifsud, Marty Larson, Andrew A. Hicks, Adriana M. Hung, Antonietta Robino, Ruifang Li-Gao, Paul Elliott, Anne U. Jackson, Michela Traglia, Martin H. de Borst, Germaine C. Verwoert, Rheinhold Schmidt, Fabiola M Del Greco, Åsa Johansson, Anders Hamsten, Csaba P. Kovesdy, Mark J. Caulfield, Cumhur Y Demirkale, John M. C. Connell, Jian'an Luan, K. Witkowska, Georg Ehret, Cecilia M. Lindgren, Oscar H. Franco, Yongmei Liu, Ioanna Tzoulaki, Eric Boerwinkle, Catharina A. Hartman, Muralidharan Sargurupremraj, Claudia Langenberg, J. Michael Gaziano, Peter K. Joshi, Cornelia M. van Duijn, Maris Laan, Nick Shrine, Peter J. van der Most, Michael Boehnke, Leo-Pekka Lyytikäinen, Samuli Ripatti, Ben A. Oostra, Robert A. Scott, Lingchan Lu, Edward G. Lakatta, Yasaman Saba, Daniel Levy, Li Lin, Harold Schneider, Alex S. F. Doney, Michael R. Barnes, Najaf Amin, Hugh Watkins, Paul M. Ridker, Janina S Reid, Ayush Giri, Sekar Kathiresan, Lorna M. Lopez, Mike A. Nalls, Marina Evangelou, Erik Ingelsson, Lili Milani, Alice Stanton, Ozren Polasek, Sara M. Willems, Colin N. A. Palmer, Stéphanie Debette, Dan E. Arking, Helena Schmidt, Paul Knekt, John M. Starr, Yong Qian, Cristina Menni, Yuri Milaneschi, Christophe Tzourio, Tamara B. Harris, Kristin L. Ayers, Peter Vollenweider, Paolo Gasparini, Dennis O. Mook-Kanamori, Rodney J. Scott, Sandosh Padmanabhan, Anubha Mahajan, Peter Almgren, Jacklyn N. Hellwege, Teemu J. Niiranen, Mika Kähönen, Shih-Jen Hwang, Elizabeth G. Holliday, Edith Hofer, Priyanka Nandakumar, Peter J. Munson, Rick Jansen, Andrew P. Morris, Walter Palmas, Ilja M. Nolte, Siim Sõber, Thibaud Boutin, Ahmad Vaez, Albert Hofman, He Gao, Brenda W.J.H. Penninx, Neil Poulter, Alan J. Gow, Caroline Hayward, Nicholas J. Wareham, Elin Org, Philip S. Tsao, Claudia P. Cabrera, Aki S. Havulinna, Dragana Vuckovic, Kelly Cho, Jie Yao, Lars Lind, Jerome I. Rotter, David J. Stott, Ivana Kolcic, Wei-Yu Lin, Tatijana Zemunik, Tineka Blake, Kenneth Rice, Veronique Vitart, Alanna C. Morrison, Kay-Tee Khaw, Marjo-Riitta Järvelin, Guillaume Paré, Jouke-Jan Hottenga, Giorgia Girotto, Chiara Batini, Niki Dimou, Stella Trompet, John Danesh, Annette Peters, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Morris A. Swertz, Jaspal S. Kooner, Niek Verweij, Ibrahim Karaman, Murielle Bochud, Christian Gieger, Ruth J. F. Loos, Daniella Ruggiero, Arno Palotie, David Conen, Raha Pazoki, Denis C. Shields, Rossella Sorice, Philippe Amouyel, Gonçalo R. Abecasis, Andres Metspalu, John Attia, Bruce M. Psaty, Sarah H. Wild, Patricia B. Munroe, Daniel I. Chasman, Ollie Melander, John C. Chambers, Roby Joehanes, Eleftheria Zeggini, Johan Sundström, Chrysovalanto Mamasoula, Benjamin Lehne, Kati Kristiansson, Christopher Oldmeadow, Eco J. C. de Geus, A. Mesut Erzurumluoglu, Anuj Goel, Adam S. Butterworth, Digna R. Velez Edwards, Xiuqing Guo, Antti Jula, Praveen Surendran, Terho Lehtimäki, Mattias Frånberg, Teresa Ferreira, Ian J. Deary, David C. Liewald, Pim van der Harst, Erwin P. Bottinger, Roberto Elosua, and Fu Liang Ng
Subjects: Genetics, 0303 health sciences, Diastole, Disease, 030204 cardiovascular system & hematology, Biology, Precision medicine, Genetic analysis, 3. Good health, Pulse pressure, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Disease prevention, 030304 developmental biology, Genetic association
Abstract: High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one 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 reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.
Published: 2017

29. Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets from Blood and the Kidney

