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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
Authors :
Justice, Anne E. Karaderi, Tugce Highland, Heather M. Young, Kristin L. Graff, Mariaelisa Lu, Yingchang Turcot, Valerie Auer, Paul L. Fine, Rebecca S. Guo, Xiuqing Schurmann, Claudia Lempradl, Adelheid Marouli, Eirini Mahajan, Anubha Winkler, Thomas W. Locke, Adam E. Medina-Gomez, Carolina Esko, Tonu Vedantam, Sailaja Giri, Ayush Lo, Ken Sin Alfred, Tamuno Mudgal, Poorva Ng, Maggie C. Y. Heard-Costa, Nancy L. Feitosa, Mary F. Manning, Alisa K. Willems, Sara M. Sivapalaratnam, Suthesh Abecasis, Goncalo Alam, Dewan S. Allison, Matthew Amouyel, Philippe Arzumanyanm, Zorayr Balkau, Beverley Bastarache, Lisa Bergmann, Sven Bielak, Lawrence F. Blueher, Matthias Boehnke, Michael Boeing, Heiner Boerwinkle, Eric Boeger, Carsten A. Bork-Jensen, Jette Bottinger, Erwin P. Bowden, Donald W. Brandslund, Ivan Broer, Linda Burt, Amber A. Butterworth, Adam S. Caulfield, Markj Cesana, Giancarlo Chambers, John C. Chasman, Daniel, I Chen, Yii-Der Ida Chowdhury, Rajiv Christensen, Cramer Chu, Audreyy Collins, Francis S. Cook, James P. Cox, Amanda J. Crosslin, David S. Danesh, John de Bakker, Paul I. W. de Denus, Simon de Mutsert, Renee Dedoussis, George Demerath, Ellen W. Dennis, Joe G. Denny, Josh C. Di Angelantonio, Emanuele Doerr, Marcus Drenos, Fotios Dube, Marie-Pierre Dunning, Alison M. Easton, Douglas F. Elliott, Paul Evangelou, Evangelos Farmaki, Aliki-Eleni Feng, Shuang Ferrannini, Ele Ferrieres, Jean Florez, Jose C. Fornage, Myriam Fox, Caroline S. Franks, Paul W. Friedrich, Nele Gan, Wei Gandin, Ilaria Gasparini, Paolo Giedraitis, Vilmantas Girotto, Giorgia Gorski, Mathias Grallert, Harald Grarup, Niels Groves, Megan L. Gustafsson, Stefan Haessler, Jeff Hansen, Torben Hattersley, Andrew T. Hayward, Caroline Heid, Iris M. Holmen, Oddgeir L. Hovingh, G. Kees Howson, Joanna M. M. Hu, Yao Hung, Yi-Jen Hveem, Kristian Ikram, M. Arfan Ingelsson, Erik Jackson, Anne U. Jarvik, Gail P. Jia, Yucheng Jorgensen, Torben Jousilahti, Pekka Justesen, Johanne M. Kahali, Bratati Karaleftheri, Maria Kardia, Sharon L. R. Karpe, Fredrik Kee, Frank Kitajima, Hidetoshi Komulainen, Pirjo Kooner, Jaspal S. Kovacs, Peter Kraemer, Bernhard K. Kuulasmaa, Kari Kuusisto, Johanna Laakso, Markku Lakka, Timo A. Lamparter, David La Nge, Leslie A. Langenberg, Claudia Larson, Eric B. Lee, Nanette R. Lee, Wen-Jane Lehtimaeki, Terho Lewis, Cora E. Li, Huaixing Li, Jin RuifangLi-Gao Lin, Li-An Lin, Xu Lind, Lars Lindstroem, Jaana Linneberg, Allan Liu, Ching-Ti Liu, Dajiang J. Luan, Jian'an Lyytikainen, Leo-Pekka MacGregor, Stuart Magi, Reedik Mannisto, Satu Marenne, Gaelle Marten, Jonathan Mascal, Nicholas G. D. McCarthy, Mark, I Meidtner, Karina Mihailov, Evelin Moilanen, Leena Moitry, Marie Mook-Kanamori, Dennis O. Morgan, Anna Morris, Andrew P. Mueller-Nurasyid, Martina Munroe, Patricia B. Narisu, Narisu Nelson, Christopher P. Neville, Matt Ntalla, Ioanna Owen, Katharine R. Pedersen, Oluf Peloso, Gina M. Pennell, Craig E. Perola, Markus James, A. Perry, John R. B. Pers, Tune H. Ewing, Ailith Polasek, Ozren Rasheed, Asif Raulerson, Chelsea K. Rauramaa, Rainer Reilly, Dermot F. Reiner, Alex P. Ridker, Paul M. Rivas, Manuel A. Robertson, Neil R. Robino, Antonietta Rudan, Igor Ruth, Katherine S. Saleheen, Danish Salomaa, Veikko Samani, Nilesh J. Schreiner, Pamela J. Schulze, Matthias B. Scott, Robert