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1. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author: Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1006528.].
Published: 2017
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2. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

Author: Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
Subjects: Genetics, QH426-470
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Published: 2017
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3. Rare variant contribution to the heritability of coronary artery disease

Author: Ghislain Rocheleau, Shoa L. Clarke, Gaëlle Auguste, Natalie R. Hasbani, Alanna C. Morrison, Adam S. Heath, Lawrence F. Bielak, Kruthika R. Iyer, Erica P. Young, Nathan O. Stitziel, Goo Jun, Cecelia Laurie, Jai G. Broome, Alyna T. Khan, Donna K. Arnett, Lewis C. Becker, Joshua C. Bis, Eric Boerwinkle, Donald W. Bowden, April P. Carson, Patrick T. Ellinor, Myriam Fornage, Nora Franceschini, Barry I. Freedman, Nancy L. Heard-Costa, Lifang Hou, Yii-Der Ida Chen, Eimear E. Kenny, Charles Kooperberg, Brian G. Kral, Ruth J. F. Loos, Sharon M. Lutz, JoAnn E. Manson, Lisa W. Martin, Braxton D. Mitchell, Rami Nassir, Nicholette D. Palmer, Wendy S. Post, Michael H. Preuss, Bruce M. Psaty, Laura M. Raffield, Elizabeth A. Regan, Stephen S. Rich, Jennifer A. Smith, Kent D. Taylor, Lisa R. Yanek, Kendra A. Young, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Austin T. Hilliard, Catherine Tcheandjieu, Patricia A. Peyser, Ramachandran S. Vasan, Jerome I. Rotter, Clint L. Miller, Themistocles L. Assimes, Paul S. de Vries, and Ron Do
Subjects: Science
Abstract: Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.
Published: 2024
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4. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author: Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1005378.].
Published: 2016
Full Text: View/download PDF

5. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author: Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
Subjects: Genetics, QH426-470
Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR
Published: 2015
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6. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Author: Joshua C Randall, Thomas W Winkler, Zoltán Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, Andre Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, DIAGRAM Consortium, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Jarvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M Van der Klauw, Jana V Van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, and Iris M Heid
Subjects: Genetics, QH426-470
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR
Published: 2013
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7. NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.

Author: Nancy L Heard-Costa, M Carola Zillikens, Keri L Monda, Asa Johansson, Tamara B Harris, Mao Fu, Talin Haritunians, Mary F Feitosa, Thor Aspelund, Gudny Eiriksdottir, Melissa Garcia, Lenore J Launer, Albert V Smith, Braxton D Mitchell, Patrick F McArdle, Alan R Shuldiner, Suzette J Bielinski, Eric Boerwinkle, Fred Brancati, Ellen W Demerath, James S Pankow, Alice M Arnold, Yii-Der Ida Chen, Nicole L Glazer, Barbara McKnight, Bruce M Psaty, Jerome I Rotter, Najaf Amin, Harry Campbell, Ulf Gyllensten, Cristian Pattaro, Peter P Pramstaller, Igor Rudan, Maksim Struchalin, Veronique Vitart, Xiaoyi Gao, Aldi Kraja, Michael A Province, Qunyuan Zhang, Larry D Atwood, Josée Dupuis, Joel N Hirschhorn, Cashell E Jaquish, Christopher J O'Donnell, Ramachandran S Vasan, Charles C White, Yurii S Aulchenko, Karol Estrada, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Jacqueline C M Witteman, Ben A Oostra, Robert C Kaplan, Vilmundur Gudnason, Jeffrey R O'Connell, Ingrid B Borecki, Cornelia M van Duijn, L Adrienne Cupples, Caroline S Fox, and Kari E North
Subjects: Genetics, QH426-470
Abstract: Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
Published: 2009
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8. Epigenetic Age Mediates the Association of Life's Essential 8 With Cardiovascular Disease and Mortality

Author: Madeleine Carbonneau, Yi Li, Brenton Prescott, Chunyu Liu, Tianxiao Huan, Roby Joehanes, Joanne M. Murabito, Nancy L. Heard‐Costa, Vanessa Xanthakis, Daniel Levy, and Jiantao Ma
Subjects: cardiovascular health, epigenetic age scores, Life's Essential 8, methylation, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear. Methods and Results LE8 score was calculated for 5682 Framingham Heart Study participants. We implemented 4 DNA methylation‐based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD‐specific mortality, and all‐cause mortality. We found that a 1 SD increase in the LE8 score was associated with a 35% (95% CI, 27–41; P=1.8E‐15) lower risk of incident CVD, a 36% (95% CI, 24–47; P=7E‐7) lower risk of CVD‐specific mortality, and a 29% (95% CI, 22–35; P=7E‐15) lower risk of all‐cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD‐specific mortality, and all‐cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score. Conclusions DNA methylation‐based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD‐specific mortality, and all‐cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.
Published: 2024
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9. Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: the Framingham Heart Study

Author: Amena Keshawarz, Helena Bui, Roby Joehanes, Jiantao Ma, Chunyu Liu, Tianxiao Huan, Shih-Jen Hwang, Brandon Tejada, Meera Sooda, Paul Courchesne, Peter J. Munson, Cumhur Y. Demirkale, Chen Yao, Nancy L. Heard-Costa, Achilleas N. Pitsillides, Honghuang Lin, Ching-Ti Liu, Yuxuan Wang, Gina M. Peloso, Jessica Lundin, Jeffrey Haessler, Zhaohui Du, Michael Cho, Craig P. Hersh, Peter Castaldi, Laura M. Raffield, Jia Wen, Yun Li, Alexander P. Reiner, Mike Feolo, Nataliya Sharopova, Ramachandran S. Vasan, Dawn L. DeMeo, April P. Carson, Charles Kooperberg, and Daniel Levy
Subjects: Medicine, Science
Abstract: Abstract Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p
Published: 2023
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10. Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease

Author: Yiyi Zhang, Jacqueline S. Dron, Brandon K. Bellows, Amit V. Khera, Junxiu Liu, Pallavi P. Balte, Elizabeth C. Oelsner, Sami Samir Amr, Matthew S. Lebo, Anna Nagy, Gina M. Peloso, Pradeep Natarajan, Jerome I. Rotter, Cristen Willer, Eric Boerwinkle, Christie M. Ballantyne, Pamela L. Lutsey, Myriam Fornage, Donald M. Lloyd-Jones, Lifang Hou, Bruce M. Psaty, Joshua C. Bis, James S. Floyd, Ramachandran S. Vasan, Nancy L. Heard-Costa, April P. Carson, Michael E. Hall, Stephen S. Rich, Xiuqing Guo, Dhruv S. Kazi, Sarah D. de Ferranti, and Andrew E. Moran
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Published: 2023
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11. Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project

Author: Regina Manansala, Jeffrey Haessler, Sandro Marini, Rebecca D. Jackson, Tanika N. Kelly, Ruth J. F. Loos, Quenna Wong, Jonathan Rosand, Sudha Seshadri, Charles Kooperberg, Adolfo Correa, Stephen S. Rich, Ron Do, Paul L. Auer, Xiao Sun, Kerri L. Wiggins, Bruce M. Psaty, Jerome I. Rotter, Alexander P. Reiner, Jaeyoon Chung, Arden Moscati, Chloé Sarnowski, Laura M. Raffield, William T. Longstreth, Themistocles L. Assimes, Christopher D. Anderson, Yao Hu, David L. Tirschwell, Joshua C. Bis, Braxton D. Mitchell, Simin Liu, Leslie A. Lange, Alexa S. Beiser, Brian Silver, Ramachandran S. Vasan, Huichun Xu, Nancy L. Heard-Costa, Sylvia Wassertheil-Smoller, and Myriam Fornage
Subjects: Male, Bioinformatics, Polymorphism, Single Nucleotide, Article, medicine, Humans, Genetic Predisposition to Disease, Precision Medicine, Stroke, Aged, Genetic association, Cause of death, Aged, 80 and over, Advanced and Specialized Nursing, Whole genome sequencing, Whole Genome Sequencing, business.industry, Racial Groups, Middle Aged, medicine.disease, Omics, Precision medicine, Embolic stroke, Genetic Loci, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract: Background and Purpose: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). Methods: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. Results: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance ( P −9 ) and 4 novel loci at genome-wide significance ( P −8 ), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke ( P −6 ). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2 , HDAC9 , ZFHX3 , and LRCH1 . Conclusions: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.
Published: 2022
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12. Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants

Author: Kristin L. Young, Virginia Fisher, Xuan Deng, Jennifer A. Brody, Misa Graff, Elise Lim, Bridget M. Lin, Hanfei Xu, Najaf Amin, Ping An, Stella Aslibekyan, Alison E. Fohner, Bertha Hidalgo, Petra Lenzini, Robert Kraaij, Carolina Medina-Gomez, Ivana Prokić, Fernando Rivadeneira, Colleen Sitlani, Ran Tao, Jeroen van Rooij, Di Zhang, Jai G. Broome, Erin J. Buth, Benjamin D. Heavner, Deepti Jain, Albert V. Smith, Kathleen Barnes, Meher Preethi Boorgula, Sameer Chavan, Dawood Darbar, Mariza De Andrade, Xiuqing Guo, Jeffrey Haessler, Marguerite R. Irvin, Rita R. Kalyani, Sharon L.R. Kardia, Charles Kooperberg, Wonji Kim, Rasika A. Mathias, Merry-Lynn McDonald, Braxton D. Mitchell, Patricia A. Peyser, Elizabeth A. Regan, Susan Redline, Alexander P. Reiner, Stephen S. Rich, Jerome I. Rotter, Jennifer A. Smith, Scott Weiss, Kerri L. Wiggins, Lisa R. Yanek, Donna Arnett, Nancy L. Heard-Costa, Suzanne Leal, Danyu Lin, Barbara McKnight, Michael Province, Cornelia M. van Duijn, Kari E. North, L. Adrienne Cupples, Ching-Ti Liu, Epidemiology, and Internal Medicine
Subjects: Anthropometry, central obesity, Quantitative Trait Loci, Human Genome, Cell Cycle Proteins, body mass index, Good Health and Well Being, Clinical Research, Genetics, Molecular Medicine, Humans, Intercellular Signaling Peptides and Proteins, 2.1 Biological and endogenous factors, Exome, Generic health relevance, Aetiology, exome sequencing, Genetics (clinical), Genome-Wide Association Study, height, Biotechnology
Abstract: Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus (eQTL) analysis within previously reported GWAS loci implicated CEP63 and RFT1 as potential functional genes for known height loci. We further assessed enrichment of SNVs, which were monogenic or syndromic variants within loci associated with our three traits. This led to the significant enrichment results for height, whereas we observed no Bonferroni-corrected significance for all SNVs. With a sample size of ∼20,000 whole-exome sequences in our discovery dataset, our findings demonstrate the importance of genomic sequencing in genetic association studies, yet they also illustrate the challenges in identifying effects of rare genetic variants.
Published: 2023
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13. Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program

Author: Nicholas L. Smith, James A. Perry, Cecelia A. Laurie, Nancy J. Cox, Gonçalo R. Abecasis, Jerome I. Rotter, Laura Almasy, Zhe Wang, Michelle Daya, Yun Li, Eric Jorgenson, Adolfo Correa, Jai G. Broome, Nancy Min, Lisa R. Yanek, Alanna C. Morrison, Lynette Ekunwe, Debby Ngo, Victor E. Ortega, Klaudia Walter, John Blangero, Laura M. Raffield, Corey Cox, Terri H. Beaty, Deborah A. Meyers, Hua Tang, Marsha M. Wheeler, Kari E. North, Xue Zhong, Yann Ilboudo, Andrew D. Johnson, Caitlin P. McHugh, Jeffrey R. O'Connell, Ming-Huei Chen, Russell P. Tracy, Ramachandran S. Vasan, Nathan Pankratz, Joshua P. Lewis, Dawn L. DeMeo, Linda M. Polfus, Leslie A. Lange, Nancy L. Heard-Costa, Robert C. Kaplan, Meher Preethi Boorgula, Robert E. Gerszten, Albert V. Smith, Paul L. Auer, Sameer Chavan, Jennifer A. Brody, Charles Kooperberg, Michael Preuss, David C. Glahn, Rasika A. Mathias, Paul S. de Vries, Jonathon Rosen, Anna V. Mikhaylova, Joe Zein, Eric Boerwinkle, Nathalie Chami, Kathleen C. Barnes, Joanne E. Curran, Edwin K. Silverman, Matthew P. Conomos, Stephen S. Rich, Nicole Soranzo, Heather M. Highland, Michael H. Cho, Donald M. Lloyd-Jones, Myriam Fornage, Guillaume Lettre, Tyne W Miller-Fleming, Kathleen A. Ryan, Thomas W. Blackwell, Bruce M. Psaty, Lewis C. Becker, Nauder Faraday, Hélène Choquet, Alexander P. Reiner, Adam S. Butterworth, Kousik Kundu, Deepti Jain, Timothy A. Thornton, Brian D. Hobbs, Braxton D. Mitchell, Jee-Young Moon, Lifang Hou, Ani Manichaikul, Praveen Surendran, Suraj S. Nongmaithem, Quan Sun, Bingshan Li, Deborah A. Nickerson, and Ruth J. F. Loos
Subjects: Proteome, Quantitative Trait Loci, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Dermatitis, Atopic, Pulmonary Disease, Chronic Obstructive, Leukocytes, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), X chromosome, Genetic association, Whole genome sequencing, Autosome, Whole Genome Sequencing, Genome, Human, Monocyte, Prognosis, Asthma, United Kingdom, United States, Phenotype, medicine.anatomical_structure, National Heart, Lung, and Blood Institute (U.S.), Biomarkers, Imputation (genetics), Genome-Wide Association Study
Abstract: Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.
Published: 2021
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14. Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

Author: Nauder Faraday, Brian D. Hobbs, Quan Sun, Michael Preuss, Ani Manichaikul, Eric Jorgenson, Ming-Huei Chen, Eric Boerwinkle, Florian Thibord, Arunoday Bhan, Alanna C. Morrison, Ramachandran S. Vasan, Nathan Pankratz, Charles Kooperberg, Deborah A. Nickerson, Joshua P. Lewis, Hélène Choquet, Jee-Young Moon, Jeffrey R. O'Connell, Marsha M. Wheeler, Albert V. Smith, Russell P. Tracy, Nathalie Chami, Ruth J. F. Loos, Alexander P. Reiner, Nicholas L. Smith, Gonçalo R. Abecasis, Laura M. Raffield, Amarise Little, Nancy L. Heard-Costa, Andrew D. Johnson, David C. Glahn, Rasika A. Mathias, Adam S. Butterworth, John Blangero, Joanne E. Curran, Timothy A. Thornton, Laura Almasy, Jerome I. Rotter, Nancy Min, Lisa R. Yanek, Donald M. Lloyd-Jones, Zhe Wang, Matthew P. Conomos, Myriam Fornage, Hua Tang, Lewis C. Becker, Lynette Ekunwe, Cecelia A. Laurie, Adolfo Correa, Jai G. Broome, Terri H. Beaty, Jennifer A. Brody, Caitlin P. McHugh, Yao Hu, Braxton D. Mitchell, Lifang Hou, Yun Li, Kathleen A. Ryan, Paul L. Auer, Stephen S. Rich, Kari E. North, Thomas W. Blackwell, Bruce M. Psaty, Deepti Jain, Paul S Vries, Praveen Surendran, Butterworth, Adam [0000-0002-6915-9015], and Apollo - University of Cambridge Repository
Subjects: Blood Platelets, Platelet disorder, Population, Genome-wide association study, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Medical and Health Sciences, Genome, 03 medical and health sciences, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, 0302 clinical medicine, Clinical Research, and Blood Institute (U.S.), Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Precision Medicine, Aetiology, Mean platelet volume, education, Hemostatic function, Lung, Molecular Biology, Genetics (clinical), 030304 developmental biology, Blood Platelet Disorders, Genetics & Heredity, 0303 health sciences, education.field_of_study, Human Genome, Single Nucleotide, National Heart, Hematology, General Medicine, Biological Sciences, United States, 3. Good health, Phenotype, Good Health and Well Being, 030220 oncology & carcinogenesis, General Article, National Heart, Lung, and Blood Institute (U.S.), Genome-Wide Association Study, Biotechnology
Abstract: Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI’s Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.
Published: 2021
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15. Elucidating the genetic architecture of DNA methylation to identify promising molecular mechanisms of disease

Author: Jiantao Ma, Roby Joehanes, Chunyu Liu, Amena Keshawarz, Hwang Shih-Jen, Helena Bui, Brandon Tejada, Meera Sooda, Peter J. Munson, Demirkale Y. Cumhur, Paul Courchesne, Nancy L. Heard-Costa, Achilleas N. Pitsillides, Mike Feolo, Nataliya Sharopova, Ramachandran S. Vasan, Tianxiao Huan, and Daniel Levy
Subjects: Cytosine, Multidisciplinary, Diabetes Mellitus, Type 2, Quantitative Trait Loci, Humans, COVID-19, CpG Islands, Coronary Artery Disease, DNA Methylation, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract: DNA methylation commonly occurs at cytosine-phosphate-guanine sites (CpGs) that can serve as biomarkers for many diseases. We analyzed whole genome sequencing data to identify DNA methylation quantitative trait loci (mQTLs) in 4126 Framingham Heart Study participants. Our mQTL mapping identified 94,362,817 cis-mQTLvariant-CpG pairs (for 210,156 unique autosomal CpGs) at P trans-mQTL variant-CpG pairs (for 213,606 unique autosomal CpGs) at P cis-mQTL variants for 1258 CpGs associated with seven cardiovascular disease (CVD) risk factors, we found 104 unique CpGs that colocalized with at least one CVD trait. For example, cg11554650 (PPP1R18) colocalized with type 2 diabetes, and was driven by a single nucleotide polymorphism (rs2516396). We performed Mendelian randomization (MR) analysis and demonstrated 58 putatively causal relations of CVD risk factor-associated CpGs to one or more risk factors (e.g., cg05337441 [APOB] with LDL; MR P = 1.2e−99, and 17 causal associations with coronary artery disease (e.g. cg08129017 [SREBF1] with coronary artery disease; MR P = 5e−13). We also showed that three CpGs, e.g., cg14893161 (PM20D1), are putatively causally associated with COVID-19 severity. To assist in future analyses of the role of DNA methylation in disease pathogenesis, we have posted a comprehensive summary data set in the National Heart, Lung, and Blood Institute’s BioData Catalyst.
Published: 2022
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16. Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program

Author: Adolfo Correa, Jai G. Broome, Chunyan Ren, Kari E. North, Nancy L. Heard-Costa, Yao Yao, Brian D. Hobbs, Mary Cushman, Leslie A. Lange, Daniel E. Bauer, Xiuwen Zheng, Braxton D. Mitchell, Yun Li, Quan Sun, Sébastian Méric de Bellefon, Terri H. Beaty, Paul S. de Vries, Ruth J. F. Loos, Adrienne M. Stilp, Albert V. Smith, Paul L. Auer, Deepti Jain, Lifang Hou, Robert C. Kaplan, Jee-Young Moon, Michael Preuss, Stephen S. Rich, Guillaume Lettre, Nicole Soranzo, Eric Boerwinkle, Kousik Kundu, Laura Almasy, Marsha M. Wheeler, Thomas W. Blackwell, Nancy Min, Nicholas L. Smith, Bruce M. Psaty, Lisa R. Yanek, Joanne E. Curran, Stacey Gabriel, Kathleen A. Ryan, Alanna C. Morrison, Lynette Ekunwe, Caitlin P. McHugh, Laura M. Raffield, Adam S. Butterworth, Deborah A. Nickerson, Ravindranath Duggirala, Gonçalo R. Abecasis, John Lane, Hélène Choquet, Andrew D. Johnson, Nauder Faraday, Russell T. Walton, Praveen Surendran, Jennifer A. Brody, Yao Hu, Alexander P. Reiner, Jerome I. Rotter, Donald M. Lloyd-Jones, Cathy C. Laurie, Zhe Wang, Hua Tang, Charles Kooperberg, Eric Jorgenson, Jeffrey R. O'Connell, Shuquan Rao, Nathalie Chami, Rasika A. Mathias, Matthew P. Conomos, Myriam Fornage, Ramachandran S. Vasan, Nathan Pankratz, Joshua P. Lewis, Lewis C. Becker, Benjamin P. Kleinstiver, Cecelia A. Laurie, Ming-Huei Chen, and John Blangero
Subjects: Adult, Male, Quality Control, 0301 basic medicine, Erythrocytes, Population, Datasets as Topic, Genome-wide association study, Biology, Quantitative trait locus, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Indel, education, Gene, Genetics (clinical), Aged, Genetic association, Gene Editing, Whole genome sequencing, education.field_of_study, Genetic Variation, Reproducibility of Results, Correction, Middle Aged, United States, Genetic architecture, HEK293 Cells, Phenotype, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, National Heart, Lung, and Blood Institute (U.S.), Chromosomes, Human, Pair 16, Genome-Wide Association Study
Abstract: Summary Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380 ), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
Published: 2021
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17. Investigating gene-diet interactions impacting the association between macronutrient intake and glycemic traits

Author: Kenneth E. Westerman, Maura E. Walker, Sheila M. Gaynor, Jennifer Wessel, Daniel DiCorpo, Jiantao Ma, Alvaro Alonso, Stella Aslibekyan, Abigail S. Baldridge, Alain G. Bertoni, Mary L. Biggs, Jennifer A. Brody, Yii-Der Ida Chen, Joseé Dupuis, Mark O. Goodarzi, Xiuqing Guo, Natalie R. Hasbani, Adam Heath, Bertha Hidalgo, Marguerite R. Irvin, W. Craig Johnson, Rita R. Kalyani, Leslie Lange, Rozenn N. Lemaitre, Ching-Ti Liu, Simin Liu, Jee-Young Moon, Rami Nassir, James S. Pankow, Mary Pettinger, Laura M. Raffield, Laura J. Rasmussen-Torvik, Elizabeth Selvin, Mackenzie K. Senn, Aladdin H. Shadyab, Albert V. Smith, Nicholas L. Smith, Lyn Steffen, Sameera Talegakwar, Kent D. Taylor, Paul S. de Vries, James G. Wilson, Alexis C. Wood, Lisa R. Yanek, Jie Yao, Yinan Zheng, Eric Boerwinkle, Alanna C. Morrison, Miriam Fornage, Tracy P. Russell, Bruce M. Psaty, Daniel Levy, Nancy L. Heard-Costa, Vasan S. Ramachandran, Rasika A. Mathias, Donna K. Arnett, Robert Kaplan, Kari E. North, Adolfo Correa, April Carson, Jerome I. Rotter, Stephen S. Rich, JoAnn E. Manson, Alexander P. Reiner, Charles Kooperberg, Jose C. Florez, James B. Meigs, Jordi Merino, Deirdre K. Tobias, Han Chen, and Alisa K. Manning
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Abstract: BackgroundHeterogeneity in the long-term metabolic response to dietary macronutrient composition can be partially explained by genetic factors. However, few studies have demonstrated reproducible gene-diet interactions (GDIs), likely due in part to measurement error in dietary intake estimation as well as insufficient capture of rare genetic variation. Discovery analyses in ancestry-diverse cohorts that include rare genetic variants from whole-genome sequencing (WGS) could help identify genetic variants modifying the effects of dietary macronutrient composition on glycemic phenotypes.ObjectiveWe aimed to identify macronutrient GDIs across the genetic frequency spectrum associated with continuous glycemic traits in genetically and culturally diverse cohorts.MethodsWe analyzed N=33,187 diabetes-free participants from 10 cohorts in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program with WGS, self-reported diet, and glycemic traits (fasting glucose [FG], insulin [FI], and hemoglobin A1c [HbA1c]). We fit multivariable-adjusted linear mixed models for the main effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and for its interactions with genetic variants genome-wide. Tests were performed for both common variants and gene-based rare variant sets in each cohort followed by a combined cohort meta-analysis.ResultsIn main effect models, participants consuming more calories from carbohydrate at the expense of fat had modestly lower glycemic trait values (β per 250 kcal substitution for FG: −0.030 mmol/L, p=2.7×10−6; lnFI: −0.008 log(pmol/L), p=0.17; HbA1c: −0.013 %, p=0.025). In GDI analyses, a common African ancestry-enriched variant (rs79762542; 78 kb upstream of the FRAS1 gene) reached study-wide significance (p = 1.14×10−8) indicating a higher HbA1c with greater proportion of calories from carbohydrate vs. fat among minor allele carriers only. This interaction was replicated in the UK Biobank cohort. Simulations revealed that there is (1) a substantial impact of measurement error on statistical power for GDI discovery at these sample sizes, especially for rare genetic variants, and (2) over 150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error.ConclusionsOur analysis identified a potential genetic interaction modifying the dietary macronutrient-HbA1c association while highlighting the importance of precise exposure measurement and significantly increased sample size to identify additional similar effects.
Published: 2022
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18. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author: Nancy L. Heard-Costa, Lucas Barwick, Clary B. Clish, Celeste Eng, Joanne M. Murabito, Esteban G. Burchard, Yii-Der Ida Chen, Daniel I. Chasman, Robert C. Kaplan, James B. Meigs, Deborah A. Nickerson, Cashell E. Jaquish, Eric Boerwinkle, Jennifer A. Brody, Charles Kooperberg, Mark T. Gladwin, Sebastian Schoenherr, Keng-Han Lin, John Barnard, Ryan D. Hernandez, Andrew D. Johnson, Edwin K. Silverman, Mollie A. Minear, Michelle Daya, Barbara A. Konkle, Sharon R. Browning, Daniel E. Weeks, Wendy S. Post, Alexander P. Reiner, Kathryn L. Lunetta, Gina M. Peloso, David Van Den Berg, Dan E. Arking, Seung-been Lee, Leslie A. Lange, Cristen J. Willer, Zachary A. Szpiech, Tasha E. Fingerlin, Wayne E. Clarke, Xutong Zhao, Stephen S. Rich, Nora Franceschini, Sudha Seshadri, Chloé Sarnowski, Hyun Min Kang, Sayantan Das, Michael C. Zody, Stephanie M. Fullerton, Dean Bobo, Alanna C. Morrison, Brian Custer, Nona Sotoodehnia, Shannon Kelly, Thomas W. Blackwell, Bruce M. Psaty, Yingze Zhang, Susan R. Heckbert, Robert E. Gerszten, M. Benjamin Shoemaker, Daniel Taliun, Leslie S. Emery, André Corvelo, Michael H. Cho, Braxton D. Mitchell, Xiaoming Liu, Stella Aslibekyan, Paul L. Auer, Brandon Chalazan, Sarah C. Nelson, Seung Hoan Choi, Jeong-Sun Seo, Matthew P. Conomos, Anne-Katrin Emde, Lawrence F. Bielak, Alisa K. Manning, Allison E. Ashley-Koch, Diane Fatkin, Xiaowen Tian, Emelia J. Benjamin, D. C. Rao, Mina K. Chung, Myriam Fornage, Daniel Levy, Michael D. Kessler, Weihong Tang, Daniel J. Gottlieb, Pradeep Natarajan, Jessica Lasky-Su, Amol C. Shetty, Cathy C. Laurie, Dan M. Roden, Timothy D. O’Connor, Jedidiah Carlson, Lewis C. Becker, Achilleas N. Pitsillides, Karine A. Viaud-Martinez, Raul Torres, Adolfo Correa, Christian Fuchsberger, Deborah A. Meyers, Alvaro Alonso, Sanghamitra Mohanty, Jonathon LeFaive, Soren Germer, Julie L. Mikulla, François Aguet, Susan K. Dutcher, Sarah A Gagliano Taliun, Ani Manichaikul, Lori Garman, Xiuqing Guo, Timothy A. Thornton, David D. McManus, Albert V. Smith, Kristin G. Ardlie, Anna Köttgen, Sharon L.R. Kardia, Quenna Wong, Jill M. Johnsen, Andrea Natale, Richard A. Gibbs, Douglas P. Kiel, Ingo Ruczinski, Susan Redline, Lukas Forer, Scott I. Vrieze, May E. Montasser, Rasika A. Mathias, Jerome I. Rotter, Jacob Pleiness, Chunyu Liu, Brian L. Browning, James G. Wilson, Weiniu Gan, Christine M. Albert, Marilyn J. Telen, Courtney G. Montgomery, Steven A. Lubitz, Robert Klemmer, Ramachandran S. Vasan, Nathan Pankratz, Mariza de Andrade, Vivien A. Sheehan, Kenneth Rice, Xihong Lin, Eimear E. Kenny, Stephanie M. Gogarten, John Blangero, Donna K. Arnett, Jiang He, Pankaj Qasba, James F. Casella, Patrick T. Ellinor, Nicholette D. Palmer, R. Graham Barr, Scott T. Weiss, Joanne E. Curran, Bruce S. Weir, Kari E. North, L. Adrienne Cupples, Dawn L. DeMeo, Tanika N. Kelly, Angel C.Y. Mak, Russell P. Tracy, David A. Schwartz, Kent D. Taylor, Rebecca L. Beer, Daniel N. Harris, George J. Papanicolaou, Marguerite R. Irvin, Stephen T. McGarvey, Sebastian Zöllner, Patricia A. Peyser, Brian E. Cade, Ruth J. F. Loos, Douglas Loesch, Nicholas L. Smith, Gonçalo R. Abecasis, Jennifer A. Smith, Michael E. Hall, Lu-Chen Weng, Jeffrey R. O'Connell, Adrienne M. Stilp, Donald W. Bowden, Kathleen C. Barnes, Stacey Gabriel, Michael Boehnke, Wayne Huey-Herng Sheu, and Dawood Darbar
Subjects: Quality Control, Heterozygote, Genomics, Computational biology, Biology, Polymorphism, Single Nucleotide, Genome, Article, DNA sequencing, INDEL Mutation, Loss of Function Mutation, Genetics research, Genetic variation, Humans, Precision Medicine, Genetic association, Population Density, Multidisciplinary, Whole Genome Sequencing, Genome, Human, Genetic Variation, Rare variants, United States, Genetic architecture, Phenotype, Cytochrome P-450 CYP2D6, Haplotypes, Mutagenesis, Sample Size, Next-generation sequencing, National Heart, Lung, and Blood Institute (U.S.), Imputation (genetics), Reference genome
Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%., The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.
Published: 2021
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19. Whole Genome DNA and RNA Sequencing of Whole Blood Elucidates the Genetic Architecture of Gene Expression Underlying a Wide Range of Diseases

Author: Chunyu Liu, Roby Joehanes, Jiantao Ma, Yuxuan Wang, Xianbang Sun, Amena Keshawarz, Meera Sooda, Tianxiao Huan, Shih-Jen Hwang, Helena Bui, Brandon Tejada, Peter J. Munson, Demirkale Cumhur, Nancy L. Heard-Costa, Achilleas N Pitsillides, Gina M. Peloso, Michael Feolo, Nataliya Sharopova, Ramachandran S. Vasan, and Daniel Levy
Subjects: Multidisciplinary, Sequence Analysis, RNA, Quantitative Trait Loci, Humans, Gene Expression, Genetic Predisposition to Disease, DNA, Article, Genome-Wide Association Study
Abstract: To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis-eQTL variant-gene transcript (eGene) pairs at p − 8 (2,855,111 unique cis-eQTL variants and 15,982 unique eGenes) and 1,469,754 trans-eQTL variant-eGene pairs at p trans-eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis-eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis-eGenes are enriched for immune functions (FDR cis-eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.
Published: 2022
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20. Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: The Framingham Heart Study

Author: Amena Keshawarz, Helena Bui, Roby Joehanes, Jiantao Ma, Chunyu Liu, Tianxiao Huan, Shih-Jen Hwang, Brandon Tejada, Meera Sooda, Paul Courchesne, Peter J. Munson, Cumhur Y. Demirkale, Chen Yao, Nancy L. Heard-Costa, Achilleas N. Pitsillides, Honghuan Lin, Ching-Ti Liu, Yuxuan Wang, Gina M. Peloso, Jessica Lundin, Jeffrey Haessler, Zhaohui Du, Michael Cho, Craig P. Hersh, Peter Castaldi, Laura M. Raffield, Jia Wen, Yun Li, Alexander P. Reiner, Mike Feolo, Nataliya Sharopova, Ramachandran S. Vasan, Edwin K. Silverman, Dawn L. DeMeo, April P. Carson, Charles Kooperberg, and Daniel Levy
Abstract: BackgroundExpression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression and may reveal molecular mechanisms of disease. The present study describes an eQTM resource of CpG-transcript pairs.MethodsDNA methylation was measured in blood samples from 1,045 Framingham Heart Study (FHS) participants using the Illumina 450K BeadChip and in 1,070 FHS participants using the Illumina EPIC array. Blood gene expression data were collected from all 2,115 participants using RNA sequencing (RNA-seq). The association between DNA methylation and gene expression was quantified for all cis (i.e., within 1Mb) and trans (>1Mb) CpG-transcript pairs. Significant results (pcis and trans) were subsequently tested for enrichment of biological pathways and of clinical traits.ResultsWe identified 70,047 significant cis CpG-transcript pairs where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1,208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1,191 clinical traits (enrichment FDR ≤ 0.05). Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with these cardiometabolic traits.ConclusionsWe developed a robust and powerful resource of eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.
Published: 2022
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21. Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

Author: George Hindy, Peter Dornbos, Mark D. Chaffin, Dajiang J. Liu, Minxian Wang, Margaret Sunitha Selvaraj, David Zhang, Joseph Park, Carlos A. Aguilar-Salinas, Lucinda Antonacci-Fulton, Diego Ardissino, Donna K. Arnett, Stella Aslibekyan, Gil Atzmon, Christie M. Ballantyne, Francisco Barajas-Olmos, Nir Barzilai, Lewis C. Becker, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Matthew J. Bown, Jennifer A. Brody, Jai G. Broome, Noël P. Burtt, Brian E. Cade, Federico Centeno-Cruz, Edmund Chan, Yi-Cheng Chang, Yii-Der I. Chen, Ching-Yu Cheng, Won Jung Choi, Rajiv Chowdhury, Cecilia Contreras-Cubas, Emilio J. Córdova, Adolfo Correa, L. Adrienne Cupples, Joanne E. Curran, John Danesh, Paul S. de Vries, Ralph A. DeFronzo, Harsha Doddapaneni, Ravindranath Duggirala, Susan K. Dutcher, Patrick T. Ellinor, Leslie S. Emery, Jose C. Florez, Myriam Fornage, Barry I. Freedman, Valentin Fuster, Ma. Eugenia Garay-Sevilla, Humberto García-Ortiz, Soren Germer, Richard A. Gibbs, Christian Gieger, Benjamin Glaser, Clicerio Gonzalez, Maria Elena Gonzalez-Villalpando, Mariaelisa Graff, Sarah E. Graham, Niels Grarup, Leif C. Groop, Xiuqing Guo, Namrata Gupta, Sohee Han, Craig L. Hanis, Torben Hansen, Jiang He, Nancy L. Heard-Costa, Yi-Jen Hung, Mi Yeong Hwang, Marguerite R. Irvin, Sergio Islas-Andrade, Gail P. Jarvik, Hyun Min Kang, Sharon L.R. Kardia, Tanika Kelly, Eimear E. Kenny, Alyna T. Khan, Bong-Jo Kim, Ryan W. Kim, Young Jin Kim, Heikki A. Koistinen, Charles Kooperberg, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Leslie A. Lange, Jiwon Lee, Juyoung Lee, Seonwook Lee, Donna M. Lehman, Rozenn N. Lemaitre, Allan Linneberg, Jianjun Liu, Ruth J.F. Loos, Steven A. Lubitz, Valeriya Lyssenko, Ronald C.W. Ma, Lisa Warsinger Martin, Angélica Martínez-Hernández, Rasika A. Mathias, Stephen T. McGarvey, Ruth McPherson, James B. Meigs, Thomas Meitinger, Olle Melander, Elvia Mendoza-Caamal, Ginger A. Metcalf, Xuenan Mi, Karen L. Mohlke, May E. Montasser, Jee-Young Moon, Hortensia Moreno-Macías, Alanna C. Morrison, Donna M. Muzny, Sarah C. Nelson, Peter M. Nilsson, Jeffrey R. O’Connell, Marju Orho-Melander, Lorena Orozco, Colin N.A. Palmer, Nicholette D. Palmer, Cheol Joo Park, Kyong Soo Park, Oluf Pedersen, Juan M. Peralta, Patricia A. Peyser, Wendy S. Post, Michael Preuss, Bruce M. Psaty, Qibin Qi, D.C. Rao, Susan Redline, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Nilesh Samani, Heribert Schunkert, Claudia Schurmann, Daekwan Seo, Jeong-Sun Seo, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Adrienne M. Stilp, E. Shyong Tai, Claudia H.T. Tam, Kent D. Taylor, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Michael Y. Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Miriam S. Udler, Rob M. van Dam, Ramachandran S. Vasan, Karine A. Viaud Martinez, Fei Fei Wang, Xuzhi Wang, Hugh Watkins, Daniel E. Weeks, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, Lisa R. Yanek, Sekar Kathiresan, Daniel J. Rader, Jerome I. Rotter, Michael Boehnke, Mark I. McCarthy, Cristen J. Willer, Pradeep Natarajan, Jason A. Flannick, Amit V. Khera, Gina M. Peloso, NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, Clinicum, Department of Medicine, HUS Internal Medicine and Rehabilitation, University of Helsinki, and Department of Public Health
Subjects: APOC3, Blood Glucose, Multifactorial Inheritance, gene-based association, Polymorphism, Single Nucleotide, Article, Open Reading Frames, ANGPTL3, lipid, OF-FUNCTION MUTATIONS, BINDING, Databases, Genetic, SEQUENCE VARIANTS, Genetics, Humans, Exome, Genetic Predisposition to Disease, SINUSOIDAL ENDOTHELIAL-CELLS, Genetics (clinical), Alleles, RISK, IDENTIFICATION, 1184 Genetics, developmental biology, physiology, association, cholesterol, Genetic Variation, Computational Biology, Molecular Sequence Annotation, PERILIPIN, Lipid Metabolism, Lipids, Genetics, Population, Phenotype, Diabetes Mellitus, Type 2, Liver, Case-Control Studies, exome sequencing, TRIGLYCERIDES, Genome-Wide Association Study
Abstract: Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels. This work was supported by a grant from the Swedish Research Council (2016-06830) and grants from the National Heart, Lung, and Blood Institute (NHLBI): R01HL142711 and R01HL127564. Please refer to the supplemental information for the full acknowledgements. Sí
Published: 2022
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22. Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Author: Natalia Trpchevska, Maxim B. Freidin, Linda Broer, Berthe C. Oosterloo, Shuyang Yao, Yitian Zhou, Barbara Vona, Charles Bishop, Argyro Bizaki-Vallaskangas, Barbara Canlon, Fabio Castellana, Daniel I. Chasman, Stacey Cherny, Kaare Christensen, Maria Pina Concas, Adolfo Correa, Ran Elkon, Jonas Mengel-From, Yan Gao, Anne B.S. Giersch, Giorgia Girotto, Alexander Gudjonsson, Vilmundur Gudnason, Nancy L. Heard-Costa, Ronna Hertzano, Jacob v.B. Hjelmborg, Jens Hjerling-Leffler, Howard J. Hoffman, Jaakko Kaprio, Johannes Kettunen, Kristi Krebs, Anna K. Kähler, Francois Lallemend, Lenore J. Launer, I-Min Lee, Hampton Leonard, Chuan-Ming Li, Hubert Lowenheim, Patrik K.E. Magnusson, Joyce van Meurs, Lili Milani, Cynthia C. Morton, Antti Mäkitie, Mike A. Nalls, Giuseppe Giovanni Nardone, Marianne Nygaard, Teemu Palviainen, Sheila Pratt, Nicola Quaranta, Joel Rämö, Elmo Saarentaus, Rodolfo Sardone, Claudia L. Satizabal, John M. Schweinfurth, Sudha Seshadri, Eric Shiroma, Eldad Shulman, Eleanor Simonsick, Christopher Spankovich, Anke Tropitzsch, Volker M. Lauschke, Patrick F. Sullivan, Andre Goedegebure, Christopher R. Cederroth, Frances M.K. Williams, Andries Paul Nagtegaal, Andres Metspalu, Mari Nelis, Reedik Mägi, Tõnu Esko, Tampere University, Clinical Medicine, Department of Otology and Oral Diseases, Institute for Molecular Medicine Finland, HUS Head and Neck Center, Clinicum, Korva-, nenä- ja kurkkutautien klinikka, Genetic Epidemiology, Genomics of Neurological and Neuropsychiatric Disorders, Complex Disease Genetics, Trpchevska, Natalia, Freidin, Maxim B, Broer, Linda, Oosterloo, Berthe C, Yao, Shuyang, Zhou, Yitian, Vona, Barbara, Bishop, Charle, Bizaki-Vallaskangas, Argyro, Canlon, Barbara, Castellana, Fabio, Chasman, Daniel I, Cherny, Stacey, Christensen, Kaare, Concas, Maria Pina, Correa, Adolfo, Elkon, Ran, Mengel-From, Jona, Gao, Yan, Giersch, Anne B S, Girotto, Giorgia, Gudjonsson, Alexander, Gudnason, Vilmundur, Heard-Costa, Nancy L, Hertzano, Ronna, Hjelmborg, Jacob V B, Hjerling-Leffler, Jen, Hoffman, Howard J, Kaprio, Jaakko, Kettunen, Johanne, Krebs, Kristi, Kähler, Anna K, Lallemend, Francoi, Launer, Lenore J, Lee, I-Min, Leonard, Hampton, Li, Chuan-Ming, Lowenheim, Hubert, Magnusson, Patrik K E, van Meurs, Joyce, Milani, Lili, Morton, Cynthia C, Mäkitie, Antti, Nalls, Mike A, Nardone, Giuseppe Giovanni, Nygaard, Marianne, Palviainen, Teemu, Pratt, Sheila, Quaranta, Nicola, Rämö, Joel, Saarentaus, Elmo, Sardone, Rodolfo, Satizabal, Claudia L, Schweinfurth, John M, Seshadri, Sudha, Shiroma, Eric, Shulman, Eldad, Simonsick, Eleanor, Spankovich, Christopher, Tropitzsch, Anke, Lauschke, Volker M, Sullivan, Patrick F, Goedegebure, Andre, Cederroth, Christopher R, Williams, Frances M K, Nagtegaal, Andries Paul, Internal Medicine, and Otorhinolaryngology and Head and Neck Surgery
Subjects: basal cells, hair cells, cochlea, spindle cell, ARHL, GWAS, genetics, hearing loss, root cells, spindle cells, stria vascularis, Animals, Cochlea, Genome-Wide Association Study, Humans, Mice, Stria Vascularis, Deafness, Hearing Loss, basal cell, hair cell, Hair-cells, Heritability, otorhinolaryngologic diseases, Genetics, Pathogenicity, Gwas data, Deafne, Ld score regression, Ganglion neurons, Genetics (clinical), Animal, 1184 Genetics, developmental biology, physiology, hearing lo, Stria Vasculari, Inner, 3142 Public health care science, environmental and occupational health, root cell, Differentiation, Degeneration, 3111 Biomedicine, genetic, Noise, Human
Abstract: Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss. publishedVersion
Published: 2022
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23. Correlations between complex human phenotypes vary by genetic background, gender, and environment

Author: Michael Elgart, Matthew O. Goodman, Carmen Isasi, Han Chen, Alanna C. Morrison, Paul S. de Vries, Huichun Xu, Ani W. Manichaikul, Xiuqing Guo, Nora Franceschini, Bruce M. Psaty, Stephen S. Rich, Jerome I. Rotter, Donald M. Lloyd-Jones, Myriam Fornage, Adolfo Correa, Nancy L. Heard-Costa, Ramachandran S. Vasan, Ryan Hernandez, Robert C. Kaplan, Susan Redline, and Tamar Sofer
Subjects: General Biochemistry, Genetics and Molecular Biology
Abstract: We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.
Published: 2022
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24. Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Author: Akhil Pampana, Xiuqing Guo, Tanika N. Kelly, Yii-Der Ida Chen, Charles Kooperberg, Chii-Min Hwu, Mariaelisa Graff, Jiang He, Xihao Li, Patrick T. Ellinor, Joshua C. Bis, Kari E. North, Nancy L. Heard-Costa, Joseph Park, Stacey Gabriel, Joanne E. Curran, Braxton D. Mitchell, Lee-Ming Chuang, Ravindranath Duggirala, Jerome I. Rotter, Robert C. Kaplan, Soren Germer, Pradeep Natarajan, Take Naseri, Xihong Lin, Susan K. Dutcher, Stella Aslibekyan, Ryan W. Kim, Daniel J. Rader, Richard A. Gibbs, Myriam Fornage, Eric Boerwinkle, Bertha Hidalgo, Muagututi’a S. Reupena, Deborah A. Nickerson, Zhe Wang, Donald W. Bowden, Yuxuan Wang, Alanna C. Morrison, Stephen S. Rich, David Zhang, Gina M. Peloso, Xiaohui Li, Martin Lisa, Lisa de las Fuentes, Zilin Li, Alexander P. Reiner, Jennifer A. Brody, Lisa R. Yanek, Marguerite R. Irvin, Bruce M. Psaty, Bao Wei, Preuss Michael, Leslie A. Lange, John T. Wilkins, Russell P. Tracy, Paul S. de Vries, Wei Zhao, Rasika A. Mathias, Susan Redline, Xiao Sun, Kent D. Taylor, Barry I. Freedman, Ani Manichaikul, Donna K. Arnett, Nicholette D. Palmer, Cristen J. Willer, Steven A. Lubitz, Sharon L.R. Kardia, L. Adrienne Cupples, Ramachandran S. Vasan, May E. Montasser, Ren-Hua Chung, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, Ruth J. F. Loos, Jennifer A. Smith, John Blangero, Brian G. Kral, Karine A. Viaud Martinez, Stephen T. McGarvey, Adolfo Correa, Michael Y. Tsai, Patricia A. Peyser, and Brian E. Cade
Subjects: Genetics, Whole genome sequencing, Genome Scan, Blood lipids, Biology, medicine.disease, Genome, symbols.namesake, Mendelian inheritance, symbols, medicine, lipids (amino acids, peptides, and proteins), Allele, Gene, Dyslipidemia
Abstract: Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rareLDLRintronic variants associated with markedly increased LDL-C, similar to rareLDLRexonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.
Published: 2021
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25. Genetic and environmental correlations between complex phenotypes differ by race/ethnicity and sex

Author: Susan Redline, Robert C. Kaplan, Carmen R. Isasi, Tamar Sofer, Ryan D. Hernandez, Donald M. Lloyd-Jones, P. De Vries, Nora Franceschini, Jerome I. Rotter, Stephen S. Rich, Han Chen, Myriam Fornage, Bruce M. Psaty, Huichun Xu, Vasan S. Ramachandran, Matthew Goodman, Xuejiang Guo, Ani Manichaikul, Adolfo Correa, M. Elgart, and Nancy L. Heard-Costa
Subjects: Correlation, White (mutation), Race ethnicity, Evolutionary biology, Biology, Phenotype
Abstract: We developed novel closed-form estimators of genetic and environmental correlation coefficients. We applied them to estimate over 4,000 genetic and environmental correlations between multiple phenotypes in a diverse sample from the Trans-Omics in Precision Medicine (TOPMed) program. We found substantial differences in heritabilities, genetic, and environmental correlations of multiple phenotypes and phenotype-pairs between Black, Hispanic/Latino and White populations as well as between sexes. Finally, we quantified genetic and environmental correlations between phenotypic domains, each characterized by multiple phenotypes. Altogether we provide a novel, in-depth framework for examining relations among complex human phenotypes and their determinants.
Published: 2021
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26. 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

27. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Author: Julia K. Goodrich, Moriel Singer-Berk, Rachel Son, Abigail Sveden, Jordan Wood, Eleina England, Joanne B. Cole, Ben Weisburd, Nick Watts, Lizz Caulkins, Peter Dornbos, Ryan Koesterer, Zachary Zappala, Haichen Zhang, Kristin A. Maloney, Andy Dahl, Carlos A. Aguilar-Salinas, Gil Atzmon, Francisco Barajas-Olmos, Nir Barzilai, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Federico Centeno-Cruz, John C. Chambers, Nathalie Chami, Edmund Chan, Juliana Chan, Ching-Yu Cheng, Yoon Shin Cho, Cecilia Contreras-Cubas, Emilio Córdova, Adolfo Correa, Ralph A. DeFronzo, Ravindranath Duggirala, Josée Dupuis, Ma Eugenia Garay-Sevilla, Humberto García-Ortiz, Christian Gieger, Benjamin Glaser, Clicerio González-Villalpando, Ma Elena Gonzalez, Niels Grarup, Leif Groop, Myron Gross, Christopher Haiman, Sohee Han, Craig L. Hanis, Torben Hansen, Nancy L. Heard-Costa, Brian E. Henderson, Juan Manuel Malacara Hernandez, Mi Yeong Hwang, Sergio Islas-Andrade, Marit E. Jørgensen, Hyun Min Kang, Bong-Jo Kim, Young Jin Kim, Heikki A. Koistinen, Jaspal Singh Kooner, Johanna Kuusisto, Soo-Heon Kwak, Markku Laakso, Leslie Lange, Jong-Young Lee, Juyoung Lee, Donna M. Lehman, Allan Linneberg, Jianjun Liu, Ruth J. F. Loos, Valeriya Lyssenko, Ronald C. W. Ma, Angélica Martínez-Hernández, James B. Meigs, Thomas Meitinger, Elvia Mendoza-Caamal, Karen L. Mohlke, Andrew D. Morris, Alanna C. Morrison, Maggie C. Y. Ng, Peter M. Nilsson, Christopher J. O’Donnell, Lorena Orozco, Colin N. A. Palmer, Kyong Soo Park, Wendy S. Post, Oluf Pedersen, Michael Preuss, Bruce M. Psaty, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Jerome I. Rotter, Danish Saleheen, Claudia Schurmann, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Timothy D. Spector, Konstantin Strauch, Tim M. Strom, E. Shyong Tai, Claudia H. T. Tam, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Russell P. Tracy, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Rob M. van Dam, Ramachandran S. Vasan, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, AMP-T2D-GENES Consortia, Noël P. Burtt, Noah Zaitlen, Mark I. McCarthy, Michael Boehnke, Toni I. Pollin, Jason Flannick, Josep M. Mercader, Anne O’Donnell-Luria, Samantha Baxter, Jose C. Florez, Daniel G. MacArthur, Miriam S. Udler, Institute for Molecular Medicine Finland, Clinicum, Centre of Excellence in Complex Disease Genetics, Leif Groop Research Group, HUS Abdominal Center, University of Helsinki, Department of Medicine, Tiinamaija Tuomi Research Group, Department of Public Health, NIH - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Estados Unidos), NIH - National Institute of Child Health and Human Development (NICHD) (Estados Unidos), and American Diabetes Association
Subjects: 0301 basic medicine, Multifactorial Inheritance, LD SCORE REGRESSION, General Physics and Astronomy, MEDICAL GENETICS, Penetrance, Disease, DISEASE, 0302 clinical medicine, Genotype, Exome, Exome sequencing, Genetics, RISK, Multidisciplinary, Molecular medicine, Endocrine system and metabolic diseases, ASSOCIATION, RARE VARIANTS, LOW-FREQUENCY, Medical genomics, Adult, Science, Biology, AMERICAN-COLLEGE, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Diabetes mellitus, medicine, Humans, Genetic Predisposition to Disease, CLINICAL EXOME, Monogenic Diabetes, Dyslipidemias, MUTATIONS, Genetic variants, General Chemistry, medicine.disease, Biomarker (cell), 030104 developmental biology, Biological Variation, Population, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, 030217 neurology & neurosurgery, Biomarkers
Abstract: Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias., Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.
Published: 2021
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28. Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability

Author: Berthe C Oosterloo, Rodolfo Sardone, Andries Paul Nagtegaal, Nancy L. Heard-Costa, Guy Van Camp, Margherita Francescatto, Maria Pina Concas, Erik Fransen, Anna Morgan, Sudha Seshadri, Giorgia Girotto, Fabrizio Serra, Paolo Gasparini, Giancarlo Logroscino, Nicola Quaranta, Concas, Maria Pina, Morgan, Anna, Serra, Fabrizio, Nagtegaal, Andries Paul, Oosterloo, Berthe C., Seshadri, Sudha, Heard-Costa, Nancy, Van Camp, Guy, Fransen, Erik, Francescatto, Margherita, Logroscino, Giancarlo, Sardone, Rodolfo, Quaranta, Nicola, Gasparini, Paolo, Girotto, Giorgia, and Otorhinolaryngology and Head and Neck Surgery
Subjects: Male, inner ear, Candidate gene, Single-nucleotide polymorphism, Genome-wide association study, hearing, GWAS, meta-analysis, gene expression, Biology, QH426-470, Article, meta-analysi, Cohort Studies, Mice, SDG 3 - Good Health and Well-being, PCNT, Genotype, Genetics, Animals, Humans, Genetics (clinical), Italy, Sensory Thresholds, Meta-analysis, Cohort, Trait, Female, Human medicine, Genome-Wide Association Study
Abstract: To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive p-value (p &lt, 10−5). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort (n = 1774) at the nominal significance threshold (p &lt, 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: BNIP3L, ELP5, MAP3K20, MATN2, MTMR7, MYO1E, PCNT, R3HDM1, SLC9A9, TGFB2, and YTHDC2. These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.
Published: 2021

29. A system for phenotype harmonization in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) program

Author: Tanika N. Kelly, May E Montasser, Alyna T. Khan, Laura M. Raffield, Carla Wilson, Elizabeth C. Oelsner, Kerri L. Wiggins, Ming-Huei Chen, Gina M. Peloso, Adolfo Correa, Andrew D. Johnson, Donna K. Arnett, Xiuqing Guo, Jai G. Broome, Daniel E. Weeks, Rebecca D. Jackson, Lucia Juarez, Stephen T. McGarvey, Pradeep Natarajan, Braxton D. Mitchell, Kent D. Taylor, Bruce M. Psaty, Santhi K Ganesh, Cathy C. Laurie, Nicola L. Hawley, Leslie S. Emery, Adrienne M. Stilp, Alanna C. Morrison, Jennifer A Smith, Charles Kooperberg, Catherine M. D’Augustine, Jan Graffelman, Paul S. de Vries, Chancellor Hohensee, Sharon L R Kardia, Patricia A Peyser, Wan-Ling Hsu, Erin J Buth, Kathleen C. Barnes, Susan R. Heckbert, Ramachandran S. Vasan, Nathan Pankratz, Karen M. Mutalik, Quenna Wong, Brian E. Cade, Jingmin Liu, Joshua C. Bis, Cecelia A. Laurie, Kari E. North, Fei Fei Wang, Mariza de Andrade, Nancy L. Heard-Costa, William Craig Johnson, L. Adrienne Cupples, Scott T. Weiss, Seyed Mehdi Nouraie, Patrick T. Ellinor, Jerome I. Rotter, Weiniu Gan, Shannon Kelly, Stephen S. Rich, Cashell E. Jaquish, Dongquan Chen, Nora Franceschini, Lisa R. Yanek, Jiwon Lee, Alexander P. Reiner, Megan L. Grove, Stella Aslibekyan, Myriam Fornage, Lawrence F Bielak, Rasika A. Mathias, Universitat Politècnica de Catalunya. Departament d'Estadística i Investigació Operativa, and Universitat Politècnica de Catalunya. COSDA-UPC - COmpositional and Spatial Data Analysis
Subjects: 0301 basic medicine, Program evaluation, Computer science, Epidemiology, common data elements, hematologic disease, Matemàtiques i estadística::Matemàtica aplicada a les ciències [Àrees temàtiques de la UPC], Medical and Health Sciences, Mathematical Sciences, 0302 clinical medicine, Documentation, cardiovascular disease, and Blood Institute (U.S.), 030212 general & internal medicine, Phenomics, Precision Medicine, Lung, lung diseases, Sleep-wake disorders, phenotypes, 92 Biology and other natural sciences::92B Mathematical biology in general [Classificació AMS], Common data elements, Cardiovascular disease, Phenotype, Phenotypes, Biomatemàtica, Information Dissemination, Harmonization, 62 Statistics::62D05 Sampling theory, sample surveys [Classificació AMS], Hematologic disease, 03 medical and health sciences, Data Aggregation, Clinical Research, Controlled vocabulary, Genetics, Humans, AcademicSubjects/MED00860, sleep-wake disorders, Sampling (Statistics), Genetic Association Studies, Lung diseases, Biomathematics, Data collection, Study Design, Matemàtiques i estadística::Estadística aplicada::Estadística biosanitària [Àrees temàtiques de la UPC], Information dissemination, Human Genome, National Heart, Precision medicine, Data science, United States, 030104 developmental biology, Good Health and Well Being, National Heart, Lung, and Blood Institute (U.S.), Mostreig (Estadística), Program Evaluation
Abstract: Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948–2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.
Published: 2021

30. Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes

Author: Marju Orho-Melander, Humberto García-Ortiz, Xueling Sim, Amp-T D-Genes, Cheol Joo Park, Gina M. Peloso, Jason Flannick, Brian Tomlinson, Hyun Min Kang, Emilio J. Cordova, Stephen S. Rich, Richard A. Gibbs, Angélica Martínez-Hernández, Lorena Orozco, Harsha Doddapaneni, Lisa R. Yanek, Jiwon Lee, Namrata Gupta, Valeriya Lyssenko, Sohee Han, James B. Meigs, Bong-Jo Kim, Bruce M. Psaty, Leslie S. Emery, Kerrin S. Small, Pradeep Natarajan, May E. Montasser, Christian Gieger, Sharon L.R. Kardia, Sarah C. Nelson, Craig L. Hanis, Heikki A. Koistinen, María Elena González-Villalpando, Edmund Chan, Michael Y. Tsai, Benjamin Glaser, Thomas Meitinger, Matthew J. Bown, Mariaelisa Graff, John Danesh, Sekar Kathiresan, Tiinamaija Tuomi, Ramachandran S. Vasan, Gil Atzmon, Alyna T. Khan, Diego Ardissino, Yii-Der Ida Chen, David Zhang, Rob M. van Dam, Wendy S. Post, Barry I. Freedman, D. C. Rao, Michael Preuss, Donna M. Lehman, L. Adrienne Cupples, Colin N. A. Palmer, Claudia H. T. Tam, Hortensia Moreno-Macías, Markku Laakso, Peter Dornbos, Teresa Tusié-Luna, Stella Aslibekyan, Marguerite R. Irvin, Daniel J. Rader, Jee-Young Moon, Eimear E. Kenny, Lisa W. Martin, Jennifer A. Brody, Amit Khera, Erwin P. Bottinger, Sarah E. Graham, Myriam Fornage, Ruth McPherson, Nancy L. Heard-Costa, Michael Boehnke, Clicerio Gonzalez, Ryan W. Kim, Yi-Cheng Chang, Peter M. Nilsson, Yik Ying Teo, Robert Sladek, Cristen J. Willer, Fei Fei Wang, Donna K. Arnett, Mark Chaffin, Karine A. Viaud Martinez, Alanna C. Morrison, Leslie A. Lange, Ravindranath Duggirala, Donna M. Muzny, Kent D. Taylor, Niels Grarup, Soren Germer, Patricia A. Peyser, Brian E. Cade, Lewis C. Becker, Steven A. Lubitz, Nicholette D. Palmer, Susan K. Dutcher, Ronald C.W. Ma, Xuenan Mi, Xiuqing Guo, Hugh Watkins, Eric Boerwinkle, Qibin Qi, Johanna Kuusisto, Christie M. Ballantyne, Tanika N. Kelly, Rajiv Chowdhury, Elvia Mendoza-Caamal, Wing-Yee So, Tien Yin Wong, Torben Hansen, Cecilia Contreras-Cubas, Jeong-Sun Seo, Mi Yeong Hwang, Daekwan Seo, Dajiang J. Liu, Cristina Revilla-Monsalve, Paul S. de Vries, Daniel R. Witte, Yi-Jen Hung, Olle Melander, Karen L. Mohlke, Lucinda Antonacci-Fulton, Francisco Barajas-Olmos, Soo Heon Kwak, Daniel E. Weeks, Claudia Schurmann, Ginger A. Metcalf, Young-Jin Kim, Adrienne M. Stilp, Lori L. Bonnycastle, John Blangero, Ralph A. DeFronzo, Donald W. Bowden, Rasika A. Mathias, Oluf Pedersen, Rozenn N. Lemaitre, Stephen T. McGarvey, Heribert Schunkert, Jaakko Tuomilehto, Farook Thameem, Valentin Fuster, Joshua C. Bis, George Hindy, Allan Linneberg, James G. Wilson, Kyong Soo Park, Sergio A. Islas-Andrade, Ching-Yu Cheng, Won Jung Choi, Minxian X. Wang, Xuzhi Wang, Adolfo Correa, Jai G. Broome, Gail P. Jarvik, Alexander P. Reiner, E. Shyong Tai, Juyoung Lee, Mark I. McCarthy, Nilesh J. Samani, Susan Redline, Carlos A. Aguilar-Salinas, Jerome I. Rotter, Ma. Eugenia Garay-Sevilla, Jiang He, Patrick T. Ellinor, Joseph Park, Joanne E. Curran, Nir Barzilai, Federico Centeno-Cruz, Seonwook Lee, Lawrence F. Bielak, Jianjun Liu, Charles Kooperberg, Juan M. Peralta, Jose C. Florez, Leif Groop, Noël P. Burtt, Margaret Sunitha Selvaraj, Jeffrey R. O'Connell, and Ruth J. F. Loos
Subjects: Genetics, 0303 health sciences, education.field_of_study, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, DNA sequencing, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, SNP, education, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
Published: 2020
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31. Whole genome sequencing association analysis of quantitative red blood cell phenotypes: the NHLBI TOPMed program

Author: Paul L. Auer, Laura Almasy, Jerome I. Rotter, Nancy Min, Lisa R. Yanek, Shuquan Rao, Hua Tang, Zhe Wang, Stacey Gabriel, Jee-Young Moon, Nancy L. Heard-Costa, Adam S. Butterworth, Ravindranath Duggirala, Cathy C. Laurie, Hélène Choquet, Ruth J. F. Loos, Alanna C. Morrison, Eric Jorgenson, Charles Kooperberg, Rasika A. Mathias, Laura M. Raffield, Nicholas L. Smith, Andrew D. Johnson, Matthew P. Conomos, Lynette Ekunwe, Donald M. Lloyd-Jones, Gonçalo R. Abecasis, Robert C. Kaplan, Myriam Fornage, Daniel E. Bauer, Nathalie Chami, Lewis C. Becker, Leslie A. Lange, Ming-Huei Chen, Brian D. Hobbs, Paul S. de Vries, Terri H. Beaty, Cecelia A. Laurie, Eric Boerwinkle, Michael Preuss, Adrienne M. Stilp, Jeffrey R. O'Connell, Kousik Kundu, Joanne E. Curran, Mary Cushman, Kari E. North, Xiuwen Zheng, John Blangero, Sébastian Méric de Bellefon, Ramachandran S. Vasan, Nathan Pankratz, Praveen Surendran, Joshua P. Lewis, Kathleen A. Ryan, Jennifer A. Brody, Deepti Jain, Braxton D. Mitchell, Marsha M. Wheeler, Lifang Hou, Deborah A. Nickerson, Guillaume Lettre, Alexander P. Reiner, Albert V. Smith, Stephen S. Rich, Nicole Soranzo, Adolfo Correa, Jai G. Broome, Nauder Faraday, Thomas W. Blackwell, Bruce M. Psaty, Quan Sun, Yun Li, Caitlin P. McHugh, Yao Hu, and John Lane
Subjects: Genetics, Whole genome sequencing, education.field_of_study, Population, Genome-wide association study, Quantitative trait locus, Biology, Genetic architecture, symbols.namesake, Mendelian inheritance, symbols, Indel, education, Genetic association
Abstract: Whole genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these newly discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3bp indel p.Lys2169del (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis [OMIM 194380], associated with higher MCHC. In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically-diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
Published: 2020
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32. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Author: Ma Elena Gonzalez, Marit E. Jørgensen, Edmund Chan, Eric Boerwinkle, Craig L. Hanis, Tim M. Strom, Young-Jin Kim, Alanna C. Morrison, Abigail Sveden, Zachary Zappala, Jianjun Liu, Markku Laakso, Russell P. Tracy, Andrew D. Morris, Farook Thameem, Ruth J. F. Loos, Robert Sladek, Moriel Singer-Berk, Jason Flannick, Stephen S. Rich, Angélica Martínez-Hernández, Rob M. van Dam, Wendy S. Post, Michael Boehnke, Peter M. Nilsson, Humberto García-Ortiz, Clicerio González-Villalpando, Samantha Baxter, Yoon Shin Cho, Sergio Islas-Andrade, Colin N. A. Palmer, Claudia H. T. Tam, Nicholas A. Watts, Lizz Caulkins, Rachel Son, Daniel G. MacArthur, Toni I. Pollin, Juan Manuel Malacara Hernandez, Jong-Young Lee, Bruce M. Psaty, Ravindranath Duggirala, Erwin P. Bottinger, Nancy L. Heard-Costa, Donna M. Lehman, Carlos A. Aguilar-Salinas, Juyoung Lee, Haichen Zhang, Mark I. McCarthy, Brian Tomlinson, Leslie A. Lange, Cecilia Contreras-Cubas, Johanna Kuusisto, Danish Saleheen, Juliana C.N. Chan, Andrew Dahl, Konstantin Strauch, Noël P. Burtt, Tien Yin Wong, Niels Grarup, Jerome I. Rotter, Ronald C.W. Ma, Julia K. Goodrich, Anne H. O’Donnell-Luria, Jose C. Florez, Miriam S. Udler-Aubrey, Kristin A. Maloney, James G. Wilson, Ramachandran S. Vasan, Bong-Jo Kim, Leif Groop, Noah Zaitlen, Kerrin S. Small, Heikki A. Koistinen, Donald W. Bowden, Wing-Yee So, Jaakko Tuomilehto, Oluf Pedersen, John C. Chambers, Mi Yeong Hwang, Karen L. Mohlke, John Blangero, Eleina M. England, Elvia Mendoza-Caamal, James B. Meigs, Federico Centeno-Cruz, Michael Preuss, Ralph A. DeFronzo, Joanne B. Cole, Jordan Wood, Allan Linneberg, Benjamin Glaser, Lorena Orozco, Jaspal S. Kooner, Valeriya Lyssenko, Sohee Han, Gil Atzmon, Ma. Eugenia Garay-Sevilla, Tiinamaija Tuomi, Brian E. Henderson, Christopher J. O'Donnell, Hyun Min Kang, Teresa Tusié-Luna, Nir Barzilai, Thomas Meitinger, Christian Gieger, Ben Weisburd, Alexander P. Reiner, Tim D. Spector, Myron D. Gross, E. Shyong Tai, Yik Ying Teo, for Amp-T D-Genes Consortia, Xueling Sim, Emilio J. Cordova, Cristina Revilla-Monsalve, Daniel R. Witte, Francisco Barajas-Olmos, Claudia Schurmann, Lori L. Bonnycastle, Josep M. Mercader, Adolfo Correa, Torben Hansen, Kyong Soo Park, Ching-Yu Cheng, Soo Heon Kwak, Nathalie Chami, Christopher A. Haiman, Xavier Soberón, Josée Dupuis, and Maggie C.Y. Ng
Subjects: Genetics, 0303 health sciences, Genetic variants, Disease, 030204 cardiovascular system & hematology, Biology, medicine.disease, Penetrance, 3. Good health, Biomarker (cell), 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Genotype, medicine, Exome sequencing, 030304 developmental biology, Monogenic Diabetes
Abstract: Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.
Published: 2020
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33. A system for phenotype harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

Author: Xiuqing Guo, Karen M. Mutalik, Nora Franceschini, Carla Wilson, Elizabeth C. Oelsner, Kerri L. Wiggins, Ming-Huei Chen, Cashell E. Jaquish, Charles Kooperberg, Nicola L. Hawley, Adrienne M. Stilp, Kathleen C. Barnes, Chancellor Hohensee, Pradeep Natarajan, Alyna T. Khan, Jingmin Liu, Gina M. Peloso, Fei Fei Wang, Adolfo Correa, Laura M. Raffield, Mariza de Andrade, Jai G. Broome, Patricia A. Peyser, Andrew D. Johnson, Brian E. Cade, Rebecca D. Jackson, Lucia Juarez, Braxton D. Mitchell, Dongquan Chen, Nancy L. Heard-Costa, Shannon Kelly, Kent D. Taylor, Susan R. Heckbert, Stephen T. McGarvey, Tanika N. Kelly, Sharon L.R. Kardia, Jerome I. Rotter, Weiniu Gan, Paul S. de Vries, Lawrence F. Bielak, May E. Montasser, Erin J Buth, Quenna Wong, Jennifer A. Smith, Patrick T. Ellinor, Alanna C. Morrison, Ramachandran S. Vasan, Nathan Pankratz, Wan-Ling Hsu, Cecelia A. Laurie, Jan Graffelman, Daniel E. Weeks, Scott T. Weiss, Seyed Mehdi Nouraie, Cathy C. Laurie, Joshua C. Bis, Kari E. North, William Craig Johnson, L. Adrienne Cupples, Catherine M. D’Augustine, Donna K. Arnett, Stephen S. Rich, Bruce M. Psaty, Leslie S. Emery, Lisa R. Yanek, Jiwon Lee, Stella Aslibekyan, Myriam Fornage, Rasika A. Mathias, Megan L. Grove, Santhi K. Ganesh, and Alexander P. Reiner
Subjects: Data sharing, Documentation, Data collection, Computer science, Controlled vocabulary, Harmonization, Precision medicine, Omics, Data science, Phenotype, Domain (software engineering), Genetic association
Abstract: Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 TOPMed studies per phenotype. We discuss the challenges faced in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
Published: 2020
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34. De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population

Author: Rasika A. Mathias, Sharon R. Browning, Deborah A. Nickerson, James G. Wilson, Ramachandran S. Vasan, Kathleen C. Barnes, Lydiana Avila, Ryan D. Hernandez, Andrew D. Johnson, Brian E. Cade, Sebastian Zöllner, Douglas Loesch, James A. Perry, Braxton D. Mitchell, Gonçalo R. Abecasis, Manuel E. Soto-Quiros, Michael D. Kessler, Juan C. Celedón, Heming Wang, Michelle Daya, Nancy L. Heard-Costa, Susan Redline, Scott T. Weiss, John Ziniti, Soma Datta, Daniel Taliun, Timothy D. O’Connor, and Jeffrey R. O'Connell
Subjects: Adult, Male, Mutation rate, Heterozygote, DNA Mutational Analysis, Biology, Genome, Loss of heterozygosity, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetic variation, Humans, De novo mutations, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Whole Genome Sequencing, Genome, Human, Correction, Heritability, 3. Good health, Pedigree, Genetics, Population, Human evolution, Evolutionary biology, Mutation, Female, Amish, 030217 neurology & neurosurgery, Founder effect
Abstract: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
Published: 2020

35. Methylome-Wide Association Study of Central Adiposity Implicate Genes Involved in Immune and Endocrine Systems

Author: Penny Gordon-Larsen, Phillip E. Melton, Yun Li, Ching-Ti Liu, Rae-Chi Huang, Rahul Gondalia, Eric Boerwinkle, Anne E. Justice, Karen N. Conneely, Lifang Hou, Ellen W. Demerath, Myriam Fornage, Daniel Levy, Annie Green Howard, Megan L. Grove, Geetha Chittoor, Kari E. North, James D. Stewart, L. Adrienne Cupples, Eric A. Whitsel, Andrea A. Baccarelli, Trevor A. Mori, Lawrence J. Beilin, Elise Lim, Lindsay Fernández-Rhodes, Weihua Guan, Nancy L. Heard-Costa, and Jan Bressler
Subjects: 2. Zero hunger, 0303 health sciences, Waist, business.industry, Physiology, Methylation, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, CpG site, DNA methylation, Endocrine system, Medicine, business, Body mass index, 030217 neurology & neurosurgery, TXNIP, 030304 developmental biology
Abstract: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist- to-hip ratio, and waist-to-height ratio adjusted for body mass index, in 2684 African American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated Cytosine-phosphate-Guanine methylation sites (CpGs) among adults using the Women’s Health Initiative and Framingham Heart Study participants (combined N=5743) and generalized associations in adolescents from The Raine Study (N=820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and 2 in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1, and RAP1GAP2 that had not previously been associated with obesity-related traits.
Published: 2019
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36. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Author: Russell P. Tracy, Mollie A. Minear, James B. Meigs, Amol C. Shetty, David Van Den Berg, Yii-Der Ida Chen, Nona Sotoodehnia, Kent D. Taylor, Soren Germer, Adolfo Correa, John Barnard, Emelia J. Benjamin, Weihong Tang, Zachary A. Szpiech, Sebastian Schoenherr, Kristin G. Ardlie, Anna Köttgen, Tanika N. Kelly, Leslie A. Lange, Michelle Daya, Dan M. Roden, Lori Garman, Xutong Zhao, Lawrence F. Bielak, Edwin K. Silverman, Daniel E. Weeks, Gina M. Peloso, Jill M. Johnsen, Hyun Min Kang, Lukas Forer, Jerome I. Rotter, Stephen T. McGarvey, Wendy S. Post, Weiniu Gan, Stephanie M. Fullerton, Jedidiah Carlson, Brian Custer, Nora Franceschini, Alvaro Alonso, Brian L. Browning, Michael H. Cho, André Corvelo, Stacey Gabriel, Xiuqing Guo, Angel C.Y. Mak, Michael Boehnke, Yingze Zhang, Timothy A. Thornton, Douglas P. Kiel, Ingo Ruczinski, Sudha Seshadri, Seung-been Lee, Scott I. Vrieze, Charles Kooperberg, Stephanie M. Gogarten, John Blangero, Brandon Chalazan, Seung Hoan Choi, Dawood Darbar, Braxton D. Mitchell, Alisa K. Manning, Anne-Katrin Emde, Xihong Lin, D. C. Rao, Eimear E. Kenny, Christine M. Albert, Xiaowen Tian, Allison E. Ashley-Koch, Mina K. Chung, Pradeep Natarajan, Rebecca L. Beer, Stella Aslibekyan, Jiang He, Patrick T. Ellinor, James F. Casella, Richard A. Gibbs, Alanna C. Morrison, Clary B. Clish, Nancy L. Heard-Costa, Susan R. Heckbert, Daniel N. Harris, Myriam Fornage, M. Benjamin Shoemaker, Kari E. North, Courtney G. Montgomery, Sanghamitra Mohanty, Lewis C. Becker, George J. Papanicolaou, Chunyu Liu, Michael D. Kessler, Susan K. Dutcher, Marguerite R. Irvin, Daniel Levy, Karine A. Viaud-Martinez, Joanne E. Curran, Jonathon LeFaive, Dawn L. DeMeo, Mark T. Gladwin, Quenna Wong, Andrea Natale, Adrienne M. Stilp, Patricia A. Peyser, Robert Klemmer, Jessica Lasky-Su, Donald W. Bowden, Kathryn L. Lunetta, Rasika A. Mathias, Brian E. Cade, Kathleen C. Barnes, Daniel Taliun, Douglas Loesch, Sharon R. Browning, Joanne M. Murabito, Esteban G. Burchard, Sarah A Gagliano Taliun, Daniel J. Gottlieb, Timothy D. O’Connor, Deborah A. Meyers, Jennifer A. Brody, Ryan D. Hernandez, Andrew D. Johnson, Eric Boerwinkle, Sebastian Zöllner, Ruth J. F. Loos, Nicholas L. Smith, Gonçalo R. Abecasis, Jennifer A. Smith, Michael E. Hall, Lu-Chen Weng, Jeffrey R. O'Connell, Kenneth Rice, Donna K. Arnett, Nicholette D. Palmer, Bruce S. Weir, L. Adrienne Cupples, Barbara A. Konkle, Paul L. Auer, Cathy C. Laurie, Julie L. Mikulla, Deborah A. Nickerson, Alexander P. Reiner, Chloé Sarnowski, Raul Torres, Susan Redline, Mariza de Andrade, Vivien A. Sheehan, Cashell E. Jaquish, Pankaj Qasba, R. Graham Barr, Scott T. Weiss, Ani Manichaikul, Robert E. Gerszten, Albert V. Smith, Steven A. Lubitz, Cristen J. Willer, Michael C. Zody, Jeong-Sun Seo, Diane Fatkin, Christian Fuchsberger, François Aguet, Sharon L.R. Kardia, James G. Wilson, Marilyn J. Telen, Ramachandran S. Vasan, Nathan Pankratz, Keng-Han Lin, Shannon Kelly, Wayne E. Clarke, Sarah C. Nelson, May E. Montasser, Stephen S. Rich, Sayantan Das, Thomas W. Blackwell, Bruce M. Psaty, Leslie S. Emery, Achilleas N. Pitsillides, and David D. McManus
Subjects: Whole genome sequencing, 0303 health sciences, Genotype imputation, Disease, Computational biology, Biology, Precision medicine, Phenotype, Genome, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030217 neurology & neurosurgery, 030304 developmental biology, Reference genome
Abstract: Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency
Published: 2019
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37. De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population

Author: Rasika A. Mathias, Sebastian Zöllner, Susan Redline, Heming Wang, Scott T. Weiss, Nancy L. Heard-Costa, Gonçalo R. Abecasis, Manuel E. Soto-Quiros, Soma Datta, Braxton D. Mitchell, James G. Wilson, Ramachandran S. Vasan, Deborah A. Nickerson, Michelle Daya, John Ziniti, Michael D. Kessler, Sharon R. Browning, Timothy D. O’Connor, Jeffrey R. O'Connell, Lydiana Avila, Juan C. Celedón, Brian E. Cade, Douglas Loesch, Kathleen C. Barnes, James A. Perry, Ryan D. Hernandez, and Andrew D. Johnson
Subjects: Genetics, Whole genome sequencing, 0303 health sciences, Mutation rate, Biology, Heritability, Genome, 3. Good health, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Human evolution, Genetic variation, 030217 neurology & neurosurgery, 030304 developmental biology, Founder effect
Abstract: de novoMutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T→C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish.SignificanceHere we provide one of the largest and most diverse humande novomutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.
Published: 2019
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38. Revisit Population-based and Family-based Genotype Imputation

Author: Xuan Deng, Hanfei Xu, Nancy L. Heard-Costa, Ching-Ti Liu, L. Adrienne Cupples, Virginia Fisher, Ramachandran S. Vasan, and Yanhua Zhou
Subjects: 0301 basic medicine, Linkage disequilibrium, Genotype, Population, lcsh:Medicine, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Correlation, 03 medical and health sciences, 0302 clinical medicine, Statistics, Humans, Inheritance Patterns, lcsh:Science, education, education.field_of_study, Multidisciplinary, Genotype imputation, lcsh:R, Heritability, Pedigree, 030104 developmental biology, lcsh:Q, Algorithms, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract: Genome-Wide Association (GWA) with population-based imputation (PBI) has been successful in identifying common variants associated with complex diseases; however, much heritability remains to be explained and low frequency variants (LFV) may contribute. To identify LFV, a study of unrelated individuals may no longer be as efficient as a family study, where rare population variants can be frequent in families. Family-based imputation (FBI) provides an opportunity to evaluate LFV. To compare the performance of PBI and FBI, we conducted extensive simulations, generating genotypes using SeqSIMLA from various reference panels for families. We masked genotype information for variants unavailable in Framingham 550 K GWA genotype data in less informative subjects selected by GIGI-Pick. We implemented IMPUTE2 with duoHMM in SHAPEIT (Impute2_duoHMM) for PBI, MERLIN and GIGI for FBI and PedBLIMP for a hybrid approach. In general, FBI in both MERLIN and GIGI outperformed other approaches with imputation accuracy greater than 0.99 for the squared correlation and imputation quality scores (IQS) especially for LFV, although imputation accuracy from MERLIN depends on pedigree splitting for larger families. PBI performed worst with the exception of good imputation accuracy for common variants when a closely ancestry matched reference is used. In summary, linkage disequilibrium (LD) information from large available genotype resources provides good imputation for common variants with well-selected reference panels without requiring densely sequenced data in family members, while imputation of LFV with FBI benefits more from information on inheritance patterns within families yielding better imputation.
Published: 2019
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39. Association of Maternal Pre-Pregnancy Weight with Offspring Adiposity Throughout Adulthood over 37 years of Follow-up

Author: Michael M. Mendelson, Nancy L. Heard-Costa, Matthew W. Gillman, Sarah D. de Ferranti, Asya Lyass, Isabelle Schoppa, Caroline S. Fox, Daniel Levy, and Ralph B. D'Agostino
Subjects: Adult, Male, Offspring, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Prepregnancy weight, 030209 endocrinology & metabolism, Overweight, Article, Direct measure, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Framingham Heart Study, Risk Factors, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Obesity, Genetic risk, Adiposity, Nutrition and Dietetics, business.industry, medicine.disease, Gestational Weight Gain, Cohort, Female, medicine.symptom, business, Demography, Follow-Up Studies
Abstract: OBJECTIVE: To determine the relation of maternal pre-pregnancy weight with offspring body mass index across adulthood from almost 40 years of follow-up. METHODS: Body mass index (BMI) was measured in Framingham Heart Study Offspring cohort participants between 1971 and 2008. We tested the association of maternal pre-pregnancy weight category (ascertained via direct measure and questionnaire) with serial offspring BMI, overweight, obesity, and change in BMI over time, adjusted for age, sex, and a BMI genetic risk score; secondary models additionally adjusted for physical activity, dietary factors, smoking, education, and familial relatedness. RESULTS: Among 863 participants at initial assessment (83 exposed and 780 controls), mean (SD) age was 33 (10) years, 53% were female, and mean BMI was 24.5 (4.1) kg/m(2). Exposed offspring BMI was higher at every examination cycle; ranging from 1.5 (0.5) to 3.0 (0.5) kg/m(2) (p
Published: 2018

40. Genetic discovery and translational decision support from exome sequencing of 20,791 type 2 diabetes cases and 24,440 controls from five ancestries

Author: Humberto García-Ortiz, Loos R, Frederick E. Dewey, Farook Thameem, John C. Chambers, Mi Yeong Hwang, Nancy L. Heard-Costa, Danish Saleheen, Shuai Wang, Morris Ad, Josep M. Mercader, Noël P. Burtt, Laura J. Scott, Torben Hansen, Mark I. McCarthy, Clicerio Gonzalez, Matsuo K, Mark Seielstad, Marijana Vujkovic, Teresa Tusié-Luna, Alanna C. Morrison, Christian Gieger, Dana Dabelea, Colm O'Dushlaine, Niels Grarup, Elvia Mendoza-Caamal, Amanda F. Elliott, Ryan P. Welch, Craig L. Hanis, Kirchner Hl, Song Chen, Jennifer A. Brody, Maria L. Cortes, Asif Rasheed, Russel Tracy, Nancy J. Cox, Miriam S. Udler, Myron D. Gross, Donald W. Bowden, Oluf Pedersen, Marit E. Jørgensen, J. Tuomilehto, Yik Ying Teo, Andrew P. Morris, Zeitler P, T. M. Strom, Aris Baras, Colin N. A. Palmer, Shin Yc, Johanna Kuusisto, Lin Chen, Donna M. Lehman, Edmund Chan, Heikki A. Koistinen, Anthony Marcketta, Boehnke M, Francis S. Collins, Rayner Nw, Leslie A. Lange, Nir Barzilai, Brian E. Henderson, Jennifer Wessel, David J. Carey, Jaspal S. Kooner, Ralph A. DeFronzo, Anthony Payne, Carlos A. Aguilar-Salinas, Tien Yin Wong, Thomas Meitinger, Lyssenko, Claudia Ht Tam, Cristina Revilla-Monsalve, Daniel R. Witte, Jerome I. Rotter, Michael Preuss, Allan Linneberg, Jose C. Florez, Alisa K. Manning, Gonçalo R. Abecasis, Hyun Min Kang, van Dam Rm, Jason M. Torres, Anubha Mahajan, Claudia Schurmann, Markku Laakso, Leif Groop, Lori L. Bonnycastle, Sohee Han, Jason Flannick, Bong-Jo Kim, Lawrence M. Dolan, Brian Burke, Ma Elena Gonzalez, Kerrin S. Small, Ching-Ti Liu, Ronald C.W. Ma, Peter M. Nilsson, Eric Boerwinkle, Garay-Sevilla Me, Ravindranath Duggirala, Anne Ndungu, Cecilia Contreras-Cubas, Wendy S. Post, Tanya M. Teslovich, Brian Tomlinson, Kimberly L. Drews, Lizz Caulkins, Lee J, Philippe M. Frossard, Jianjun Liu, Hanks S, Ki-Sun Park, Tai Es, Kelsey M, S. Gabriel, Erwin P. Bottinger, Alexander P. Reiner, Tim D. Spector, Lorena Orozco, James S. Pankow, Juliana C.N. Chan, Wing-Yee So, Tiinamaija Tuomi, Malacara-Hernandez Jm, Karen L. Mohlke, S. S. Rich, de Vries Ps, Konstantin Strauch, Graeme I. Bell, Angélica Martínez-Hernández, Elizabeth J. Mayer-Davis, Thomas W. Blackwell, Heather M. Stringham, Bruce M. Psaty, Soo Heon Kwak, Catherine Pihoker, James S. Floyd, Christian Fuchsberger, Ching-Yu Cheng, Neil R. Robertson, Adolfo Correa, James G. Wilson, Ramachandran S. Vasan, Robert Sladek, James B. Meigs, Benjamin Glaser, Gil Atzmon, David Altshuler, Josée Dupuis, Xueling Sim, John Blangero, Emilio J. Cordova, C.J. O'Donnell, Maggie C.Y. Ng, Heckbert, Young-Jin Kim, Joseph B. Leader, Anne U. Jackson, Ryan Koesterer, Nicola Santoro, and Christopher A. Haiman
Subjects: Genetics, 0303 health sciences, Candidate gene, SLC30A8, Heritability, Biology, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Sample size determination, biology.protein, Allele, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: Protein-coding genetic variants that strongly affect disease risk can provide important clues into disease pathogenesis. Here we report an exome sequence analysis of 20,791 type 2 diabetes (T2D) cases and 24,440 controls from five ancestries. We identify rare (minor allele frequency30 SLC30A8 alleles, and (b) within 12 gene sets, including those corresponding to T2D drug targets (p=6.1×10−3) and candidate genes from knockout mice (p=5.2×10−3). Within our study, the strongest T2D rare variant gene-level signals explain at most 25% of the heritability of the strongest common single-variant signals, and the rare variant gene-level effect sizes we observe in established T2D drug targets will require 110K-180K sequenced cases to exceed exome-wide significance. To help prioritize genes using associations from current smaller sample sizes, we present a Bayesian framework to recalibrate association p-values as posterior probabilities of association, estimating that reaching ppwww.type2diabetesgenetics.org.
Published: 2018
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41. Evaluation of power of the Illumina HumanOmni5M-4v1 BeadChip to detect risk variants for human complex diseases

Author: Philip A. Wolf, Yi-Hsiang Hsu, Sudha Seshadri, Anita L. DeStefano, Nancy L. Heard-Costa, Chuanhua Xing, Douglas P. Kiel, Josée Dupuis, Jie Huang, and L. Adrienne Cupples
Subjects: 0301 basic medicine, Genotyping Techniques, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Computational biology, Quantitative trait locus, Biology, Hippocampus, Sensitivity and Specificity, Article, 03 medical and health sciences, Bone Density, Genetics, Humans, Genetic Testing, International HapMap Project, 1000 Genomes Project, Genotyping, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Organ Size, Minor allele frequency, 030104 developmental biology, Mutation, Imputation (genetics), Genome-Wide Association Study
Abstract: Although emerging sequencing technologies can characterize all genetic variants, the cost is still high. Illumina released the HumanOmni5M-4v1 (Omni5) genotype array with ~4.3M assayed SNPs, a much denser array compared with other available arrays. The Omni5 balances both cost and array density. In this article, we illustrate the power of Omni5 to detect genetic associations. The Omni5 includes variants with a wide range of minor allele frequencies down to
Published: 2015
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42. 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
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43. Integrating genetic, transcriptional, and biological information provides insights into obesity

Author: Ching-Ti Liu, L. Adrienne Cupples, Audrey Y. Chu, Nancy L. Heard-Costa, Caroline S. Fox, Peter J. Munson, Lan Wang, Daniel Levy, Jeremiah Perez, and Roby Joehanes
Subjects: Adult, Male, Endocrinology, Diabetes and Metabolism, Adipose Tissue, White, Medicine (miscellaneous), Adipose tissue, 030209 endocrinology & metabolism, Genome-wide association study, Computational biology, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, medicine, Humans, Body Weights and Measures, Gene Regulatory Networks, 030212 general & internal medicine, Longitudinal Studies, Obesity, KEGG, Gene, Genetic association, Nutrition and Dietetics, Gene Expression Profiling, medicine.disease, 3. Good health, Female, Tomography, X-Ray Computed, Transcriptome, Body mass index, Genome-Wide Association Study
Abstract: Objective: Indices of body fat distribution are heritable, but few genetic signals have been reported from genome-wide association studies (GWAS) of computed tomography (CT) imaging measurements of body fat distribution. We aimed to identify genes associated with adiposity traits and the key drivers that are central to adipose regulatory networks. Subjects: We analyzed gene transcript expression data in blood from participants in the Framingham Heart Study, a large community-based cohort (n up to 4,303), as well as implemented an integrative analysis of these data and existing biological information. Results: Our association analyses identified unique and common gene expression signatures across several adiposity traits, including body mass index, waist-hip ratio, waist circumference, and CT-measured indices, including volume and quality of visceral and subcutaneous adipose tissues. We identified six enriched KEGG pathways and two co-expression modules for further exploration of adipose regulatory networks. The integrative analysis revealed four gene sets (Apoptosis, p53 signaling pathway, Proteasome, Ubiquitin mediated proteolysis) and two co-expression modules with significant genetic variants and 94 key drivers/genes whose local networks were enriched with adiposity-associated genes, suggesting that these enriched pathways or modules have genetic effects on adiposity. Most identified key driver genes are involved in essential biological processes such as controlling cell cycle, DNA repair and degradation of regulatory proteins and are cancer related. Conclusion: Our integrative analysis of genetic, transcriptional and biological information provides a list of compelling candidates for further follow-up functional studies to uncover the biological mechanisms underlying obesity. These candidates highlight the value of examining CT-derived and central adiposity traits.
Published: 2017

44. Whole-exome imputation of sequence variants identified two novel alleles associated with adult body height in African Americans

Author: Yii-Der Ida Chen, Nancy L. Heard-Costa, James G. Wilson, Jeffrey Haessler, Stephanie A. Rosse, Paul L. Auer, Mengmeng Du, Nora Franceschini, Rebecca D. Jackson, Ulrike Peters, Keith R. Curtis, Kari E. North, Deborah A. Nickerson, Guillaume Lettre, Keri L. Monda, Alexander P. Reiner, Cara L. Carty, Shuo Jiao, Christopher S. Carlson, Leslie A. Lange, Stephen S. Rich, Li Hsu, Cristen J. Willer, Jerome I. Rotter, Charles Kooperberg, David Altshuler, and Eric Boerwinkle
Subjects: Adult, Male, Genome-wide association study, Single-nucleotide polymorphism, Biology, White People, Quantitative Trait, Heritable, Gene Frequency, Genetics, Humans, Exome, Molecular Biology, Allele frequency, Alleles, Genetics (clinical), Exome sequencing, Aged, Genetic association, Chromosomes, Human, Pair 13, Association Studies Articles, General Medicine, Middle Aged, Body Height, Black or African American, Minor allele frequency, Genetic Loci, Chromosomes, Human, Pair 5, Female, Imputation (genetics), Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain
Published: 2014
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45. Sequence Variation in TMEM18 in Association With Body Mass Index

Author: Matthias Olden, Nancy L. Heard-Costa, Kari E. North, Lynne E. Wagenknecht, Eric Boerwinkle, Guo Li, Caroline S. Fox, Jeffrey G. Reid, L. Adrienne Cupples, Barbara McKnight, Donna M. Muzny, Gerardo Heiss, Yanhua Zhou, Ingrid B. Borecki, Yaming Shao, Jennifer A. Brody, Richard A. Gibbs, Kristin L. Young, Mary K. Wojczynski, Alanna C. Morrison, and Ching-Ti Liu
Subjects: Adult, Male, Aging, Heart Diseases, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Body Mass Index, Cohort Studies, Young Adult, Framingham Heart Study, Genetics, Humans, Allele, Genetic Association Studies, Genetics (clinical), Aged, Genetic association, Genetic Variation, Membrane Proteins, nutritional and metabolic diseases, Genomics, Sequence Analysis, DNA, Middle Aged, Minor allele frequency, Female, Cardiology and Cardiovascular Medicine, Body mass index, Genome-Wide Association Study, Cohort study
Abstract: Background— Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI. Methods and Results— We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, 2 higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P =3.46×10 −4 ) using a Bonferroni threshold of P −4 . Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent ( r 2 P =2.11×10 −4 ). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3′ genome-wide association study region. Conclusions— Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.
Published: 2014
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46. Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations

Author: Sandosh Padmanabhan, Susan Kirkland, Patricia B. Munroe, Salim Yusuf, Brian E. Cade, Marten H. Hofker, Jose M. Ordovas, Jeffrey R. O'Connell, Liz Speilotes, Fridtjof Thomas, Caroline S. Fox, Brendan J. Keating, Gerald S. Berenson, Toby Johnson, Alan R. Shuldiner, Leslie A. Lange, Jeanne M. McCaffery, Thomas Illig, Christopher P. Nelson, Muredach P. Reilly, Wolfgang König, Keri L. Monda, Yan Gong, Olle Melander, Caitrin W. McDonough, Annette Peters, Sachiko Yoneyama, Nancy L. Heard-Costa, Cisca Wijmenga, Alexander P. Reiner, Mathias Gorski, Anna F. Dominiczak, Jens Baumert, Florianne Bauer, Karina W. Davidson, Erin N. Smith, Jonathan A. Shaffer, Konrad J. Karczewski, Clara C. Elbers, Kari E. North, Nicholas J. Schork, Sarah S. Murray, Christian Gieger, Iris M. Heid, Tom R. Gaunt, Julie A. Johnson, N. Charlotte Onland-Moret, Yvonne T. van der Schouw, Nilesh J. Samani, Ellen W. Demerath, Rhonda M. Cooper-DeHoff, Gordon S. Huggins, George J. Papanicolaou, Hakon Hakonarson, Sonia S. Anand, Daichi Shimbo, Kira C. Taylor, Jolanda M. A. Boer, Susan Redline, Martin D. Tobin, Yiran Guo, Robert A. Hegele, Michael J. LaMonte, Haiqinq Shen, Barbara Thorand, Amber L. Beitelshees, Inga Peter, Braxton D. Mitchell, Wei Chen, Matthew B. Lanktree, Michael R. Barnes, W. M. Monique Verschuren, Gregory L. Burke, Taimour Y. Langaee, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Vascular Ageing Programme (VAP)
Subjects: Adult, Male, DRUGGABLE GENOME, Candidate gene, Single-nucleotide polymorphism, Genome-wide association study, BLOOD-PRESSURE, Biology, Population stratification, White People, Body Mass Index, Young Adult, Waist–hip ratio, Genetics, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, IDENTIFIES 13, Genetics (clinical), Adiposity, Aged, METABOLIC SYNDROME, Aged, 80 and over, INSULIN-RESISTANCE, Association Studies Articles, CARDIOVASCULAR-DISEASE RISK, General Medicine, Middle Aged, BODY-MASS INDEX, ABDOMINAL OBESITY, Expression quantitative trait loci, Population study, Female, Waist Circumference, WAIST-HIP RATIO, Body mass index, Genome-Wide Association Study
Abstract: Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
Published: 2014
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47. Sequence Kernel Association Test for Survival Traits

Author: Nancy L. Heard-Costa, Caroline S. Fox, Han Chen, L. Adrienne Cupples, Thomas Lumley, Josée Dupuis, and Jennifer A. Brody
Subjects: Score test, Epidemiology, Omnibus test, Likelihood-ratio test, Statistics, Test statistic, Econometrics, Score, Logistic regression, Genetics (clinical), Statistical power, Mathematics, Type I and type II errors
Abstract: Rare variant tests have been of great interest in testing genetic associations with diseases and disease-related quantitative traits in recent years. Among these tests, the sequence kernel association test (SKAT) is an omnibus test for effects of rare genetic variants, in a linear or logistic regression framework. It is often described as a variance component test treating the genotypic effects as random. When the linear kernel is used, its test statistic can be expressed as a weighted sum of single-marker score test statistics. In this paper, we extend the test to survival phenotypes in a Cox regression framework. Because of the anticonservative small-sample performance of the score test in a Cox model, we substitute signed square-root likelihood ratio statistics for the score statistics, and confirm that the small-sample control of type I error is greatly improved. This test can also be applied in meta-analysis. We show in our simulation studies that this test has superior statistical power except in a few specific scenarios, as compared to burden tests in a Cox model. We also present results in an application to time-to-obesity using genotypes from Framingham Heart Study SNP Health Association Resource.
Published: 2014
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48. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author: P. Eline Slagboom, Massimo Mangino, David J. Porteous, Karin Leander, Nancy L. Heard-Costa, Sharon L.R. Kardia, Jennifer Bragg, Ken K. Ong, Igor Rudan, Blair H. Smith, Mark A. Sarzynski, Torben Hansen, James F. Wilson, Weihua Zhang, Zoltán Kutalik, Karl Gertow, Yii-Der Ida Chen, Daniele Cusi, Lu Qi, Nicholas G. Martin, Peter Vollenweider, Thomas W. Winkler, Graciela E. Delgado, Thorkild I. A. Sørensen, André G. Uitterlinden, J. Wouter Jukema, Rajesh Rawal, Dena G. Hernandez, Amy J. Swift, Naveed Sattar, Ruth J. F. Loos, George Dedoussis, Ani Manichaikul, Henrik Vestergaard, Jian'an Luan, Luting Xue, Charles Kooperberg, Rona J. Strawbridge, John-Olov Jansson, Jian Gong, Martina Müller-Nurasyid, L. Adrienne Cupples, Frida Renström, Stephan J. L. Bakker, Ivana Kolcic, Mathias Gorski, Tamara B. Harris, Sandosh Padmanabhan, Stephanie A. Bien, Arthur W. Musk, Cristina Menni, Steve Buyske, Anubha Mahajan, Claudia Schurmann, John Blangero, Natalia Pervjakova, Inês Barroso, Kristin L. Young, Momoko Horikoshi, Robert A. Scott, Ozren Polasek, Shafqat Ahmad, Jeremiah Perez, Stella Trompet, Claude Bouchard, Claudia Langenberg, Paul M. Ridker, Tuomas O. Kilpeläinen, Oddgeir L. Holmen, Tarunveer S. Ahluwalia, Alan F. Wright, Ulf de Faire, Cecilia M. Lindgren, Misa Graff, Jie Huang, Liesbeth Vandenput, Marcel Bruinenberg, Luigi Ferrucci, Johanne Marie Justesen, Audrey Y. Chu, Melanie Waldenberger, Karen L. Mohlke, Ching-Ti Liu, Barbara Thorand, Joseph Hung, Pim van der Harst, Colin A. McKenzie, Sailaja Vedantam, Gitta H. Lubke, Bruna Gigante, Göran Hallmans, Sara Lupoli, Anja Ludolph-Donislawski, Michael Boehnke, Treva Rice, Lori L. Bonnycastle, Daniele Braga, Mika Kähönen, Joel Eriksson, Gonçalo R. Abecasis, Joseph M. Wu, Niels Grarup, Ilja M. Nolte, Jonathan Marchini, Georg Homuth, Pamela A. F. Madden, John Beilby, Andrew D. Johnson, Nanette R. Lee, Caroline Hayward, Unhee Lim, Bamidele O. Tayo, Peter S. Chines, Lynda M. Rose, Amélie Bonnefond, Elena Tremoli, Serena Sanna, David P. Strachan, Barbara McKnight, Narisu Narisu, Anton J. M. de Craen, David R. Weir, Albertine J. Oldehinkel, Jessica Tyrrell, Beverley Balkau, Kirsti Kvaløy, Marie-Claude Vohl, Jennifer A. Smith, Rainer Rauramaa, Andrew C. Heath, Erwin P. Bottinger, Andrew Wong, Günther Silbernagel, Mattias Lorentzon, Philippe Froguel, Uzma Afzal, Tanja B. Grammer, Dabeeru C. Rao, Charlotta Pisinger, Nicola Glorioso, Najaf Amin, Andrew P. Morris, Tanguy Corre, Alan James, Julius S. Ngwa, Jennifer E. Huffman, Gudny Eiriksdottir, Maija Hassinen, Lenore J. Launer, Marit E. Jørgensen, Dorret I. Boomsma, Harry Campbell, Scott Coggeshall, Timothy M. Frayling, Konstantin Strauch, Johanna Kuusisto, David Hadley, Penny Gordon-Larsen, Xuan Deng, Dorothée Thuillier, Albert V. Smith, Jaakko Tuomilehto, Harald Grallert, Lynne J. Hocking, Dan Mellström, M. Carola Zillikens, Lars Lind, Hester M. den Ruijter, Gemma Cadby, Joanne E. Curran, Richard N. Bergman, David J. Stott, Matthias Olden, Veronique Vitart, Robert Luben, Cinzia Sarti, Gert J. de Borst, Lyle J. Palmer, Sven Bergmann, Alexander Teumer, John D. Eicher, Marcus E. Kleber, Marie Loh, Genovefa Kolovou, Iris M. Heid, Gonneke Willemsen, Marie Neergaard Harder, David J. Hunter, Stefania Bandinelli, Francis S. Collins, Hans J. Grabe, Virginia Fisher, John Whitfield, Leo-Pekka Lyytikäinen, Salome Scholtens, Tamuno Alfred, Richard S. Cooper, Jouke-Jan Hottenga, Martina Chittani, Jan A. Staessen, Bernhard K. Krämer, Markku Laakso, Min A. Jhun, Marjo-Riitta Järvelin, Saima Afaq, Rita P. S. Middelberg, Jing Hua Zhao, Toshiko Tanaka, Kent D. Taylor, Rudi G. J. Westendorp, Panagiotis Deloukas, Nina Hutri-Kähönen, Reiner Biffar, Krista Fischer, Leena Kinnunen, Diana Kuh, Jaspal S. Kooner, Caroline S. Fox, Harold Snieder, Pau Navarro, Stéphane Lobbens, Tao Huang, Vilmundur Gudnason, Jacqueline M. Vink, Terrence Forrester, Kari E. North, Annette Peters, Mika Kivimäki, David Schlessinger, Ian Ford, Kristian Hveem, Christopher A. Haiman, Lucia A. Hindorff, Oluf Pedersen, Ingrid B. Borecki, Bruce H. R. Wolffenbuttel, Nicholas J. Wareham, Cornelia M. van Duijn, Lawrence F. Bielak, Loic Le Marchand, Linda S. Adair, Tõnu Esko, Anne U. Jackson, Ying Wu, Eco J. C. de Geus, Jana V. van Vliet-Ostaptchouk, Louis Pérusse, Peter J. van der Most, Ulrike Peters, Magnus Karlsson, Anders Hamsten, Anne E. Justice, Alena Stančáková, Henning Tiemeier, Eric Boerwinkle, Catharina A. Hartman, Claes Ohlsson, Grant W. Montgomery, Elise Lim, Traci M. Bartz, Erik Ingelsson, Martina E. Zimmermann, Laura J. Rasmussen-Torvik, Terho Lehtimäki, Heikki A. Koistinen, Pirjo Komulainen, Damiano Baldassarre, Marten A. Siemelink, Niek Verweij, Gerard Pasterkamp, Markus Juonala, Wei Zhao, Andres Metspalu, Sander W. van der Laan, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Heather M. Stringham, Bruce M. Psaty, Niha Zubair, Stavroula Kanoni, Saskia Haitjema, Bengt Sennblad, Llilda Barata, Morris A. Swertz, Mary F. Feitosa, Tim D. Spector, Paul W. Franks, Qibin Qi, Francesco Cucca, Allan Linneberg, Reija Männikkö, Jonathan Marten, Olli T. Raitakari, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Sarah H. Wild, Meena Kumari, Nese Direk, Patricia A. Peyser, Jessica D. Faul, John C. Chambers, Nicholas D. Hastie, Mette Hollensted, Jacek Czajkowski, Daniel I. Chasman, Matthias Nauck, Gérard Waeber, Brendan M. Buckley, Kai Savonen, Judith M. Vonk, Carsten A. Böger, Loic Yengo, Anna Eriksson, Henry Völzke, Pedro Marques-Vidal, Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Cardiovascular Centre (CVC), Clinicum, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Internal Medicine and Rehabilitation, Luan, Jian'an [0000-0003-3137-6337], Marten, Jonathan [0000-0001-6916-2014], Langenberg, Claudia [0000-0002-5017-7344], Luben, Robert [0000-0002-5088-6343], Ong, Kenneth [0000-0003-4689-7530], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, APH - Methodology, APH - Personalized Medicine, Epidemiology, Erasmus MC other, Medical Microbiology & Infectious Diseases, Internal Medicine, Child and Adolescent Psychiatry / Psychology, and Psychiatry
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, Offita, Chemistry(all), Epidemiology, General Physics and Astronomy, Genome-wide association study, methods [Genome-Wide Association Study], Biochemistry, Genome-wide association studies, Medical and Health Sciences, Body Mass Index, genetics [Obesity], Genetics research, IMPUTATION, Body Fat Distribution, genetics [Genetic Predisposition to Disease], OXIDATIVE STRESS, POPULATION, Adiposity, METABOLIC SYNDROME, Genetics, education.field_of_study, Multidisciplinary, Smoking, Public Health, Global Health, Social Medicine and Epidemiology, genetics [Smoking], ASSOCIATION, 3142 Public health care science, environmental and occupational health, 3. Good health, Multidisciplinary Sciences, DEFICIENCY, Phenotype, ADDICTION, Science & Technology - Other Topics, Medical genetics, ddc:500, Waist Circumference, Reykingar, genetics [Adiposity], Adult, medicine.medical_specialty, Science, Quantitative Trait Loci, Population, genetics [Waist Circumference], Accounting, Biology, Quantitative trait locus, Physics and Astronomy(all), Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, GWAS, obesity, smoking, MD Multidisciplinary, Genetic predisposition, medicine, Journal Article, Erfðafræði, Humans, Genetic Predisposition to Disease, Obesity, education, Genetic association, Science & Technology, VITAMIN-C, genetics [Quantitative Trait Loci], Waist-Hip Ratio, business.industry, Biochemistry, Genetics and Molecular Biology(all), Epistasis, Genetic, Rannsóknir, General Chemistry, ta3121, R1, GENE, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, MICE, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, business, Body mass index, Developmental Psychopathology, Imputation (genetics), Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution., A full list of acknowledgments appears in the Supplementary Note 4. Co-author A.J.M.d.C. recently passed away while this work was in process. This work was performed under the auspices of the Genetic Investigation of ANthropometric Traits (GIANT) consortium. We acknowledge the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium for encouraging CHARGE studies to participate in this effort and for the contributions of CHARGE members to the analyses conducted for this research. Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (41071, 77299, 102318, 110413, 117787, 121584, 123885, 124243, 124282, 126925, 129378, 134309, 286284); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la 359 Recherche; Agency for Health Care Policy Research (HS06516); ALF/LUA research grant in Gothenburg; ALFEDIAM; ALK-Abelló A/S; Althingi; American Heart Association (13POST16500011); Amgen; Andrea and Charles Bronfman Philanthropies; Ardix Medical; Arthritis Research UK; Association Diabète Risque Vasculaire; Australian National Health and Medical Research Council (241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496739, 552485, 552498); Avera Institute; Bayer Diagnostics; Becton Dickinson; BHF (RG/14/5/30893); Boston Obesity Nutrition Research Center (DK46200), Bristol-Myers Squibb; British Heart Foundation (RG/10/12/28456, RG2008/08, RG2008/014, SP/04/002); Medical Research Council of Canada; Canadian Institutes for Health Research (FRCN-CCT-83028); Cancer Research UK; Cardionics; Cavadis B.V., Center for Medical Systems Biology; Center of Excellence in Genomics; CFI; CIHR; City of Kuopio; CNAMTS; Cohortes Santé TGIR; Contrat de Projets État-Région; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF-1333-00124, DFF-1331-00730B); County Council of Dalarna; Dalarna University; Danish Council for Strategic Research; Danish Diabetes Academy; Danish Medical Research Council; Department of Health, UK; Development Fund from the University of Tartu (SP1GVARENG); Diabetes Hilfs- und Forschungsfonds Deutschland; Diabetes UK; Diabetes Research and Wellness Foundation Fellowship; Donald W. Reynolds Foundation; Dr Robert Pfleger-Stiftung; Dutch Brain Foundation; Dutch Diabetes Research Foundation; Dutch Inter University Cardiology Institute; Dutch Kidney Foundation (E033); Dutch Ministry of Justice; the DynaHEALTH action No. 633595, Economic Structure Enhancing Fund of the Dutch Government; Else Kröner-Fresenius-Stiftung (2012_A147, P48/08//A11/08); Emil Aaltonen Foundation; Erasmus University Medical Center Rotterdam; Erasmus MC and Erasmus University Rotterdam; the Municipality of Rotterdam; Estonian Government (IUT20-60, IUT24-6); Estonian Research Roadmap through the Estonian Ministry of Education and Research (3.2.0304.11-0312); European Research Council (ERC Starting Grant and 323195:SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC); European Regional Development Fund; European Science Foundation (EU/QLRT-2001-01254); European Commission (018947, 018996, 201668, 223004, 230374, 279143, 284167, 305739, BBMRI-LPC-313010, HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-2011-278913, HEALTH-2011-294713-EPLORE, HEALTH-F2-2008-201865-GEFOS, HEALTH-F2-2013-601456, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550-HYPERGENES, HEALTH-F7-305507 HOMAGE, IMI/115006, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2004-005272, LSHM-CT-2006-037697, LSHM-CT-2007-037273, QLG1-CT-2002-00896, QLG2-CT-2002-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ0103, 01ZZ0403, 01ZZ9603, 03IS2061A, 03ZIK012); Federal State of Mecklenburg-West Pomerania; Fédération Française de Cardiologie; Finnish Cultural Foundation; Finnish Diabetes Association; Finnish Foundation of Cardiovascular Research; Finnish Heart Association; Fondation Leducq; Food Standards Agency; Foundation for Strategic Research; French Ministry of Research; FRSQ; Genetic Association Information Network (GAIN) of the Foundation for the NIH; German Federal Ministry of Education and Research (BMBF, 01ER1206, 01ER1507); GlaxoSmithKline; Greek General Secretary of Research and Technology; Göteborg Medical Society; Health and Safety Executive; Healthcare NHS Trust; Healthway; Western Australia; Heart Foundation of Northern Sweden; Helmholtz Zentrum München—German Research Center for Environmental Health; Hjartavernd; Ingrid Thurings Foundation; INSERM; InterOmics (PB05 MIUR-CNR); INTERREG IV Oberrhein Program (A28); Interuniversity Cardiology Institute of the Netherlands (ICIN, 09.001); Italian Ministry of Health (ICS110.1/RF97.71); Italian Ministry of Economy and Finance (FaReBio di Qualità); Marianne and Marcus Wallenberg Foundation; the Ministry of Health, Welfare and Sports, the Netherlands; J.D.E. and Catherine T, MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; KfH Stiftung Präventivmedizin e.V.; King's College London; Knut and Alice Wallenberg Foundation; Kuopio University Hospital; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001); La Fondation de France; Leenaards Foundation; Lilly; LMUinnovativ; Lundberg Foundation; Magnus Bergvall Foundation; MDEIE; Medical Research Council UK (G0000934, G0601966, G0700931, MC_U106179471, MC_UU_12019/1); MEKOS Laboratories; Merck Santé; Ministry for Health, Welfare and Sports, The Netherlands; Ministry of Cultural Affairs of Mecklenburg-West Pomerania; Ministry of Economic Affairs, The Netherlands; Ministry of Education and Culture of Finland (627;2004-2011); Ministry of Education, Culture and Science, The Netherlands; Ministry of Science, Education and Sport in the Republic of Croatia (108-1080315-0302); MRC centre for Causal Analyses in Translational Epidemiology; MRC Human Genetics Unit; MRC-GlaxoSmithKline pilot programme (G0701863); MSD Stipend Diabetes; National Institute for Health Research; Netherlands Brain Foundation (F2013(1)-28); Netherlands CardioVascular Research Initiative (CVON2011-19); Netherlands Genomics Initiative (050-060-810); Netherlands Heart Foundation (2001 D 032, NHS2010B280); Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) (56-464-14192, 60-60600-97-118, 100-001-004, 261-98-710, 400-05-717, 480-04-004, 480-05-003, 481-08-013, 904-61-090, 904-61-193, 911-11-025, 985-10-002, Addiction-31160008, BBMRI–NL 184.021.007, GB-MaGW 452-04-314, GB-MaGW 452-06-004, GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MW 940-38-011, Middelgroot-911-09-032, NBIC/BioAssist/RK 2008.024, Spinozapremie 175.010.2003.005, 175.010.2007.006); Neuroscience Campus Amsterdam; NHS Foundation Trust; National Institutes of Health (1RC2MH089951, 1Z01HG000024, 24152, 263MD9164, 263MD821336, 2R01LM010098, 32100-2, 32122, 32108, 5K99HL130580-02, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, AG13196, CA047988, DA12854, DK56350, DK063491, DK078150, DK091718, DK100383, DK078616, ES10126, HG004790, HHSN268200625226C, HHSN268200800007C, HHSN268201200036C, HHSN268201500001I, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, HL043851, HL45670, HL080467, HL085144, HL087660, HL054457, HL119443, HL118305, HL071981, HL034594, HL126024, HL130114, KL2TR001109, MH66206, MH081802, N01AG12100, N01HC55015, N01HC55016, N01C55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, N01HG65403, N01WH22110, N02HL6‐4278, N01-HC-25195, P01CA33619, R01HD057194, R01HD057194, R01AG023629, R01CA63, R01D004215701A, R01DK075787, R01DK062370, R01DK072193, R01DK075787, R01DK089256, R01HL53353, R01HL59367, R01HL086694, R01HL087641, R01HL087652, R01HL103612, R01HL105756, R01HL117078, R01HL120393, R03 AG046389, R37CA54281, RC2AG036495, RC4AG039029, RPPG040710371, RR20649, TW008288, TW05596, U01AG009740, U01CA98758, U01CA136792, U01DK062418, U01HG004402, U01HG004802, U01HG007376, U01HL080295, UL1RR025005, UL1TR000040, UL1TR000124, UL1TR001079, 2T32HL007055-36, T32GM074905, HG002651, HL084729, N01-HC-25195, UM1CA182913); NIH, National Institute on Aging (Intramural funding, NO1-AG-1-2109); Northern Netherlands Collaboration of Provinces; Novartis Pharma; Novo Nordisk; Novo Nordisk Foundation; Nutricia Research Foundation (2016-T1); ONIVINS; Parnassia Bavo group; Pierre Fabre; Province of Groningen; Päivikki and Sakari Sohlberg Foundation; Påhlssons Foundation; Paavo Nurmi Foundation; Radboud Medical Center Nijmegen; Research Centre for Prevention and Health, the Capital Region of Denmark; the Research Institute for Diseases in the Elderly; Research into Ageing; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Roche; Royal Society; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Sanofi-Aventis; Scottish Government Health Directorates, Chief Scientist Office (CZD/16/6); Siemens Healthcare; Social Insurance Institution of Finland (4/26/2010); Social Ministry of the Federal State of Mecklenburg-West Pomerania; Société Francophone du 358 Diabète; State of Bavaria; Stiftelsen för Gamla Tjänarinnor; Stockholm County Council (560183, 592229); Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council; Stroke Association; Swedish Diabetes Association; Swedish Diabetes Foundation (2013-024); Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20120197, 20150711); Swedish Research Council (0593, 8691, 2012-1397, 2012-1727, and 2012-2215); Swedish Society for Medical Research; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 31003A-143914, 33CSCO-122661, 33CS30-139468, 33CS30-148401, 51RTP0_151019); Tampere Tuberculosis Foundation; Technology Foundation STW (11679); The Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community (G.0880.13, G.0881.13); The Great Wine Estates of the Margaret River Region of Western Australia; Timber Merchant Vilhelm Bangs Foundation; Topcon; Tore Nilsson Foundation; Torsten and Ragnar Söderberg's Foundation; United States – Israel Binational Science Foundation (Grant 2011036), Umeå University; University Hospital of Regensburg; University of Groningen; University Medical Center Groningen; University of Michigan; University of Utrecht; Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) (b2011036); Velux Foundation; VU University’s Institute for Health and Care Research; Västra Götaland Foundation; Wellcome Trust (068545, 076113, 079895, 084723, 088869, WT064890, WT086596, WT098017, WT090532, WT098051, 098381); Wissenschaftsoffensive TMO; Yrjö Jahnsson Foundation; and Åke Wiberg Foundation. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute (NHLBI); the National Institutes of Health (NIH); or the U.S. Department of Health and Human Services.
Published: 2017
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49. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