Author: Peter Vollenweider, Christophe Tzourio, Stefan Enroth, Cinzia Sala, Mark J. Caulfield, Murielle Bochud, Peter P. Pramstaller, Ozren Polasek, Paul Elliott, Dennis O. Mook-Kanamori, Daniel I. Chasman, Christian Gieger, Harriëtte Riese, Rodney J. Scott, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Priyanka Nandakumar, Tatijana Zemunik, Dragana Vuckovic, Tõnu Esko, Franco Giulianini, Michael Boehnke, Antonietta Robino, Anne U. Jackson, Roby Joehanes, Alanna C. Morrison, Kay-Tee Khaw, Alison Pattie, Peter J. van der Most, Mika Kähönen, Rick Jansen, Andrew D. Johnson, John M. Starr, Marcus Dörr, Anders Hamsten, Kenneth Rice, Alice Stanton, James F. Wilson, Nabi Shah, Weihua Zhang, Andrew A. Hicks, Jeffrey Damman, Jing Hua Zhao, Aarno Palotie, Veronique Vitart, Alan J. Gow, Caroline Hayward, Alan James, Ben A. Oostra, Janina S. Ried, John Beilby, David P. Strachan, Martin D. Tobin, Eco J. C. de Geus, Vilmundur Gudnason, Bruce M. Psaty, Zoltán Kutalik, Neil Poulter, Paul M. Ridker, Johan Sundström, Cornelia M. van Duijn, Eleftheria Zeggini, Christopher Oldmeadow, Borbala Mifsud, Giorgia Girotto, Aravinda Chakravarti, Jonathan Marten, Alexander Teumer, Joanne Knight, Robert A. Scott, Vilmantas Giedraitis, Paul F. O'Reilly, Marco Brumat, Brenda W.J.H. Penninx, Peter J. Munson, Olli T. Raitakari, Leo-Pekka Lyytikäinen, He Gao, Massimo Mangino, Benjamin Lehne, J. Wouter Jukema, Paul Knekt, Catharina A. Hartman, Rona J. Strawbridge, Jouke-Jan Hottenga, Jaspal S. Kooner, Nilesh J. Samani, Kristin L. Ayers, A. Mesut Erzurumluoglu, Joshua C. Bis, Archie Campbell, Dan E. Arking, Germaine C. Verwoert, John Attia, Samuli Ripatti, Yuri Milaneschi, Caterina Barbieri, Fabiola M. Del Greco, C M Lindgren, Peter K. Joshi, Helen R. Warren, Nicholas J. Wareham, Simon Thom, Seppo Koskinen, Tamara B. Harris, Ilaria Gandin, Kent D. Taylor, Andrew D. Morris, Anna Morgan, Chiara Batini, Terho Lehtimäki, Walter Palmas, David Conen, Harold Snieder, Martin H. de Borst, Sarah E. Harris, Igor Rudan, Ruth J. F. Loos, Claudia Langenberg, Anuj Goel, Christopher P. Nelson, Peter S. Braund, Rossella Sorice, Yasaman Saba, Oscar H. Franco, Yongmei Liu, Mattias Frånberg, David S. Siscovick, Patricia B. Munroe, Rainer Rettig, Michela Traglia, Daniel Levy, Li Lin, Michael R. Barnes, Elin Org, Anne-Claire Vergnaud, Andres Metspalu, Stéphanie Debette, Yusuf Demirkale, John M. C. Connell, Jian'an Luan, Paolo Gasparini, Tim D. Spector, Marina Ciullo, Antti-Pekka Sarin, Ian J. Deary, Teemu J. Niiranen, Marty Larson, Heather J. Cordell, Jerome I. Rotter, Sekar Kathiresan, Teresa Nutile, Andrew P. Morris, Denis C. Shields, Alan F. Wright, Lorna M. Lopez, Aki S. Havulinna, Gonçalo R. Abecasis, Edith Hofer, Siim Sõber, Sébastien Thériault, Ahmad Vaez, Albert Hofman, Gonneke Willemsen, Lynda M. Rose, John C. Chambers, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, François Mach, Massimiliano Cocca, Sarah H Wild, Reinhold Schmidt, Jaume Marrugat, Marc A. Seelen, Maris Laan, Aude Saint Pierre, David C. Liewald, Pim van der Harst, Sandosh Padmanabhan, Martin Farrall, Georg Ehret, Albert V. Smith, Quang Tri Nguyen, Ulf Gyllensten, Helena Schmidt, Ganesh Chauhan, Jennifer E. Huffman, Morris A. Swertz, Jaakko Tuomilehto, Louise V. Wain, Meixia Ren, Erwin P. Bottinger, Roberto Elosua, Ivana Kolcic, Veikko Salomaa, Stella Trompet, Bernard Keavney, Claudia P. Cabrera, Bram P. Prins, Jennie Hui, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Shih-Jen Hwang, Jie Yao, Francis S. Collins, Chrysovalanto Mamasoula, Kati Kristiansson, Markus Perola, Renée de Mutsert, Xiuqing Guo, Antti Jula, Daniela Toniolo, Ruifang Li-Gao, Åsa Johansson, Nick Shrine, Teresa Ferreira, Lars Lind, David J. Stott, Tineka Blake, Daniela Ruggiero, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Christopher Newton-Cheh, Marjo-Riitta Järvelin, Guillaume Paré, Joris Deelen, Morris Brown, Gail Davies, Annette Peters, Ioanna Tzoulaki, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Hugh Watkins, Yingchang Lu, Wain, Lv, Vaez, A, Jansen, R, Joehanes, R, van der Most, Pj, Erzurumluoglu, Am, O'Reilly, Pf, Cabrera, Cp, Warren, Hr, Rose, Lm, Verwoert, Gc, Hottenga, Jj, Strawbridge, Rj, Esko, T, Arking, De, Hwang, Sj, Guo, X, Kutalik, Z, Trompet, S, Shrine, N, Teumer, A, Ried, J, Bis, Jc, Smith, Av, Amin, N, Nolte, Im, Lyytikäinen, Lp, Mahajan, A, Wareham, Nj, Hofer, E, Joshi, Pk, Kristiansson, K, Traglia, M, Havulinna, A, Goel, A, Nalls, Ma, Sõber, S, Vuckovic, Dragana, Luan, J, Del Greco, M. F, Ayers, Kl, Marrugat, J, Ruggiero, D, Lopez, Lm, Niiranen, T, Enroth, S, Jackson, Au, Nelson, Cp, Huffman, Je, Zhang, W, Marten, J, Gandin, I, Harris, Se, Zemunik, T, Lu, Y, Evangelou, E, Shah, N, de Borst, Mh, Mangino, M, Prins, Bp, Campbell, A, Li Gao, R, Chauhan, G, Oldmeadow, C, Abecasis, G, Abedi, M, Barbieri, Cm, Barnes, Mr, Batini, C, Beilby, J, Blake, T, Boehnke, M, Bottinger, Ep, Braund, P, Brown, M, Brumat, M, Campbell, H, Chambers, Jc, Cocca, M, Collins, F, Connell, J, Cordell, Hj, Damman, Jj, Davies, G, de Geus, Ej, de Mutsert, R, Deelen, J, Demirkale, Y, Doney, Asf, Dörr, M, Farrall, M, Ferreira, T, Frånberg, M, Gao, H, Giedraitis, V, Gieger, C, Giulianini, F, Gow, Aj, Hamsten, A, Harris, Tb, Hofman, A, Holliday, Eg, Hui, J, Jarvelin, Mr, Johansson, Å, Johnson, Ad, Jousilahti, P, Jula, A, Kähönen, M, Kathiresan, S, Khaw, Kt, Kolcic, I, Koskinen, S, Langenberg, C, Larson, M, Launer, Lj, Lehne, B, Liewald, Dcm, Lin, L, Lind, L, Mach, F, Mamasoula, C, Menni, C, Mifsud, B, Milaneschi, Y, Morgan, Anna, Morris, Ad, Morrison, Ac, Munson, Pj, Nandakumar, P, Nguyen, Qt, Nutile, T, Oldehinkel, Aj, Oostra, Ba, Org, E, Padmanabhan, S, Palotie, A, Paré, G, Pattie, A, Penninx, Bwjh, Poulter, N, Pramstaller, Pp, Raitakari, Ot, Ren, M, Rice, K, Ridker, Pm, Riese, H, Ripatti, S, Robino, A, Rotter, Ji, Rudan, I, Saba, Y, Saint Pierre, A, Sala, Cf, Sarin, Ap, Schmidt, R, Scott, R, Seelen, Ma, Shields, Dc, Siscovick, D, Sorice, R, Stanton, A, Stott, Dj, Sundström, J, Swertz, M, Taylor, Kd, Thom, S, Tzoulaki, I, Tzourio, C, Uitterlinden, Ag, Völker, U, Vollenweider, P, Wild, S, Willemsen, G, Wright, Af, Yao, J, Thériault, S, Conen, D, Attia, J, Sever, P, Debette, S, Mook Kanamori, Do, Zeggini, E, Spector, Td, van der Harst, P, Palmer, Cna, Vergnaud, Ac, Loos, Rjf, Polasek, O, Starr, Jm, Girotto, Giorgia, Hayward, C, Kooner, J, Lindgren, Cm, Vitart, V, Samani, Nj, Tuomilehto, J, Gyllensten, U, Knekt, P, Deary, Ij, Ciullo, M, Elosua, R, Keavney, Bd, Hicks, Aa, Scott, Ra, Gasparini, Paolo, Laan, M, Liu, Y, Watkins, H, Hartman, Ca, Salomaa, V, Toniolo, D, Perola, M, Wilson, Jf, Schmidt, H, Zhao, Jh, Lehtimäki, T, van Duijn, Cm, Gudnason, V, Psaty, Bm, Peters, A, Rettig, R, James, A, Jukema, Jw, Strachan, Dp, Palmas, W, Metspalu, A, Ingelsson, E, Boomsma, Di, Franco, Oh, Bochud, M, Newton Cheh, C, Munroe, Pb, Elliott, P, Chasman, Di, Chakravarti, A, Knight, J, Morris, Ap, Levy, D, Tobin, Md, Snieder, H, Caulfield, Mj, Ehret, G. b., Home Office, Medical Research Council (MRC), National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Institute for Organ Transplantation (GIOT), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Epidemiology, Gastroenterology & Hepatology, Clinical Genetics, Internal Medicine, Erasmus MC other, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Epidemiology and Data Science, Division 6, APH - Mental Health, APH - Digital Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology
Subjects: 0301 basic medicine, cardiovascular risk, Netherlands Twin Register (NTR), hypertension, NETHERLANDS, Sistema cardiovascular -- Malalties, GWAS, blood pressure, complex traits, eSNP, Locus (genetics), Genome-wide association study, Disease, Biology, PERIPHERAL-BLOOD, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Internal Medicine, Journal Article, Cardiac and Cardiovascular Systems, 1000 Genomes Project, Gene, CENTRIC ARRAY, METAANALYSIS, Genetics, ddc:616, Kardiologi, PULSE PRESSURE, COMMON VARIANTS, 1103 Clinical Sciences, ta3121, 3. Good health, INDIVIDUALS, 030104 developmental biology, Blood pressure, TARGET, Cardiovascular System & Hematology, complex trait, GWAS, blood pressure, cardiovascular risk, complex traits, eSNP, hypertension, Hipertensió, Imputation (genetics), TRAITS
Abstract: 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 HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA . 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.
Published: 2017

