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 Valérie , 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 Tõnu , Vedantam Sailaja , Giri Ayush , Lo Ken Sin , Alfred Tamuno , Mudgal Poorva , Ng Maggie CY , Heard-Costa Nancy L , Feitosa Mary F , Manning Alisa K , Willems Sara M , Sivapalaratnam Suthesh , Abecasis Goncalo , Alam Dewan S , Allison Matthew , Amouyel Philippe , Arzumanyan Zorayr , Balkau Beverley , Bastarache Lisa , Bergmann Sven , Bielak Lawrence F , Blüher Matthias , Boehnke Michael , Boeing Heiner , Boerwinkle Eric , Boger Carsten A , Bork-Jensen Jette , Bottinger Erwin P , Bowden Donald W , Brandslund Ivan , Broer Linda , Burt Amber A , Butterworth Adam S , Caulfield Mark J , Cesana Giancarlo , Chambers John C , Chasman Daniel I , Chen Yii-Der Ida , Chowdhury Rajiv , Christensen Cramer , Chu Audrey Y , Collins Francis S , Cook James P , Cox Amanda J , Crosslin David S , Danesh John , de Bakker Paul IW , de Denus Simon , de Mutsert Renee , Dedoussis George , Demerath Ellen W , Dennis Joe G , Denny Josh C , Di Angelantonio Emanuele , Dorr 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 , Grove Megan L , Gustafsson Stefan , Haessler Jeff , Hansen Torben , Hattersley Andrew T , Hayward Caroline , Heid Iris M , Holmen Oddgeir L , Hovingh G Kees , Howson Joanna MM , Hu Yao , Hung Yi-Jen , Hveem Kristian , Ikram M Arfan , Ingelsson Erik , Jackson Anne U , Jarvik Gail P , Jia Yucheng , Jørgensen Torben , Jousilahti Pekka , Justesen Johanne M , Kahali Bratati , Karaleftheri Maria , Kardia Sharon LR , Karpe Fredrik , Kee Frank , Kitajima Hidetoshi , Komulainen Pirjo , Kooner Jaspal S , Kovacs Peter , Kramer Bernhard K , Kuulasmaa Kari , Kuusisto Johanna , Laakso Markku , Lakka Timo A , Lamparter David , Lange Leslie A , Langenberg Claudia , Larson Eric B , Lee Nanette R , Lee Wen-Jane , Lehtimäki Terho , Lewis Cora E , Li Huaixing , Li Jin , Li-Gao Ruifang , Lin Li-An , Lin Xu , Lind Lars , Lindström Jaana , Linneberg Allan , Liu Ching-Ti , Liu Dajiang J , Luan Jian’an , Lyytikäinen Leo-Pekka , MacGregor Stuart , Mägi Reedik , Männistö Satu , Marenne Gaëlle , Marten Jonathan , Masca Nicholas GD , McCarthy Mark I , Meidtner Karina , Mihailov Evelin , Moilanen Leena , Moitry Marie , Mook-Kanamori Dennis O , Morgan Anna , Morris Andrew P , Muller-Nurasyid Martina , Munroe Patricia B , Narisu Narisu , Nelson Christopher P , Neville Matt , Ntalla Ioanna , O’Connel Jeffrey R , Owen Katharine R , Pedersen Oluf , Peloso Gina M , Pennell Craig E , Perola Markus , Perry James A , Perry John RB , Pers Tune H , Pirie Ailith , Polasek Ozren , Raitakari Olli T , 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 P , 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 MA , Tardif Jean-Claude , Taylor Kent D , Teumer Alexander , Thompson Deborah J , Thorleifsson Gudmar , Thorsteinsdottir Unnur , Thuesen Betina H , Tönjes Anke , Torres Mina , Tsafantakis Emmanouil , Tuomilehto Jaakko , Uitterlinden André G , Uusitupa Matti , Duijn Cornelia M van , Vanhala Mauno , Varma Rohit , Vermeulen Sita H , Vestergaard Henrik , Vitart Veronique , Vogt Thomas F , Ntalla Dragana , Wagenknecht Lynne E , Walker Mark , Wallentin Lars , Wang Feijie , Wang Carol A , Wang Shuai , Wareham Nicholas 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 , Yerges-Armstrong Laura M , Young Robin , Zeggini Eleftheria , Zhan Xiaowei , Zhang Weihua , Zhao Jing Hua , Zhao Wei , Zheng He , Zhou Wei , Zillikens M Carola ,   GoT2D Genes Consortium CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, The MAGIC Investigators, Rivadeneira Fernando , Borecki Ingrid B , Pospisilik John A , Deloukas Panos , Frayling Timothy M , Lettre Guillaume , Mohlke Karen L , Rotter Jerome I , Kutalik Zoltan , Hirschhorn Joel N , Cupples L Adrienne , Loos Ruth JF , North Kari E , Lindgren Cecilia M 
Published: June 2018

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.