A. Segura-Lepe, Marcelo Sim, Xueling Slater, Andrew J. Small, Kerrin S. Smith, Blair H. Smith, Jennifer A. Southam, Lorraine Spector, Timothy D. Speliotes, Elizabeth K. Stefansson, Kari Steinthorsdottir, Valgerdur Stirrups, Kathleen E. Strauch, Konstantin Stringham, Heather M. Stumvoll, Michael Sun, Liang Surendran, Praveen Swart, Karin M. A. Tardif, Jean-Claude Taylor, Kent D. Teumer, Alexander Thompson, Deborah J. Thorleifsson, Gudmar Thorsteinsdottir, Unnur Thuesen, Betina H. Toenjes, Anke Torres, Mina Tsafantakis, Emmanouil Tuomilehto, Jaakko Uitterlinden, Andre G. Uusitupa, Matti van Duijn, Cornelia M. Vanhala, Mauno Varma, Rohit Vermeulen, Sita H. Vestergaard, Henrik Vitart, Veronique Vogt, Thomas F. Vuckovic, Dragana Wagenknecht, Lynne E. Walker, Mark Wallentin, Lars Wang, Feijie Wang, Carol A. Wang, Shuai Wareham, N. Icholas J. Warren, Helen R. Waterworth, Dawn M. Wessel, Jennifer White, Harvey D. Willer, Cristen J. Wilson, James G. Wood, Andrew R. Wu, Ying Yaghootkar, Hanieh Yao, Jie Verges-Armstrong, Laura M. Young, Robin Zeggini, Eleftheria Zhan, Xiaowei Zhang, Weihua Zhao, Jing Hua Zhao, Wei Zheng, He Zhou, Wei Zillikens, M. Carola Rivadeneira, Fernando Borecki, Ingrid B. Pospisilik, J. Andrew Deloukas, Panos Frayling, Timothy M. Lettre, Guillaume Mohlke, Karen L. Rotter, Jerome, I Kutalik, Zoltan Hirschhorn, Joel N. Cupples, L. Adrienne Loos, Ruth J. F. North, Kari E. Lindgren, Cecilia M. O'Connell, Jeffrey R. Raitakari, Olli T. Lange, Leslie A. Uitterlinden, Andr G. Grove, Megan L. Masca, Nicholas G. D. Luan, Jianan Wareham, Nicholas J. Esko, Tnu De Bakker, Paul Iw Caulfield, Mark J. Mller-Nurasyid, Martina Justice, Anne E. Karaderi, Tugce Highland, Heather M. Young, Kristin L. Graff, Mariaelisa Lu, Yingchang Turcot, Valerie Auer, Paul L. Fine, Rebecca S. Guo, Xiuqing Schurmann, Claudia Lempradl, Adelheid Marouli, Eirini Mahajan, Anubha Winkler, Thomas W. Locke, Adam E. Medina-Gomez, Carolina Esko, Tonu Vedantam, Sailaja Giri, Ayush Lo, Ken Sin Alfred, Tamuno Mudgal, Poorva Ng, Maggie C. Y. Heard-Costa, Nancy L. Feitosa, Mary F. Manning, Alisa K. Willems, Sara M. Sivapalaratnam, Suthesh Abecasis, Goncalo Alam, Dewan S. Allison, Matthew Amouyel, Philippe Arzumanyanm, Zorayr Balkau, Beverley Bastarache, Lisa Bergmann, Sven Bielak, Lawrence F. Blueher, Matthias Boehnke, Michael Boeing, Heiner Boerwinkle, Eric Boeger, Carsten A. Bork-Jensen, Jette Bottinger, Erwin P. Bowden, Donald W. Brandslund, Ivan Broer, Linda Burt, Amber A. Butterworth, Adam S. Caulfield, Markj Cesana, Giancarlo Chambers, John C. Chasman, Daniel, I Chen, Yii-Der Ida Chowdhury, Rajiv Christensen, Cramer Chu, Audreyy Collins, Francis S. Cook, James P. Cox, Amanda J. Crosslin, David S. Danesh, John de Bakker, Paul I. W. de Denus, Simon de Mutsert, Renee Dedoussis, George Demerath, Ellen W. Dennis, Joe G. Denny, Josh C. Di Angelantonio, Emanuele Doerr, Marcus Drenos, Fotios Dube, Marie-Pierre Dunning, Alison M. Easton, Douglas F. Elliott, Paul Evangelou, Evangelos Farmaki, Aliki-Eleni Feng, Shuang Ferrannini, Ele Ferrieres, Jean Florez, Jose C. Fornage, Myriam Fox, Caroline S. Franks, Paul W. Friedrich, Nele Gan, Wei Gandin, Ilaria Gasparini, Paolo Giedraitis, Vilmantas Girotto, Giorgia Gorski, Mathias Grallert, Harald Grarup, Niels Groves, Megan L. Gustafsson, Stefan Haessler, Jeff Hansen, Torben Hattersley, Andrew T. Hayward, Caroline Heid, Iris M. Holmen, Oddgeir L. Hovingh, G. Kees