30. Whole-genome sequencing reveals new insights into age-related hearing loss: cumulative effects, pleiotropy and the role of selection

Author: Eulalia Catamo, Mario Pirastu, Annamaria Franzè, Massimiliano Cocca, Dragana Vuckovic, Giorgia Girotto, Marco Brumat, Umberto Ambrosetti, Maria Pina Concas, Massimo Mezzavilla, Paolo Gasparini, Anna Morgan, Ginevra Biino, Vuckovic, Dragana, Mezzavilla, Massimo, Cocca, Massimiliano, Morgan, Anna, Brumat, Marco, Catamo, Eulalia, Concas, Maria Pina, Biino, Ginevra, Franzè, Annamaria, Ambrosetti, Umberto, Pirastu, Mario, Gasparini, Paolo, Girotto, Giorgia, Vuckovic, D., Mezzavilla, M., Cocca, M., Morgan, A., Brumat, M., Catamo, E., Concas, M. P., Biino, G., Franze, A., Ambrosetti, U., Pirastu, M., Gasparini, P., and Girotto, G.
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, Genetics, Genetics (clinical), Hearing loss, Presbycusi, Genome-wide association study, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic, Pleiotropy, medicine, Genetic Pleiotropy, Humans, Cognitive decline, Selection, Genetic, Gene, Aged, Whole genome sequencing, Natural selection, Polymorphism, Genetic, Whole Genome Sequencing, Middle Aged, Presbycusis, 030104 developmental biology, Female, medicine.symptom, 030217 neurology & neurosurgery, Human, Genome-Wide Association Study
Abstract: Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls. Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the "sensory perception of sound", suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and re-sequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.
Published: 2017

