Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

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, T. nu Esko, Sailaja Vedantam, Ayush GiriKen 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, Jin Li, Karin M. A. Swart, Sita H. Vermeulen, CHD Exome+ Consortium, Timothy M. Frayling, Guillaume Lettre, Karen L. Mohlke, Jerome I. Rotter, Zoltán Kutalik, Joel N. Hirschhorn, L. Adrienne Cupples, Ruth J. F. Loos, Kari E. North, Cecila M. Lindgren

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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.
Original languageEnglish
Pages (from-to)452–469
JournalNature Genetics
Publication statusPublished - 1 Mar 2019

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