Howson, Joanna M. M. Hu, Yao Hung, Yi-Jen Hveem, Kristian Ikram, M. Arfan Ingelsson, Erik Jackson, Anne U. Jarvik, Gail P. Jia, Yucheng Jorgensen, Torben Jousilahti, Pekka Justesen, Johanne M. Kahali, Bratati Karaleftheri, Maria Kardia, Sharon L. R. Karpe, Fredrik Kee, Frank Kitajima, Hidetoshi Komulainen, Pirjo Kooner, Jaspal S. Kovacs, Peter Kraemer, Bernhard K. Kuulasmaa, Kari Kuusisto, Johanna Laakso, Markku Lakka, Timo A. Lamparter, David La Nge, Leslie A. Langenberg, Claudia Larson, Eric B. Lee, Nanette R. Lee, Wen-Jane Lehtimaeki, Terho Lewis, Cora E. Li, Huaixing Li, Jin RuifangLi-Gao Lin, Li-An Lin, Xu Lind, Lars Lindstroem, Jaana Linneberg, Allan Liu, Ching-Ti Liu, Dajiang J. Luan, Jian'an Lyytikainen, Leo-Pekka MacGregor, Stuart Magi, Reedik Mannisto, Satu Marenne, Gaelle Marten, Jonathan Mascal, Nicholas G. D. McCarthy, Mark, I Meidtner, Karina Mihailov, Evelin Moilanen, Leena Moitry, Marie Mook-Kanamori, Dennis O. Morgan, Anna Morris, Andrew P. Mueller-Nurasyid, Martina Munroe, Patricia B. Narisu, Narisu Nelson, Christopher P. Neville, Matt Ntalla, Ioanna Owen, Katharine R. Pedersen, Oluf Peloso, Gina M. Pennell, Craig E. Perola, Markus James, A. Perry, John R. B. Pers, Tune H. Ewing, Ailith Polasek, Ozren Rasheed, Asif Raulerson, Chelsea K. Rauramaa, Rainer Reilly, Dermot F. Reiner, Alex P. Ridker, Paul M. Rivas, Manuel A. Robertson, Neil R. Robino, Antonietta Rudan, Igor Ruth, Katherine S. Saleheen, Danish Salomaa, Veikko Samani, Nilesh J. Schreiner, Pamela J. Schulze, Matthias B. Scott, Robert A. Segura-Lepe, Marcelo Sim, Xueling Slater, Andrew J. Small, Kerrin S. Smith, Blair H. Smith, Jennifer A. Southam, Lorraine Spector, Timothy D. Speliotes, Elizabeth K. Stefansson, Kari Steinthorsdottir, Valgerdur Stirrups, Kathleen E. Strauch, Konstantin Stringham, Heather M. Stumvoll, Michael Sun, Liang Surendran, Praveen Swart, Karin M. A. Tardif, Jean-Claude Taylor, Kent D. Teumer, Alexander Thompson, Deborah J. Thorleifsson, Gudmar Thorsteinsdottir, Unnur Thuesen, Betina H. Toenjes, Anke Torres, Mina Tsafantakis, Emmanouil Tuomilehto, Jaakko Uitterlinden, Andre G. Uusitupa, Matti van Duijn, Cornelia M. Vanhala, Mauno Varma, Rohit Vermeulen, Sita H. Vestergaard, Henrik Vitart, Veronique Vogt, Thomas F. Vuckovic, Dragana Wagenknecht, Lynne E. Walker, Mark Wallentin, Lars Wang, Feijie Wang, Carol A. Wang, Shuai Wareham, N. Icholas J. Warren, Helen R. Waterworth, Dawn M. Wessel, Jennifer White, Harvey D. Willer, Cristen J. Wilson, James G. Wood, Andrew R. Wu, Ying Yaghootkar, Hanieh Yao, Jie Verges-Armstrong, Laura M. Young, Robin Zeggini, Eleftheria Zhan, Xiaowei Zhang, Weihua Zhao, Jing Hua Zhao, Wei Zheng, He Zhou, Wei Zillikens, M. Carola Rivadeneira, Fernando Borecki, Ingrid B. Pospisilik, J. Andrew Deloukas, Panos Frayling, Timothy M. Lettre, Guillaume Mohlke, Karen L. Rotter, Jerome, I Kutalik, Zoltan Hirschhorn, Joel N. Cupples, L. Adrienne Loos, Ruth J. F. North, Kari E. Lindgren, Cecilia M. O'Connell, Jeffrey R. Raitakari, Olli T. Lange, Leslie A. Uitterlinden, Andr G. Grove, Megan L. Masca, Nicholas G. D. Luan, Jianan Wareham, Nicholas J. Esko, Tnu De Bakker, Paul Iw Caulfield, Mark J. Mller-Nurasyid, Martina
Publication Year :
2019
Abstract
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
Details
Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1234597726
Document Type :
Electronic Resource
Full Text :
https://doi.org/10.1038.s41588-018-0334-2