31. Novel blood pressure locus and gene discovery using GWAS and expression datasets from blood and the kidney

Author: Ganesh Chauhan, Dragana Vuckovic, Yingchang Lu, Bernard Keavney, Patricia B. Munroe, Tim D. Spector, Tamara B. Harris, Chiara Batini, Harold Snieder, Yusuf Demirkale, Ulf Gyllensten, Heather J. Cordell, Christopher Newton-Cheh, Anne-Claire Vergnaud, Christophe Tzourio, Giorgia Girotto, Morris A. Swertz, John C. Chambers, Xiuqing Guo, Caterina Barbieri, Joris Deelen, Morris Brown, Igor Rudan, Christopher P. Nelson, Paul Knekt, Antti-Pekka Sarin, Peter Vollenweider, Lynda M. Rose, Ozren Polasek, Nilesh J. Samani, Murielle Bochud, James F. Wilson, Anna Morgan, Gail Davies, Ian J. Deary, Massimiliano Cocca, Antti Jula, Ioanna Tzoulaki, Jaspal S. Kooner, Sarah H Wild, Peter S. Braund, John M. Starr, Simon Thom, Christian Gieger, Rainer Rettig, John M. C. Connell, Marina Ciullo, Jian'an Luan, Rodney J. Scott, Franco Giulianini, Brenda W.J.H. Penninx, Mika Kähönen, Alison Pattie, Nabi Shah, Weihua Zhang, Ruth J. F. Loos, Maris Laan, Martin Farrall, Rick Jansen, Albert V. Smith, Sarah E. Harris, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Paul M. Ridker, John Attia, Alanna C. Morrison, Kay-Tee Khaw, Jaume Marrugat, Hugh Watkins, David C. Liewald, Pim van der Harst, Benjamin Lehne, Jennifer E. Huffman, Meixia Ren, Zoltán Kutalik, Lars Lind, Walter Palmas, Teresa Ferreira, David J. Stott, Janina S. Ried, Bruce M. Psaty, Paul F. O'Reilly, Massimo Mangino, Tõnu Esko, Jonathan Marten, Nick Shrine, Anders Hamsten, Tineka Blake, Yuri Milaneschi, Jing Hua Zhao, David Conen, Kristin L. Ayers, Germaine C. Verwoert, Veikko Salomaa, Olli T. Raitakari, Jaakko Tuomilehto, Louise V. Wain, Jennie Hui, Elin Org, Gonçalo R. Abecasis, Vilmundur Gudnason, Andrew A. Hicks, Rossella Sorice, Borbala Mifsud, Helen R. Warren, Jerome I. Rotter, Erwin P. Bottinger, Roberto Elosua, Antonietta Robino, Ilaria Gandin, Andres Metspalu, Marjo-Riitta Järvelin, Guillaume Paré, Anne U. Jackson, Jie Yao, Kent D. Taylor, Denis C. Shields, Andrew D. Morris, Daniela Ruggiero, Samuli Ripatti, C M Lindgren, Mike A. Nalls, Erik Ingelsson, Michela Traglia, Jeffrey Damman, J. Wouter Jukema, Catharina A. Hartman, Eco J. C. de Geus, Colin N. A. Palmer, Peter J. van der Most, Neil Poulter, Robert A. Scott, Anuj Goel, Aude Saint Pierre, Annette Peters, Paul Elliott, Daniel I. Chasman, Marco Brumat, Dennis O. Mook-Kanamori, Priyanka Nandakumar, Roby Joehanes, Cornelia M. van Duijn, Joshua C. Bis, Eleftheria Zeggini, Archie Campbell, Ivana Kolcic, Terho Lehtimäki, Mattias Frånberg, David S. Siscovick, Dan E. Arking, Shih-Jen Hwang, Stella Trompet, Christopher Oldmeadow, A. Mesut Erzurumluoglu, Nicholas J. Wareham, Alice Stanton, Chrysovalanto Mamasoula, Seppo Koskinen, Uwe Völker, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Dorret I. Boomsma, Harry Campbell, Peter J. Munson, Aarno Palotie, Daniela Toniolo, He Gao, Ruifang Li-Gao, Claudia Langenberg, Kati Kristiansson, Åsa Johansson, Johan Sundström, Francis S. Collins, Alan J. Gow, Caroline Hayward, Markus Perola, Renée de Mutsert, Alan James, Ben A. Oostra, Alexander Teumer, Joanne Knight, Vilmantas Giedraitis, Marty Larson, Helena Schmidt, Sébastien Thériault, Peter S. Sever, Maryam Abedi, André G. Uitterlinden, Marc A. Seelen, Georg Ehret, Cristina Menni, Anubha Mahajan, Elizabeth G. Holliday, Ilja M. Nolte, Stéphanie Debette, Paolo Gasparini, Teemu J. Niiranen, Stefan Enroth, Mark J. Caulfield, Andrew P. Morris, Aki S. Havulinna, Cinzia Sala, Peter P. Pramstaller, Marcus Dörr, Quang Tri Nguyen, Claudia P. Cabrera, Bram P. Prins, Peter K. Joshi, Sekar Kathiresan, Lorna M. Lopez, Reinhold Schmidt, Sandosh Padmanabhan, Teresa Nutile, Gonneke Willemsen, François Mach, Michael Boehnke, John Beilby, Leo-Pekka Lyytikäinen, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Martin H. de Borst, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Aravinda Chakravarti, Jouke-Jan Hottenga, Fabiola M. Del Greco, Yasaman Saba, Daniel Levy, Li Lin, Michael R. Barnes, Rona J. Strawbridge, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, and Martin D. Tobin
Subjects: Genetics, 0303 health sciences, Genomics, Locus (genetics), Genome-wide association study, Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Blood pressure, Genetic variation, 1000 Genomes Project, Gene, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology
Abstract: 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 HSPB7, TNXB, LRP12, LOC283335, SEPT9 and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. 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 BP 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.
Published: 2017
Full Text: View/download PDF

32. Publisher Correction: Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability

Author: Gu Zhu, Cornelia M. van Duijn, M. Arfan Ikram, Alessia Visconti, Maria Pina Concas, Veronique Bataille, Nicholas G. Martin, George Davey Smith, Merel A. Hamer, Gonneke Willemsen, Massimiliano Cocca, Fan Liu, Marco Brumat, Antonietta Robino, Bochao D. Lin, Pirro G. Hysi, Tamar Nijsten, Changqing Zeng, Scott D. Gordon, Ilaria Gandin, David M. Evans, Dorret I. Boomsma, Susan M. Ring, Mario Falchi, Yan Chen, Alex W. Hewitt, Gibran Hemani, Jouke-Jan Hottenga, Seyhan Yazar, Tim D. Spector, David L. Duffy, Nicholas A. Furlotte, André G. Uitterlinden, Paolo Gasparini, Sarah E. Medland, Dragana Vuckovic, Giorgia Girotto, Cinzia Sala, David A. Mackey, George McMahon, Daniela Toniolo, Manfred Kayser, David A. Hinds, Ana M. Valdes, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Methodology
Subjects: Netherlands Twin Register (NTR), Variation (linguistics), Meta-analysis, Published Erratum, Genetics, Fraction (mathematics), Genome-wide association study, Biology, Heritability, Genealogy, Genetic association
Abstract: In the HTML version of this article initially published, the author groups ‘23andMe Research Team’ and ‘Social Science Genetic Association Consortium’ appeared at the end of the author list but should have appeared earlier in the list, after author Nicholas A. Furlotte. The errors have been corrected in the HTML version of the article.
Published: 2019

33. Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Aravinda Chakravarti, Jennifer E. Huffman, Meixia Ren, Veikko Salomaa, Christopher Newton-Cheh, Johan Sundström, Alan L. James, Joris Deelen, Raha Pazoki, Michela Traglia, Tõnu Esko, Seppo Koskinen, Christopher J. O'Donnell, Csaba P. Kovesdy, Daniel I. Chasman, Paul F. O'Reilly, Roby Joehanes, Paul M. Ridker, G. Abecasis, Lars Lind, Dragana Vuckovic, Yingchang Lu, Antonietta Robino, Anders Hamsten, Muralidharan Sargurupremraj, Caterina Barbieri, Anne U. Jackson, Anna Morgan, Claudia Langenberg, Peter S. Braund, Rainer Rettig, Murielle Bochud, Vilmundur Gudnason, Eleftheria Zeggini, David J. Stott, Joop Jukema, Nick Shrine, Jun Ding, Olle Melander, Massimo Mangino, Borbala Mifsud, Frank H. Collins, Liewald Dcm., Tineka Blake, Peter K. Joshi, Yan V. Sun, Aarno Palotie, Maciej Tomaszewski, Jarvelin M-R., Kati Kristiansson, L. J. Launer, Sara M. Willems, Ian J. Deary, Christophe Tzourio, Alan J. Gow, Caroline Hayward, Guillaume Paré, Christopher Oldmeadow, John M. Starr, Paul Elliott, Morris A. Swertz, C M van Duijn, Sekar Kathiresan, Lorna M. Lopez, Neil R Poulter, Mike A. Nalls, Erik Ingelsson, Eric Boerwinkle, Catharina A. Hartman, Giorgia Girotto, Ben A. Oostra, Markus Perola, Paul Knekt, Lyytikäinen L-P., T.B. Harris, J. C. Bis, Harriëtte Riese, J. Marrugat, Samuli Ripatti, Howson Jmm., Archie Campbell, C M Lindgren, Adam S. Butterworth, Xiuqing Guo, Lin W-Y., Priyanka Nandakumar, David Mosen-Ansorena, Alison Pattie, Marco Brumat, Annette Peters, Georgios Ntritsos, Ivana Kolcic, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Stella Trompet, K. Witkowska, Hottenga J-J., Tim D. Spector, Maris Laan, Vilmantas Giedraitis, Bram P. Prins, Loos Rjf., M. H. de Borst, Antti Jula, Lynda M. Rose, Massimiliano Cocca, Daniela Toniolo, Igor Rudan, P. J. van der Most, Fu Liang Ng, Heather J. Cordell, Walter Palmas, John Danesh, John Attia, Dan E. Arking, Ganesh Chauhan, C Gieger, P. van der Harst, Penninx Bwjh., Kristin L. Ayers, Germaine C. Verwoert, Bruce M. Psaty, Jaspal S. Kooner, Ruifang Li-Gao, Benjamin Lehne, Khaw K-T., Sandosh Padmanabhan, Franco Giulianini, Erwin P. Bottinger, Roberto Elosua, Christopher P. Nelson, Ozren Polasek, D.R. Velez Edwards, Martin Farrall, Ioanna Tzoulaki, Peter Vollenweider, Uwe Völker, Albertine J. Oldehinkel, Åsa Johansson, Helen R. Warren, Evan Tzanis, Albert V. Smith, Hwang S-J., Teresa Ferreira, E.J.C. de Geus, Evangelos Evangelou, Niek Verweij, R. J. Scott, Pekka Jousilahti, Elin Org, Stefan Enroth, Dorret I. Boomsma, Harry Campbell, Andrew D. Johnson, David Conen, James F. Wilson, Edward G. Lakatta, Anuj Goel, Raymond Noordam, Najaf Amin, David P. Strachan, Martin D. Tobin, Francesco Cucca, Doney Asf., Todd L. Edwards, Jerome I. Rotter, Mika Kähönen, Hugh Watkins, Rossella Sorice, John M. C. Connell, David S. Siscovick, Sébastien Thériault, Jian'an Luan, Marty Larson, Philippe Amouyel, A C Morrison, Louise V. Wain, Reedik Mägi, Jonathan Marten, Thibaud Boutin, Nabi Shah, Weihua Zhang, Palmer Cna., Daniela Ruggiero, Zhao J-H., Olli T. Raitakari, Bernard Keavney, Peter S. Sever, Philip S. Tsao, Jie Yao, André G. Uitterlinden, Marina Evangelou, Zoltán Kutalik, Robert A. Scott, Helena Schmidt, J. Tuomilehto, Nilesh J. Samani, Quang Tri Nguyen, John Michael Gaziano, Georg Ehret, Praveen Surendran, Terho Lehtimäki, Mark J. Caulfield, Denis C. Shields, Rick Jansen, Sarin A-P., Alice Stanton, Mattias Frånberg, Cumhur Y Demirkale, Stéphanie Debette, Paolo Gasparini, Ilaria Gandin, Simon Thom, Kent D. Taylor, Andrew D. Morris, Claudia P. Cabrera, Teemu J. Niiranen, Nicholas J. Wareham, Andrew P. Morris, Yasaman Saba, Daniel Levy, Aki S. Havulinna, Kelly Cho, Sarah E. Harris, Li Lin, Janina S. Ried, Michael R. Barnes, Sarah H. Wild, Patricia B. Munroe, Vergnaud A-C., Lorenz Risch, Rona J. Strawbridge, Y. Milaneschi, John C. Chambers, Yong Qian, Cristina Menni, Anubha Mahajan, Peter Almgren, Gary Davies, Jacklyn N. Hellwege, Elizabeth G. Holliday, A. Metspalu, Ilja M. Nolte, Peter J. Munson, He Gao, Marcus Dörr, Cinzia Sala, Peter P. Pramstaller, Teresa Nutile, Wilson Pwf., Gonneke Willemsen, Markku Laakso, Chiara Batini, Harold Snieder, Ibrahim Karaman, Adriana M. Hung, Reinhold Schmidt, R. de Mutsert, Michael Boehnke, Lili Milani, Alan F. Wright, Edith Hofer, Siim Sõber, Ahmad Vaez, Albert Hofman, Oscar H. Franco, Yongmei Liu, Tatijana Zemunik, Kenneth Rice, Veronique Vitart, Marina Ciullo, Niki Dimou, Morris J. Brown, Crysovalanto Mamasoula, A.M. Erzurumluoglu, Andrew A. Hicks, Ayush Giri, Dennis O. Mook-Kanamori, Home Office, UNIVERSITY OF OULU, Commission of the European Communities, Medical Research Council (MRC), Action on Hearing Loss, British Heart Foundation, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and UK DRI Ltd
Subjects: Genetics & Heredity, 0301 basic medicine, Netherlands Twin Register (NTR), Science & Technology, computer.internet_protocol, Million Veteran Program, Genome-wide association study, Computational biology, 06 Biological Sciences, Biology, Genetic analysis, 03 medical and health sciences, 030104 developmental biology, Genetics, Genome informatics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, computer, 11 Medical and Health Sciences, XML, Developmental Biology
Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.
Published: 2018

34. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author: Martin, Nicholas G., Gudbjartsson, Daniel F., Nutile, Teresa, De Mutsert, Renée, Ong, Ken K., Tung, Joyce Y., Timpson, Nicholas J., Easton, Douglas F., Meitinger, Thomas, Franceschini, Nora, Crisponi, Laura, Ulivi, Sheila, Sulem, Patrick, Völzke, Henry, Völker, Uwe, Flesch-Janys, Dieter, Mulligan, Anna M., Perjakova, Natalia, Karasik, David, Chenevix-Trench, Georgia, Bandinelli, Stefania, Järvelin, Marjo-Riitta, Pharoah, Paul D.P., Vitart, Veronique, Scott, Robert A., Tanaka, Toshiko, Paternoster, Lavinia, Rueedi, Rico, Altmaier, Elisabeth, Murray, Anna, Palotie, Aarno, Mägi, Reedik, Catamo, Eulalia, Grallert, Harald, McMahon, George, Mbarek, Hamdi, Joshi, Peter K., Tyrer, Jonathan P., Giri, Ayush, Hopper, John L., Boerwinkle, Eric, Spector, Tim D., Loh, Po-Ru, Alizadeh, Behrooz Z., Barbieri, Caterina M., Rahman, Iffat, Ikram, M. Arfan, Amini, Marzyeh, Magnusson, Patrik K.E., Wang, Qin, Lawlor, Debbie A., Hu, Frank, Hartman, Catharina A., Willemsen, Gonneke, Padmanabhan, Sandosh, Southey, Melissa C., Schraut, Katharina E., Montgomery, Grant W., Brauch, Hiltrud, Couch, Fergus J., Heiss, Gerardo, Luan, Jian'An, Murabito, Joanne M., Pedersen, Nancy, Beckmann, Matthias W., Thorsteindottir, Unnur, Wareham, Nicholas J., Cucca, Francesco, Noordam, Raymond, Im, Hae Kyung, Visser, Jenny A., Teumer, Alexander, McCarthy, Mark I., Liu, Yongmei, Oldehinkel, Albertine J., Rudan, Igor, Czene, Kamila, Hamann, Ute, Menni, Cristina, Medland, Sarah E., Kolcic, Ivana, Polasek, Ozren, Demerath, Ellen, Li, Jingmei, Mook-Kanamori, Dennis O., Smith, Albert V., Toniolo, Daniela, Lenarduzzi, Stefania, Zhao, Jing Hua, Uitterlinden, André G., Campbell, Harry, Stöckl, Doris, Segrè, Ayellet V., Day, Felix R., Benitez, Javier, Andrulis, Irene L., Ridker, Paul M., Nyholt, Dale R., Edwards, Digna R. Velez, Mannermaa, Arto, Gabrielson, Marike, Boutin, Thibaud, Wolffenbuttel, Bruce H.R., Launer, Lenore J., Lindstrom, Sara, Meisinger, Christa, Buring, Julie E., Whalen, Sean, Zoledziewska, Magdalena, Milne, Roger L., Rosendaal, Frits R., Helgason, Hannes, Lunetta, Kathryn L., Mangino, Massimo, Tikkanen, Emmi, Hallberg, Emily, Cox, Angela, Strauch, Konstantin, Pollard, Katherine S., Hottenga, Jouke J., Widen, Elisabeth, Gieger, Christian, Gandin, Ilaria, Dunning, Alison M., Kraft, Peter, Dos-Santos-Silva, Isabel, Van Dijk, Ko Willems, Brand, Judith S., Giles, Graham G., Stolk, Lisette, Michailidou, Kyriaki, Bolla, Manjeet K., Fernández-Rhodes, Lindsay, Hinds, David, Davey Smith, George, Bochud, Murielle, Radice, Paolo, Marco, Brumat, Fasching, Peter A., Chang-Claude, Jenny, Price, Alkes L., Lind, Penelope A., Ruggiero, Daniela, Campbell, Archie, Robino, Antonietta, Hall, Per, Laven, Joop S.E., Metspalu, Andres, Finucane, Hilary, Lambrechts, Diether, Navarro, Pau, Devilee, Peter, Nevanlinna, Heli, O'Mara, Tracy A., Peto, Julian, Ferrucci, Luigi, Schmidt, Marjanka K., Corre, Tanguy, Sorice, Rossella, Ring, Susan M., Winqvist, Robert, Harris, Tamara B., Hayward, Caroline, De Vivo, Immaculata, Dennis, Joe, Porteous, David, Brenner, Hermann, Guénel, Pascal, Kutalik, Zoltan, Truong, Thérèse, Nohr, Ellen A., Perry, John R.B., Porcu, Eleonora, Eriksson, Johan G., Karlsson, Robert, Chanock, Stephen, Esko, Tõnu, Zygmunt, Marek, Nalls, Mike A., Stampfer, Meir, De Geus, Eco J.C.N., Snieder, Harold, Franke, Lude, Boomsma, Dorret I., Bojesen, Stig E., Sala, Cinzia F., Spurdle, Amanda B., Sarkar, Abhishek K., Brüning, Thomas, Hunter, David J., Gudnason, Vilmundur, Chasman, Daniel I., Stefansson, Kari, Vollenweider, Peter, Cousminer, Diana L., Albrecht, Eva, Steri, Maristella, Milani, Lili, Thompson, Deborah J., Broer, Linda, Rose, Lynda M., Lachance, Genevieve, Shah, Mitul, Bergmann, Sven, Ciullo, Marina, Peters, Annette, Pouta, Anneli, Hooning, Maartje J., Langenberg, Claudia, Ruth, Katherine S., Sovio, Ulla, Traglia, Michela, Nolte, Ilja M., He, Chunyan, Wilson, James F., and Kellis, Manolis
Subjects: 2. Zero hunger, 3. Good health
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P

35. Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Author: Dragana Vuckovic, Mariaelisa Graff, M. Arfan Ikram, Marit E. Jørgensen, Lia E. Bang, Gerome Breen, Torben Jørgensen, Matthias Blüher, Ivan Brandslund, Hester M. den Ruijter, Ian Ford, Timo A. Lakka, Jennifer Wessel, J. Wouter Jukema, Adam S. Butterworth, Iris M. Heid, Xiuqing Guo, Shuai Wang, Paul L. Auer, Tamuno Alfred, Katja K.H. Aben, Inês Barroso, Gail Davies, Helen Griffiths, Heather M. Highland, Myriam Fornage, Claudia Langenberg, Daniel R. Witte, Ilaria Gandin, Kent D. Taylor, Patrick T. Ellinor, Matti Uusitupa, Laura M. Yerges-Armstrong, Fotios Drenos, Lars Wallentin, Joanna M. M. Howson, Jaakko Tuomilehto, Andrew D. Morris, Lawrence F. Bielak, Mengmeng Du, Andrew J. Lotery, Ailith Pirie, Francis S. Collins, Eva Rabing Brix Petersen, Carolina Medina-Gomez, Manuel A. Rivas, Maria Karaleftheri, Jan-Håkan Jansson, Peter Kovacs, Jaspal S. Kooner, Markku Laakso, Fredrik Karpe, Markus Perola, Anubha Mahajan, Heather M. Stringham, Rohit Varma, Alex W. Hewitt, Chris J. Packard, Andrew C. Heath, Claudia Schurmann, Nele Friedrich, David Lamparter, Vanisha Mistry, Renée de Mutsert, Unnur Thorsteinsdottir, Naveed Sattar, Jennifer E. Huffman, Dale R. Nyholt, Johanna Kuusisto, Angela L. Mazul, Hanieh Yaghootkar, George Dedoussis, Yadav Sapkota, Elizabeth K. Speliotes, Amanda J. Cox, Jane Gibson, Christian Theil Have, Penny Gordon-Larsen, Alisa K. Manning, Jaakko Kaprio, Sita H. Vermeulen, Stella Trompet, Yucheng Jia, Dennis O. Mook-Kanamori, Torben Hansen, Kathleen Stirrups, Jean Ferrières, Douglas F. Easton, Ruth J. F. Loos, Gerard Pasterkamp, John M. Starr, Tellervo Korhonen, Betina H. Thuesen, Olov Rolandsson, Veikko Salomaa, Eric B. Larson, Thomas F. Vogt, John Danesh, Honghuang Lin, Gaëlle Marenne, Timothy M. Frayling, Anette Varbo, Daniel I. Chasman, Aliki-Eleni Farmaki, Lorraine Southam, Martina Müller-Nurasyid, Katharine R. Owen, Paul Mitchell, Ching-Ti Liu, Massimiliano Cocca, Anette P. Gjesing, Charles Kooperberg, Rebecca S. Fine, Wei Gan, Amy J. Swift, Gerard Tromp, Krina T. Zondervan, Henrik Vestergaard, Katherine S. Ruth, Angela D'Eustacchio, Uwe Völker, Beverley Balkau, Hayato Tada, Ingrid B. Borecki, Xueling Sim, Gudmar Thorleifsson, Wei Zhou, Yiqin Wang, Eleftheria Zeggini, Cora E. Lewis, Michael Boehnke, Evangelos Evangelou, Gabriel Cuellar-Partida, Sven Bergmann, Tinca J. C. Polderman, Philippe Amouyel, Roberta McKean-Cowdin, Ellen W. Demerath, Marco Brumat, Kjell Nikus, Anneke I den Hollander, Stefan Gustafsson, Allan Linneberg, Peter T. Campbell, Weihua Zhang, Leslie A. Lange, Gina M. Peloso, Jonathan P. Bradfield, Cornelia M. van Duijn, Xiaowei Zhan, Marie-Pierre Dubé, Liang He, André G. Uitterlinden, Anne Tybjærg-Hansen, Yingchang Lu, Wei Zhao, Liang Sun, Yii-Der Ida Chen, Paul I. W. de Bakker, Børge G. Nordestgaard, Karina Meidtner, Carsten A. Böger, Lynne E. Wagenknecht, Eric Kim, Pang Yao, Olli T. Raitakari, Nanette R. Lee, René S. Kahn, Lili Milani, Tessel E. Galesloot, Jussi Hernesniemi, Valgerdur Steinthorsdottir, Jie Yao, Eulalia Catamo, Kerrin S. Small, Sara M. Willems, Marcelo P. Segura-Lepe, Cecilia M. Lindgren, Asif Rasheed, Gonçalo R. Abecasis, Adam E. Locke, Konstantin Strauch, Albert V. Smith, Anke R. Hammerschlag, Frida Renström, Zoltán Kutalik, Giovanni Veronesi, Paul M. Ridker, David J. Carey, Yao Hu, Jaana Lindström, John Andrew Pospisilik, Mike A. Nalls, Erik Ingelsson, Colin N. A. Palmer, Mary F. Feitosa, John R. B. Perry, Anne E. Justice, Ele Ferrannini, Shuang Feng, Helen R. Warren, David J. Roberts, Igor Rudan, Jeffrey R. O'Connel, Alison Pattie, Christopher P. Nelson, Lars Lind, Feijie Wang, Tamara B. Harris, Keng-Hung Lin, Jerome I. Rotter, Matthew A. Allison, Robin Young, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Stefan Johansson, Alexander P. Reiner, Jing Hua Zhao, Poorva Mudgal, Tim D. Spector, Paul W. Franks, Loes M. Olde Loohuis, Harvey D. White, Pirjo Komulainen, Michelle L. O'Donoghue, Todd L. Edwards, Ozren Polasek, Andrew R. Wood, Dermot F. Reilly, Myriam Rheinberger, Cramer Christensen, G. Kees Hovingh, Hidetoshi Kitajima, Kristin L. Young, Audrey Y. Chu, Megan L. Grove, Suthesh Sivapalaratnam, Lisa Bastarache, Martin den Heijer, Oddgeir L. Holmen, Vilmundur Gudnason, Sameer E. Al-Harthi, Dewan S. Alam, Robert E. Schoen, Jin Li, Sascha Fauser, Janie Corley, Paolo Gasparini, Niels Grarup, Guillaume Lettre, Thomas N. Person, Mark I. McCarthy, Joel N. Hirschhorn, Ying Wu, Pia R. Kamstrup, Nilesh J. Samani, Panos Deloukas, Ethan M. Lange, Helena Kuivaniemi, Mika Kähönen, Michiel L. Bots, Annette Peters, Peggy L. Peissig, Wayne Huey-Herng Sheu, Steven A. Lubitz, Stefania Cappellani, Mauno Vanhala, Andrew P. Morris, Struan F.A. Grant, Mark Walker, Trevor A. Mori, Jian'an Luan, Matthias B. Schulze, Josh C. Denny, Sarah E. Medland, Sander W. van der Laan, Maggie C.Y. Ng, Eric Boerwinkle, Tibor V. Varga, Øyvind Helgeland, Anke Tönjes, Jessica van Setten, James P. Cook, Patricia B. Munroe, Heiner Boeing, Robert A. Scott, Karen L. Mohlke, Leena Moilanen, Ayush Giri, Andrew J. Slater, Andrew T. Hattersley, Mark J. Caulfield, Tõnu Esko, Mark C. H. Groot, Nancy L. Heard-Costa, Narisu Narisu, Danish Saleheen, Valérie Turcot, Lambertus A. Kiemeney, Nicholas G. D. Masca, Ruifang Li-Gao, Jean-Claude Tardif, Xu Lin, Kathleen Mullan Harris, Antonietta Robino, Alison M. Dunning, Jonathan Tyrer, Audrey E. Hendricks, Linda Broer, Patricia A. Peyser, Jessica D. Faul, Jose C. Florez, Anne U. Jackson, Eirini Marouli, Jette Bork-Jensen, John C. Chambers, Jordi Corominas Galbany, Ruth Frikke-Schmidt, David S. Crosslin, Bratati Kahali, Stavroula Kanoni, Gorm B. Jensen, Nicholas J. Wareham, Paul Elliott, Tune H. Pers, James A. Perry, Tugce Karaderi, Matt J. Neville, Marianne Benn, Svati H. Shah, Mathias Gorski, Michael Stumvoll, David Ellinghaus, Amber A. Burt, Kari E. North, Jeffrey Haessler, Rajiv Chowdhury, Folkert W. Asselbergs, Marie Moitry, Aniruddh P. Patel, Pamela J. Schreiner, Frank Kee, Donald W. Bowden, Sune F. Nielsen, Oluf Pedersen, John D. Rioux, Rainer Rauramaa, Satu Männistö, Deborah J. Thompson, Cristen J. Willer, Andre Franke, Kari Kuulasmaa, Nienke van Leeuwen, Carmel Moore, Sharon L.R. Kardia, Neil R. Robertson, Sekar Kathiresan, Erin B. Ware, Dawn M. Waterworth, James G. Wilson, Sandosh Padmanabhan, Emmanouil Tsafantakis, Hakon Hakonarson, Dajiang J. Liu, Digna R. Velez Edwards, Artitaya Lophatananon, Craig E. Pennell, Gail P. Jarvik, Adelheid Lempradl, Anu Loukola, Joe Dennis, Hans-Jörgen Grabe, Oscar H. Franco, Yongmei Liu, I. Sadaf Farooqi, Hannu Puolijoki, Huaixing Li, Caroline Hayward, Rudolf Uher, Veronique Vitart, Murray H. Brilliant, Kari Stefansson, Alexander Teumer, Nicholette D. Palmer, Vilmantas Giedraitis, Roel A. Ophoff, Sailaja Vedantam, Emanuele Di Angelantonio, Ken S. Lo, Grant W. Montgomery, Paul L. Huang, Praveen Surendran, Terho Lehtimäki, Katherine E. Tansey, Li-An Lin, Pål R. Njølstad, Thomas W. Winkler, Ian J. Deary, Erwin P. Bottinger, Carol A. Wang, Biological Psychology, Complex Trait Genetics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: 0301 basic medicine, 2. Zero hunger, 0303 health sciences, ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION, Published Erratum, Computational biology, Biology, medicine.disease, Obesity, Genealogy, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, ddc:570, Genetics, medicine, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Biological sciences, Body mass index, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
Full Text: View/download PDF

