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PROTEIN-CODING VARIANTS IMPLICATE NOVEL GENES RELATED TO LIPID HOMEOSTASIS CONTRIBUTING TO BODY FAT DISTRIBUTION

By Anne E Justice, Tugce Karaderi, Heather M Highland, Kristin L. Young, Mariaelisa Graff, Yingchang Lu, Valérie Turcot, Paul L. Auer, Rebecca S. Fine, Xiuqing Guo, Claudia Schurmann, Adelheid Lempradl, Eirini Marouli, Anubha Mahajan, Thomas W Winkler, Adam E Locke, Carolina Medina-Gomez, Tõnu Esko, Sailaja Vedantam, Ayush Giri, Ken Sin Lo, Tamuno Alfred, Poorva Mudgal, Maggie C.Y. Ng, Nancy L. Heard-Costa, Mary F. Feitosa, Alisa K. Manning, Sara M Willems, Suthesh Sivapalaratnam, Goncalo Abecasis, Dewan S Alam, Matthew Allison, Philippe Amouyel, Zorayr Arzumanyan, Beverley Balkau, Lisa Bastarache, Sven Bergmann, Lawrence F Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Carsten A Boger, Jette Bork-Jensen, Erwin P. Bottinger, Donald W Bowden, Ivan Brandslund, Linda Broer, Amber A Burt, Adam S. Butterworth, Mark J. Caulfield, Giancarlo Cesana, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y Chu, Francis S Collins, James P Cook, Amanda J Cox, David S Crosslin, John Danesh, Paul IW de Bakker, Simon de Denus, Renee de Mutsert, George Dedoussis, Ellen W Demerath, Joe G Dennis, Josh C Denny, Emanuele Di Angelantonio, Marcus Dorr, Fotios Drenos, Marie-Pierre Dube, Alison M Dunning, Douglas F. Easton, Paul Elliott, Evangelos Evangelou, Aliki-Eleni Farmaki, Shuang Feng, Ele Ferrannini, Jean Ferrieres, Jose C Florez, Myriam Fornage, Caroline S. Fox, Paul W. Franks, Nele Friedrich, Wei Gan, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Giorgia Girotto, Mathias Gorski, Harald Grallert, Niels Grarup, Megan L Grove, Stefan Gustafsson, Jeff Haessler, Torben Hansen, Andrew T Hattersley, Caroline Hayward, Iris M Heid, Oddgeir L Holmen, G Kees Hovingh, Joanna MM Howson, Yao Hu, Yi-Jen Hung, Kristian Hveem, M. Arfan Ikram, Erik Ingelsson, Anne U. Jackson, Gail P Jarvik, Yucheng Jia, Torben Jørgensen, Pekka Jousilahti, Johanne M. Justesen, Bratati Kahali, Maria Karaleftheri, Sharon LR Kardia, Fredrik Karpe, Frank Kee, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S Kooner, Peter Kovacs, Bernhard K Kramer, Kari Kuulasmaa, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, David Lamparter, Leslie A Lange, Claudia Langenberg, Eric B Larson, Nanette R Lee, Wen-Jane Lee, Terho Lehtimäki, Cora E Lewis, Huaixing Li, Jin Li, Ruifang Li-Gao, Li-An Lin, Xu Lin, Lars Lind, Jaana Lindström, Allan Linneberg, Ching-Ti Liu, Dajiang J Liu, Jian’an Luan, Leo-Pekka Lyytikäinen, Stuart MacGregor, Reedik Mägi, Satu Männistö, Gaëlle Marenne, Jonathan Marten, Nicholas GD Masca, Mark I. McCarthy, Karina Meidtner, Evelin Mihailov, Leena Moilanen, Marie Moitry, Dennis O. Mook-Kanamori, Anna Morgan, Andrew P Morris, Martina Muller-Nurasyid, Patricia B. Munroe, Narisu Narisu, Christopher P Nelson, Matt Neville, Ioanna Ntalla, Jeffrey R O’Connel, Katharine R Owen, Oluf Pedersen, Gina M Peloso, Craig E. Pennell, Markus Perola, James A Perry, John R.B. Perry, Tune H. Pers, Ailith Pirie, Ozren Polasek, Olli T Raitakari, Asif Rasheed, Chelsea K Raulerson, Rainer Rauramaa, Dermot F Reilly, Alex P Reiner, Paul M Ridker, Manuel A. Rivas, Neil R Robertson, Antonietta Robino, Igor Rudan, Katherine S. Ruth, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Pamela J Schreiner, Matthias B Schulze, Robert A Scott, Marcelo P Segura-Lepe, Xueling Sim, Andrew J Slater, Kerrin S. Small, Blair H Smith, Jennifer A. Smith, Lorraine Southam, Timothy D. Spector, Elizabeth K Speliotes, Kari Stefansson, Valgerdur Steinthorsdottir, Kathleen E Stirrups, Konstantin Strauch, Heather M Stringham, Michael Stumvoll, Liang Sun, Praveen Surendran, Karin MA Swart, Jean-Claude Tardif, Kent D Taylor, Alexander Teumer, Deborah J. Thompson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Betina H Thuesen, Anke Tönjes, Mina Torres, Emmanouil Tsafantakis, Jaakko Tuomilehto, André G. Uitterlinden, Matti Uusitupa, Cornelia M. van Duijn, Mauno Vanhala, Rohit Varma, Sita H Vermeulen, Henrik Vestergaard, Veronique Vitart, Thomas F Vogt, Dragana Ntalla, Lynne E Wagenknecht, Mark Walker, Lars Wallentin, Feijie Wang, Carol A Wang, Shuai Wang, Nicholas J. Wareham, Helen R. Warren, Dawn M Waterworth, Jennifer Wessel, Harvey D White, Cristen J. Willer, James G Wilson, Andrew R. Wood, Ying Wu, Hanieh Yaghootkar, Jie Yao, Laura M Yerges-Armstrong, Robin Young, Eleftheria Zeggini, Xiaowei Zhan, Weihua Zhang, Jing Hua Zhao, Wei Zhao, He Zheng, Wei Zhou, M. Carola Zillikens, GoT2D Genes Consortium CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, The MAGIC Investigators, Fernando Rivadeneira, Ingrid B Borecki, John A Pospisilik, Panos Deloukas, TM Frayling, Guillaume Lettre, Karen L. Mohlke, Jerome I. Rotter, Zoltan Kutalik, Joel N. Hirschhorn, L. Adrienne Cupples, Ruth J.F. Loos, Kari E. North, Cecilia M. Lindgren

Posted 30 Jun 2018
bioRxiv DOI: 10.1101/352674 (published DOI: 10.1038/s41588-018-0334-2)

Body fat distribution is a heritable risk factor for a range of adverse health consequences, including hyperlipidemia and type 2 diabetes. To identify protein-coding variants associated with body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, we analyzed 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries for discovery and 132,177 independent European-ancestry individuals for validation. We identified 15 common (minor allele frequency, MAF ≥ 5%) and 9 low frequency or rare (MAF < 5%) coding variants that have not been reported previously. Pathway/gene set enrichment analyses of all associated variants highlight lipid particle, adiponectin level, abnormal white adipose tissue physiology, and bone development and morphology as processes affecting fat distribution and body shape. Furthermore, the cross-trait associations and the analyses of variant and gene function highlight a strong connection to lipids, cardiovascular traits, and type 2 diabetes. In functional follow-up analyses, specifically in Drosophila RNAi-knockdown crosses, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). By examining variants often poorly tagged or entirely missed by genome-wide association studies, we implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

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