Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.
Authors
Justice, Anne E
Karaderi, Tugce
Highland, Heather M
Graff, Mariaelisa
Lu, Yingchang
Turcot, Valérie
Auer, Paul L
Fine, Rebecca S
Guo, Xiuqing
Schurmann, Claudia
Lempradl, Adelheid
Marouli, Eirini
Esko, Tõnu
Vedantam, Sailaja
Lo, Ken Sin
Alfred, Tamuno
Mudgal, Poorva
Feitosa, Mary F
Willems, Sara M
Sivapalaratnam, Suthesh
Abecasis, Goncalo
Allison, Matthew
Arzumanyan, Zorayr
Balkau, Beverley
Bastarache, Lisa
Bielak, Lawrence F
Blüher, Matthias
Boeing, Heiner
Boerwinkle, Eric
Böger, Carsten A
Bork-Jensen, Jette
Bottinger, Erwin P
Bowden, Donald W
Brandslund, Ivan
Broer, Linda
Burt, Amber A
Cesana, Giancarlo
Chambers, John C
Chasman, Daniel I
Chen, Yii-Der Ida
Christensen, Cramer
Chu, Audrey Y
Cook, James P
Cox, Amanda J
Crosslin, David S
Denus, Simon de
Mutsert, Renée de
Dedoussis, George
Demerath, Ellen W
Denny, Josh C
Dörr, Marcus
Drenos, Fotios
Dubé, Marie-Pierre
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
Gorski, Mathias
Grallert, Harald
Grove, Megan L
Haessler, Jeff
Hattersley, Andrew T
Heid, Iris M
Holmen, Oddgeir L
Hovingh, G Kees
Hu, Yao
Hung, Yi-Jen
Hveem, Kristian
Ingelsson, Erik
Jarvik, Gail P
Jia, Yucheng
Jørgensen, Torben
Jousilahti, Pekka
Kahali, Bratati
Karaleftheri, Maria
Kardia, Sharon LR
Karpe, Fredrik
Kee, Frank
Kitajima, Hidetoshi
Komulainen, Pirjo
Kooner, Jaspal S
Krämer, Bernhard K
Kuusisto, Johanna
Laakso, Markku
Lakka, Timo A
Lamparter, David
Lange, Leslie A
Larson, Eric B
Lee, Nanette R
Lee, Wen-Jane
Lehtimäki, Terho
Lewis, Cora E
Li, Huaixing
Li, Jin
Li-Gao, Ruifang
Lin, Xu
Lind, Lars
Lindström, Jaana
Liu, Dajiang J
Luan, Jian'an
Mägi, Reedik
Männistö, Satu
Marenne, Gaëlle
Marten, Jonathan
Masca, Nicholas GD
Meidtner, Karina
Mihailov, Evelin
Moilanen, Leena
Moitry, Marie
Mook-Kanamori, Dennis O
Morris, Andrew P
Nelson, Christopher P
Ntalla, Ioanna
O'Connell, Jeffrey R
Owen, Katharine R
Pedersen, Oluf
Peloso, Gina M
Pennell, Craig E
Perola, Markus
Perry, James A
Pers, Tune H
Ewing, Ailith
Polasek, Ozren
Raitakari, Olli T
Rasheed, Asif
Raulerson, Chelsea K
Rauramaa, Rainer
Reiner, Alex P
Ridker, Paul M
Rivas, Manuel A
Robertson, Neil R
Robino, Antonietta
Ruth, Katherine S
Samani, Nilesh J
Schreiner, Pamela J
Schulze, Matthias B
Scott, Robert A
Segura-Lepe, Marcelo
Slater, Andrew J
Spector, Timothy D
Speliotes, Elizabeth K
Steinthorsdottir, Valgerdur
Strauch, Konstantin
Stumvoll, Michael
Sun, Liang
Surendran, Praveen
Swart, Karin MA
Tardif, Jean-Claude
Taylor, Kent D
Thorleifsson, Gudmar
Thorsteinsdottir, Unnur
Thuesen, Betina H
Tönjes, Anke
Torres, Mina
Tsafantakis, Emmanouil
Tuomilehto, Jaakko
Uitterlinden, André G
Uusitupa, Matti
van Duijn, Cornelia M
Vanhala, Mauno
Varma, Rohit
Vermeulen, Sita H
Vogt, Thomas F
Vuckovic, Dragana
Wagenknecht, Lynne E
Walker, Mark
Wallentin, Lars
Wang, Feijie
Wang, Shuai
Warren, Helen R
Waterworth, Dawn M
White, Harvey D
Wilson, James G
Wood, Andrew R
Wu, Ying
Yaghootkar, Hanieh
Yao, Jie
Yerges-Armstrong, Laura M
Young, Robin
Zhan, Xiaowei
Zhang, Weihua
Zhao, Wei
Zheng, He
Zhou, Wei
Zillikens, M Carola
Borecki, Ingrid B
Frayling, Timothy M
Lettre, Guillaume
Rotter, Jerome I
Hirschhorn, Joel N
Cupples, L Adrienne
North, Kari E
CHD Exome+ Consortium
Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
EPIC-CVD Consortium
ExomeBP Consortium
Global Lipids Genetic Consortium
GoT2D Genes Consortium
InterAct
ReproGen Consortium
T2D-Genes Consortium
MAGIC Investigators
Publication Date
2019-03Journal Title
Nat Genet
ISSN
1061-4036
Publisher
Springer Science and Business Media LLC
Volume
51
Issue
3
Pages
452-469
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Justice, A. E., Karaderi, T., Highland, H. M., Young, K. L., Graff, M., Lu, Y., Turcot, V., et al. (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.. Nat Genet, 51 (3), 452-469. https://doi.org/10.1038/s41588-018-0334-2
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.
Keywords
CHD Exome+ Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, InterAct, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Animals, Humans, Drosophila, Genetic Predisposition to Disease, Lipids, Proteins, Body Mass Index, Waist-Hip Ratio, Risk Factors, Case-Control Studies, Homeostasis, Gene Frequency, Female, Male, Body Fat Distribution, Genetic Variation, Genome-Wide Association Study, Exome
Sponsorship
Cancer Research UK (16565)
Medical Research Council (MC_UU_12015/1)
European Commission (37197)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
British Heart Foundation (None)
British Heart Foundation (None)
Medical Research Council (MR/S003746/1)
Medical Research Council (MC_UU_12015/2)
Identifiers
External DOI: https://doi.org/10.1038/s41588-018-0334-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290292
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