36. Genetic insights into biological mechanisms governing human ovarian ageing.

Author: Ruth KS, Day FR, Hussain J, Martínez-Marchal A, Aiken CE, Azad A, Thompson DJ, Knoblochova L, Abe H, Tarry-Adkins JL, Gonzalez JM, Fontanillas P, Claringbould A, Bakker OB, Sulem P, Walters RG, Terao C, Turon S, Horikoshi M, Lin K, Onland-Moret NC, Sankar A, Hertz EPT, Timshel PN, Shukla V, Borup R, Olsen KW, Aguilera P, Ferrer-Roda M, Huang Y, Stankovic S, Timmers PRHJ, Ahearn TU, Alizadeh BZ, Naderi E, Andrulis IL, Arnold AM, Aronson KJ, Augustinsson A, Bandinelli S, Barbieri CM, Beaumont RN, Becher H, Beckmann MW, Benonisdottir S, Bergmann S, Bochud M, Boerwinkle E, Bojesen SE, Bolla MK, Boomsma DI, Bowker N, Brody JA, Broer L, Buring JE, Campbell A, Campbell H, Castelao JE, Catamo E, Chanock SJ, Chenevix-Trench G, Ciullo M, Corre T, Couch FJ, Cox A, Crisponi L, Cross SS, Cucca F, Czene K, Smith GD, de Geus EJCN, de Mutsert R, De Vivo I, Demerath EW, Dennis J, Dunning AM, Dwek M, Eriksson M, Esko T, Fasching PA, Faul JD, Ferrucci L, Franceschini N, Frayling TM, Gago-Dominguez M, Mezzavilla M, García-Closas M, Gieger C, Giles GG, Grallert H, Gudbjartsson DF, Gudnason V, Guénel P, Haiman CA, Håkansson N, Hall P, Hayward C, He C, He W, Heiss G, Høffding MK, Hopper JL, Hottenga JJ, Hu F, Hunter D, Ikram MA, Jackson RD, Joaquim MDR, John EM, Joshi PK, Karasik D, Kardia SLR, Kartsonaki C, Karlsson R, Kitahara CM, Kolcic I, Kooperberg C, Kraft P, Kurian AW, Kutalik Z, La Bianca M, LaChance G, Langenberg C, Launer LJ, Laven JSE, Lawlor DA, Le Marchand L, Li J, Lindblom A, Lindstrom S, Lindstrom T, Linet M, Liu Y, Liu S, Luan J, Mägi R, Magnusson PKE, Mangino M, Mannermaa A, Marco B, Marten J, Martin NG, Mbarek H, McKnight B, Medland SE, Meisinger C, Meitinger T, Menni C, Metspalu A, Milani L, Milne RL, Montgomery GW, Mook-Kanamori DO, Mulas A, Mulligan AM, Murray A, Nalls MA, Newman A, Noordam R, Nutile T, Nyholt DR, Olshan AF, Olsson H, Painter JN, Patel AV, Pedersen NL, Perjakova N, Peters A, Peters U, Pharoah PDP, Polasek O, Porcu E, Psaty BM, Rahman I, Rennert G, Rennert HS, Ridker PM, Ring SM, Robino A, Rose LM, Rosendaal FR, Rossouw J, Rudan I, Rueedi R, Ruggiero D, Sala CF, Saloustros E, Sandler DP, Sanna S, Sawyer EJ, Sarnowski C, Schlessinger D, Schmidt MK, Schoemaker MJ, Schraut KE, Scott C, Shekari S, Shrikhande A, Smith AV, Smith BH, Smith JA, Sorice R, Southey MC, Spector TD, Spinelli JJ, Stampfer M, Stöckl D, van Meurs JBJ, Strauch K, Styrkarsdottir U, Swerdlow AJ, Tanaka T, Teras LR, Teumer A, Þorsteinsdottir U, Timpson NJ, Toniolo D, Traglia M, Troester MA, Truong T, Tyrrell J, Uitterlinden AG, Ulivi S, Vachon CM, Vitart V, Völker U, Vollenweider P, Völzke H, Wang Q, Wareham NJ, Weinberg CR, Weir DR, Wilcox AN, van Dijk KW, Willemsen G, Wilson JF, Wolffenbuttel BHR, Wolk A, Wood AR, Zhao W, Zygmunt M, Chen Z, Li L, Franke L, Burgess S, Deelen P, Pers TH, Grøndahl ML, Andersen CY, Pujol A, Lopez-Contreras AJ, Daniel JA, Stefansson K, Chang-Claude J, van der Schouw YT, Lunetta KL, Chasman DI, Easton DF, Visser JA, Ozanne SE, Namekawa SH, Solc P, Murabito JM, Ong KK, Hoffmann ER, Murray A, Roig I, and Perry JRB
Subjects: Adult, Alleles, Animals, Bone and Bones metabolism, Checkpoint Kinase 1 genetics, Checkpoint Kinase 2 genetics, Diabetes Mellitus, Type 2, Diet, Europe ethnology, Asia, Eastern ethnology, Female, Fertility genetics, Fragile X Mental Retardation Protein genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Healthy Aging genetics, Humans, Longevity genetics, Menopause genetics, Menopause, Premature genetics, Mice, Mice, Inbred C57BL, Middle Aged, Primary Ovarian Insufficiency genetics, Uterus, Aging genetics, Ovary metabolism
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women 1,2 , but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations 3 . The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Published: 2021
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Region

Database

Publisher

36 results on '"Marco, Brumat"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources