Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
| Citation | . “Protein-Coding Variants Implicate Novel Genes Related To Lipid Homeostasis Contributing To Body-Fat Distribution.”. Nature Genetics, pp. 452-469. |
| Center | University of Michigan University of Alabama at Birmingham |
| Multicenter |
Multicenter
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| Author | 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 Böger, 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 I W de Bakker, Simon de Denus, Renée de Mutsert, George Dedoussis, Ellen W Demerath, Joe G Dennis, Josh C Denny, Emanuele Di Angelantonio, Marcus Dörr, Fotios Drenos, Marie-Pierre Dubé, 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, Kees Hovingh, Joanna M M Howson, Yao Hu, Yi-Jen Hung, Kristian Hveem, Arfan Ikram, Erik Ingelsson, Anne U Jackson, Gail P Jarvik, Yucheng Jia, Torben Jørgensen, Pekka Jousilahti, Johanne M Justesen, Bratati Kahali, Maria Karaleftheri, Sharon L R Kardia, Fredrik Karpe, Frank Kee, Hidetoshi Kitajima, Pirjo Komulainen, Jaspal S Kooner, Peter Kovacs, Bernhard K Krämer, 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 Magi, Satu Männistö, Gaëlle Marenne, Jonathan Marten, Nicholas G D Masca, Mark I McCarthy, Karina Meidtner, Evelin Mihailov, Leena Moilanen, Marie Moitry, Dennis O Mook-Kanamori, Anna Morgan, Andrew P Morris, Martina Müller-Nurasyid, Patricia B Munroe, Narisu Narisu, Christopher P Nelson, Matt Neville, Ioanna Ntalla, Jeffrey R O'Connell, Katharine R Owen, Oluf Pedersen, Gina M Peloso, Craig E Pennell, Markus Perola, James A Perry, John R B Perry, Tune H Pers, Ailith Ewing, 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 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 M A 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 Vuckovic, 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, Carola Zillikens, Fernando Rivadeneira, Ingrid B Borecki, Andrew Pospisilik, Panos Deloukas, Timothy M Frayling, Guillaume Lettre, Karen L Mohlke, Jerome I Rotter, Zoltan Kutalik, Joel N Hirschhorn, Adrienne Cupples, Ruth J F Loos, Kari E North, Cecilia M Lindgren, CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators |
| 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. |
| Year of Publication |
2019
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| Journal |
Nature genetics
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| Volume |
51
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| Issue |
3
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| Number of Pages |
452-469
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| Date Published |
12/2019
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| ISSN Number |
1546-1718
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| DOI |
10.1038/s41588-018-0334-2
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| Alternate Journal |
Nat. Genet.
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| PMID |
30778226
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| PMCID |
PMC6560635
|
| Download citation |