Author: Xiuqing Guo, Jack W. Kent, Xinggang Liu, Wolfram Goessling, Alexander W. Drong, Lawrence F. Bielak, Jerome I. Rotter, René Laqua, Kurt Lohman, Juan M. Peralta, Nancy L. Heard-Costa, Henry Völzke, Matthias Nauck, Tamara B. Harris, Matthew A. Allison, Carl D. Langefeld, Braxton D. Mitchell, Audrey Y. Chu, Jie Yao, John D. Eicher, J. Jeffrey Carr, V. Gudnason, Georg Homuth, Henri Wallaschofski, Bradford Towne, Thomas H. Mosley, Anubha Mahajan, Ahmed H. Kissebah, Andrew P. Morris, Sharon L.R. Kardia, Lenore J. Launer, Patricia A. Peyser, Virginia Fisher, Nele Friedrich, Mary F. Feitosa, Stefan A. Czerwinski, Joel Kullberg, Erik Ingelsson, Thomas D. Dyer, Yi Zhang, Olivia Weeks, Jeffrey R. O'Connell, James G. Terry, James G. Wilson, Ingrid B. Borecki, Cecilia M. Lindgren, Matthew L. Steinhauser, Lars Lind, Yang Zhang, Albert V. Smith, Yongmei Liu, Alan R. Shuldiner, John Blangero, Jingzhong Ding, L. Adrienne Cupples, Caroline S. Fox, Ankita Parihar, Xuan Deng, Lingyi Lu, Donald W. Bowden, Mary K. Wojczynski, Audrey C. Choh, Michael Olivier, Tim Kacprowski, Ching-Ti Liu, Andrew D. Johnson, Leslie A. Lange, and Qing Duan
Subjects: Male, 0301 basic medicine, Adipose tissue, Genome-wide association study, Type 2 diabetes, Inbred C57BL, Medical and Health Sciences, Cohort Studies, Mice, chemistry.chemical_compound, Adipocyte, Ethnicity, Adipocytes, Body Fat Distribution, 2.1 Biological and endogenous factors, 610 Medicine & health, Genetics, Cell Differentiation, Single Nucleotide, Biological Sciences, Phenotype, Adipogenesis, Medical genetics, Female, Genetic Markers, medicine.medical_specialty, Ethnic Groups, Biology, Metabolic and Endocrine, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, medicine, Animals, Humans, Genetic Predisposition to Disease, Obesity, Polymorphism, Nutrition, Human Genome, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, chemistry, Genetic Loci, Genome-Wide Association Study, Developmental Biology
Abstract: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
Published: 2017
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50. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author: Niina Eklund, Robert C. Kaplan, Niek Verweij, Marcus Richards, Nancy L. Heard-Costa, Angelo Tremblay, Lu Qi, Andres Metspalu, Mark A. Sarzynski, Charleston W. K. Chiang, Tõnu Esko, Jaana Lindström, Pirro G. Hysi, Torben Hansen, James F. Wilson, Serena Sanna, Marie-Claude Vohl, Lynda M. Rose, Daniele Cusi, Megan T. Smith, Anne U. Jackson, Jing Hua Zhao, Anubha Mahajan, Nele Friedrich, Marcel Bruinenberg, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Weihua Zhang, Lavinia Paternoster, Jenny van Dongen, Torben Jørgensen, Aarno Palotie, Jana V. van Vliet-Ostaptchouk, Martin Farrall, Konstantin Strauch, Jan Smit, Zoltán Kutalik, Anne E. Justice, Elisabeth Widen, Tuomo Rankinen, Timo A. Lakka, Maria Dimitriou, Louis Pérusse, Peter J. van der Most, Yun Ju Sung, George Dedoussis, Caroline Hayward, Tom Wilsgaard, Peter P. Pramstaller, Maria Karaleftheri, Seppo Koskinen, Clive Osmond, Panos Deloukas, David J. Hunter, Kathleen Stirrups, Nicola Glorioso, Andrew T. Hattersley, Hugh Watkins, Sven Bergmann, Eric Boerwinkle, Catharina A. Hartman, Anke Tönjes, Daniel I. Chasman, May E. Montasser, Alan James, Ben A. Oostra, Nigel W. Rayner, Massimo Mangino, Ron T. Gansevoort, Cristina Barlassina, Johanna Kuusisto, Andrew A. Hicks, Roberto Lorbeer, Tomi Laitinen, Narisu Narisu, Stefan R. Bornstein, Gemma Cadby, Johan G. Eriksson, Gudmar Thorleifsson, Erika Salvi, Jari Lahti, Cornelia M. van Duijn, Janina M. Jeff, Heather M. Stringham, Bruce M. Psaty, Thomas W. Winkler, Paul M. Ridker, Unnur Thorsteinsdottir, Lyle J. Palmer, Alexander Teumer, Jürgen Gräßler, Allan Linneberg, Francesca D'Avila, Markku Heliövaara, Harald Grallert, Ivana Kolcic, Kari E. North, Eleftheria Zeggini, James S. Pankow, Alena Standáková, Marjo-Riitta Järvelin, Ozren Polasek, Krista Fischer, Valeriya Lyssenko, Thorkild I. A. Sørensen, André G. Uitterlinden, Stavroula Kanoni, Caroline S. Fox, Sophie R. Wang, Treva Rice, Maria Grazia Pilia, Olli T. Raitakari, Claudia Langenberg, Thomas Sparsø, Emmanouil Tsafantakis, Irene Pichler, Kathy Ryan, Eero Jokinen, Mika Kähönen, Leif Groop, Irene Mateo Leach, Gabriele Müller, Annette Peters, Peter Vollenweider, Oddgeir L. Holmen, David Schlessinger, Paul Knekt, M. Carola Zillikens, Evelin Mihailov, Erkki Vartiainen, Nicholas J. Wareham, Francis S. Collins, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Joel N. Hirschhorn, Frank B. Hu, Janina S. Ried, Valgerdur Steinthorsdottir, Shapour Jalilzadeh, Peter Kovacs, Anuj Goel, Pim van der Harst, Peter Schwarz, Mathias Gorski, Jorma Viikari, Uwe Völker, Cecilia M. Lindgren, Theodosios Kyriakou, Morris A. Swertz, Inga Prokopenko, Ken K. Ong, Leena Kinnunen, Markus Perola, Kristian Hveem, Matthias Blüher, Rebecca Mills, Albertine J. Oldehinkel, Anders Hamsten, Mattias Lorentzon, Joel Eriksson, Karen L. Mohlke, Rasmus Ribel-Madsen, Pekka Jousilahti, Paolo Manunta, Eva Albrecht, Jeffrey R. O'Connell, Wendy L. McArdle, Amy J. Swift, Dorret I. Boomsma, Harry Campbell, Fracensco Cucca, Aaron Isaacs, Andrew Wong, Georg Homuth, Laura M. Yerges-Armstrong, Carolina Medina-Gomez, Kay-Tee Khaw, Claes Ohlsson, Claude Bouchard, John Blangero, Aliki-Eleni Farmaki, Lorraine Southam, Anette P. Gjesing, Traci M. Bartz, Dabeeru C. Rao, Andrew P. Morris, David P. Strachan, Nita G. Forouhi, Eco J. C. de Geus, Jaakko Tuomilehto, Antti Jula, Ryan W. Walker, Mary F. Feitosa, Reedik Mägi, Aki S. Havulinna, Inger Njølstad, Alan R. Shudiner, Jennifer E. Huffman, Peter Lichtner, Richard N. Bergman, Mariaelisa Graff, Diana Kuh, Tim D. Spector, Robert Luben, Veikko Salomaa, Christian Gieger, Jaspal S. Kooner, Teresa Ferreira, Jennifer L. Bragg-Gresham, Sylvain Sebert, Terho Lehtimäki, Heikki A. Koistinen, Alexandra M. Lewin, Alexessander Couto Alves, Peter S. Chines, Lise Lotte N. Husemoen, Salome Scholtens, Yii-Der Ida Chen, Kati Kristiansson, Barbara McKnight, Sara M. Willems, Rainer Rauramaa, Satu Männistö, Stephan J. L. Bakker, Angela Döring, Audrey Y. Chu, Niels Grarup, Matti Uusitupa, Hannu Puolijoki, L. Adrienne Cupples, Veronique Vitart, Marie Neergaard Harder, Jouke-Jan Hottenga, Kari Stefansson, Alan F. Wright, Igor Rudan, Keri L. Monda, Jian'an Luan, Robert A. Scott, Albert Hofman, Tarunveer S. Ahluwalia, Liesbeth Vandenput, Maija Hassinen, Sarah H. Wild, Iris M. Heid, Brenda W.J.H. Penninx, John C. Chambers, Claire Bellis, Nicholas D. Hastie, Ruth J. F. Loos, Martina Müller-Nurasyid, Johanne Marie Justesen, Gérard Waeber, Jennie Hui, Gonçalo R. Abecasis, Ishminder K. Kooner, Harold Snieder, Judith M. Vonk, Ioanna Tachmazidou, Ronald P. Stolk, Michael Stumvoll, Till Ittermann, Oluf Pedersen, Ingrid B. Borecki, Gonneke Willemsen, Jagvir Grewal, Markku Laakso, Arthur W. Musk, Eero Kajantie, Hans L. Hillege, Michael Boehnke, Cristina Venturini, Lili Milani, John Beilby, Fernando Rivadeneira, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Goel, Anuj [0000-0003-2307-4021], Jackson, Anne U [0000-0002-9672-2547], Kristiansson, Kati [0000-0003-4688-107X], Medina-Gomez, Carolina [0000-0001-7999-5538], Nolte, Ilja M [0000-0001-5047-4077], Prokopenko, Inga [0000-0003-1624-7457], Teumer, Alexander [0000-0002-8309-094X], Wong, Andrew [0000-0003-2079-4779], Beilby, John [0000-0002-4915-2254], Bergmann, Sven [0000-0002-6785-9034], Strachan, David P [0000-0001-7854-1366], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Energy & Sustainability Programme, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Children's Hospital, Lastentautien yksikkö, Clinicum, Institute for Molecular Medicine Finland, Behavioural Sciences, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Department of Medicine, Endokrinologian yksikkö, Aarno Palotie / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, University of Helsinki, Leif Groop Research Group, Quantitative Genetics, HUS Children and Adolescents, Developmental Psychology Research Group, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, School of Medicine / Clinical Medicine, School of Medicine / Biomedicine,School of Medicine / Clinical Nutrition, Ried, Janina S., Jeff, Janina M., Chu, Audrey Y., Bragg Gresham, Jennifer L., Van Dongen, Jenny, Huffman, Jennifer E., Ahluwalia, Tarunveer S., Cadby, Gemma, Eklund, Niina, Eriksson, Joel, Esko, Toñu, Feitosa, Mary F., Goel, Anuj, Gorski, Mathia, Hayward, Caroline, Heard Costa, Nancy L., Jackson, Anne U., Jokinen, Eero, Kanoni, Stavroula, Kristiansson, Kati, Kutalik, Zoltán, Lahti, Jari, Luan, Jian'An, Mägi, Reedik, Mahajan, Anubha, Mangino, Massimo, Medina Gomez, Carolina, Monda, Keri L., Nolte, Ilja M., Pérusse, Loui, Prokopenko, Inga, Qi, Lu, Rose, Lynda M., Salvi, Erika, Smith, Megan T., Snieder, Harold, Standáková, Alena, Ju Sung, Yun, Tachmazidou, Ioanna, Teumer, Alexander, Thorleifsson, Gudmar, Van Der Harst, Pim, Walker, Ryan W., Wang, Sophie R., Wild, Sarah H., Willems, Sara M., Wong, Andrew, Zhang, Weihua, Albrecht, Eva, Couto Alves, Alexessander, Bakker, Stephan J. L., Barlassina, Cristina, Bartz, Traci M., Beilby, John, Bellis, Claire, Bergman, Richard N., Bergmann, Sven, Blangero, John, Blüher, Matthia, Boerwinkle, Eric, Bonnycastle, Lori L., Bornstein, Stefan R., Bruinenberg, Marcel, Campbell, Harry, Chen, Yii Der Ida, Chiang, Charleston W. K., Chines, Peter S., Collins, Francis S, Cucca, Fracensco, Cupples, L. Adrienne, D'Avila, Francesca, De Geus, Eco J. C., Dedoussis, George, Dimitriou, Maria, Döring, Angela, Eriksson, Johan G., Farmaki, Aliki Eleni, Farrall, Martin, Ferreira, Teresa, Fischer, Krista, Forouhi, Nita G., Friedrich, Nele, Gjesing, Anette Prior, Glorioso, Nicola, Graff, Mariaelisa, Grallert, Harald, Grarup, Niel, Gräßler, Jürgen, Grewal, Jagvir, Hamsten, Ander, Harder, Marie Neergaard, Hartman, Catharina A., Hassinen, Maija, Hastie, Nichola, Hattersley, Andrew Tym, Havulinna, Aki S., Heliövaara, Markku, Hillege, Han, Hofman, Albert, Holmen, Oddgeir, Homuth, Georg, Hottenga, Jouke Jan, Hui, Jennie, Husemoen, Lise Lotte, Hysi, Pirro G., Isaacs, Aaron, Ittermann, Till, Jalilzadeh, Shapour, James, Alan L., Jørgensen, Torben, Jousilahti, Pekka, Jula, Antti, Marie Justesen, Johanne, Justice, Anne E., Kähönen, Mika, Karaleftheri, Maria, Tee Khaw, Kay, Keinanen Kiukaanniemi, Sirkka M., Kinnunen, Leena, Knekt, Paul B., Koistinen, Heikki A., Kolcic, Ivana, Kooner, Ishminder K., Koskinen, Seppo, Kovacs, Peter, Kyriakou, Theodosio, Laitinen, Tomi, Langenberg, Claudia, Lewin, Alexandra M., Lichtner, Peter, Lindgren, Cecilia M., Lindström, Jaana, Linneberg, Allan, Lorbeer, Roberto, Lorentzon, Mattia, Luben, Robert, Lyssenko, Valeriya, Männistö, Satu, Manunta, Paolo, Leach, Irene Mateo, Mcardle, Wendy L., Mcknight, Barbara, Mohlke, Karen L., Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Montasser, May E., Morris, Andrew P., Müller, Gabriele, Musk, Arthur W., Narisu, Narisu, Ong, Ken K., Oostra, Ben A., Osmond, Clive, Palotie, Aarno, Pankow, James S., Paternoster, Lavinia, Penninx, Brenda W., Pichler, Irene, Pilia, Maria G., Polašek, Ozren, Pramstaller, Peter P., Raitakari, Olli T, Rankinen, Tuomo, Rao, D. C., Rayner, Nigel W., Ribel Madsen, Rasmu, Rice, Treva K., Richards, Marcu, Ridker, Paul M., Rivadeneira, Fernando, Ryan, Kathy A., Sanna, Serena, Sarzynski, Mark A., Scholtens, Salome, Scott, Robert A., Sebert, Sylvain, Southam, Lorraine, Sparsø, Thomas Hempel, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Stolk, Ronald P., Strauch, Konstantin, Stringham, Heather M., Swertz, Morris A., Swift, Amy J., Tönjes, Anke, Tsafantakis, Emmanouil, Van Der Most, Peter J., Van Vliet Ostaptchouk, Jana V., Vandenput, Liesbeth, Vartiainen, Erkki, Venturini, Cristina, Verweij, Niek, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie Claude, Vonk, Judith M., Waeber, Gérard, Widén, Elisabeth, Willemsen, Gonneke, Wilsgaard, Tom, Winkler, Thomas W., Wright, Alan F., Yerges Armstrong, Laura M., Zhao, Jing Hua, Carola Zillikens, M., Boomsma, Dorret I., Bouchard, Claude, Chambers, John C., Chasman, Daniel I., Cusi, Daniele, Gansevoort, Ron T., Gieger, Christian, Hansen, Torben, Hicks, Andrew A., Hu, Frank, Hveem, Kristian, Jarvelin, Marjo Riitta, Kajantie, Eero, Kooner, Jaspal S., Kuh, Diana, Kuusisto, Johanna, Laakso, Markku, Lakka, Timo A., Lehtimäki, Terho, Metspalu, Andre, Njølstad, Inger, Ohlsson, Clae, Oldehinkel, Albertine J., Palmer, Lyle J., Pedersen, Oluf, Perola, Marku, Peters, Annette, Psaty, Bruce M., Puolijoki, Hannu, Rauramaa, Rainer, Rudan, Igor, Salomaa, Veikko, Schwarz, Peter E. H., Shudiner, Alan R., Smit, Jan H., Sørensen, Thorkild I. A., Spector, Timothy D., Stefansson, Kari, Stumvoll, Michael, Tremblay, Angelo, Tuomilehto, Jaakko, Uitterlinden, André G., Uusitupa, Matti, Völker, Uwe, Vollenweider, Peter, Wareham, Nicholas J., Watkins, Hugh, Wilson, James F., Zeggini, Eleftheria, Abecasis, Goncalo R., Boehnke, Michael, Borecki, Ingrid B., Deloukas, Pano, Van Duijn, Cornelia M., Fox, Caroline, Groop, Leif C., Heid, Iris M., Hunter, David J., Kaplan, Robert C., Mccarthy, Mark I., North, Kari E., O'Connell, Jeffrey R., Schlessinger, David, Thorsteinsdottir, Unnur, Strachan, David P., Frayling, Timothy, Hirschhorn, Joel N., Müller Nurasyid, Martina, Loos, Ruth J. F., Internal medicine, Psychiatry, EMGO - Mental health, Public Health, Epidemiology, Surgery, Internal Medicine, Erasmus MC other, and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, Genome-wide association studies, Mice, HEIGHT, Body Size, Mass index, 2. Zero hunger, Genetics, Principal Component Analysis, Multidisciplinary, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, Chemistry (all), Phenotype, Common, gene, body, shape, Multidisciplinary Sciences, Principal component analysis, Trait, Science & Technology - Other Topics, DIET-INDUCED OBESITY, Waist, Genotype, 515 Psychology, Science, EARLY-ONSET, Snp, BIOLOGY, HIP RATIO, Genome-wide association studies Statistical methods, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), MASS INDEX, DISEASE ASSOCIATIONS, RESOURCE, MD Multidisciplinary, Humans, GENOME-WIDE ASSOCIATION, Biochemistry, Genetics and Molecular Biology (all), Science & Technology, Models, Genetic, ta1184, FAT DISTRIBUTION, General Chemistry, ta3121, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Body mass index, Genome-Wide Association Study
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways., published version, peerReviewed
Published: 2016
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