Protein-Coding Variants Implicate Novel Genes Related to Lipid Homeostasis Contributing to Body-Fat Distribution

Citation

Justice, Anne E.; Karaderi, Tugce; Highland, Heather M.; Young, Kristin L.; Graff, Mariaelisa; Lu, Yingchang; Turcot, Valerie; Auer, Paul L.; Fine, Rebecca S.; & Guo, Xiuqing, et al. (2019). Protein-Coding Variants Implicate Novel Genes Related to Lipid Homeostasis Contributing to Body-Fat Distribution. Nature Genetics, 51(3), 452-469. PMCID: PMC6560635

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.

URL

http://dx.doi.org/10.1038/s41588-018-0334-2

Reference Type

Journal Article

Year Published

2019

Journal Title

Nature Genetics

Author(s)

Justice, Anne E.
Karaderi, Tugce
Highland, Heather M.
Young, Kristin L.
Graff, Mariaelisa
Lu, Yingchang
Turcot, Valerie
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, Tonu
Vedantam, Sailaja
Giri, Ayush
Lo, Ken Sin
Alfred, Tamuno
Mudgal, Poorva
Ng, Maggie C. Y.
Heard-Costa, Nancy L.
Feitosa, Mary F.
Manning, Alisa K.
Willems, Sara M.
Sivapalaratnam, Suthesh
Abecasis, Gonçalo R.
Alam, Dewan S.
Allison, Matthew A.
Amouyel, Philippe
Arzumanyan, Zorayr
Balkau, Beverley
Bastarache, Lisa
Bergmann, Sven
Bielak, Lawrence F.
Bluher, Matthias
Boehnke, Michael
Boeing, Heiner
Boerwinkle, Eric A.
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 I. W.
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, Jeffrey
Hansen, Torben
Hattersley, Andrew T.
Hayward, Caroline
Heid, Iris M.
Holmen, Oddgeir L.
Hovingh, G. Kees
Howson, Joanna M. M.
Hu, Yao
Hung, Yi-Jen
Hveem, Kristian
Ikram, M. Arfan
Ingelsson, Erik
Jackson, Anne U.
Jarvik, Gail P.
Jia, Yucheng
Jorgensen, Torben
Jousilahti, Pekka
Justesen, Johanne M.
Kahali, Bratati
Karaleftheri, Maria
Kardia, Sharon L. R.
Karpe, Fredrik
Kee, Frank
Kitajima, Hidetoshi
Komulainen, Pirjo
Kooner, Jaspal Singh 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
Lehtimaki, Terho
Lewis, Cora E.
Li, Huaixing
Li, Jin
Li-Gao, Ruifang
Lin, Li-An
Lin, Xu
Lind, Lars
Lindstrom, Jaana
Linneberg, Allan
Liu, Ching-Ti
Liu, Dajiang J.
Luan, Jian'an
Lyytikainen, Leo-Pekka
MacGregor, Stuart
Magi, Reedik
Mannisto, Satu
Marenne, Gaelle
Marten, Jonathan
Masca, Nicholas G. D.
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'Connell, Jeffrey R.
Owen, Katharine R.
Pedersen, Oluf
Peloso, Gina M.
Pennell, Craig E.
Perola, Markus
Perry, James A.
Perry, John R. B.
Pers, Tune H.
Ewing, Ailith
Polasek, Ozren
Raitakari, Olli T.
Rasheed, Asif
Raulerson, Chelsea K.
Rauramaa, Rainer
Reilly, Dermot F.
Reiner, Alexander 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 M. A.
Tardif, Jean-Claude
Taylor, Kent D.
Teumer, Alexander
Thompson, Deborah J.
Thorleifsson, Gudmar
Thorsteinsdottir, Unnur
Thuesen, Betina H.
Tonjes, Anke
Torres, Mina
Tsafantakis, Emmanouil
Tuomilehto, Jaakko
Uitterlinden, Andre G.
Uusitupa, Matti
van Duijn, Cornelia M.
Vanhala, Mauno
Varma, Rohit
Vermeulen, Sita H.
Vestergaard, Henrik
Vitart, Veronique
Vogt, Thomas F.
Vuckovic, 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 D.
Zeggini, Eleftheria
Zhan, Xiaowei
Zhang, Weihua
Zhao, Jing Hua
Zhao, Wei
Zheng, He
Zhou, Wei
Zillikens, M. Carola
CHD Exome+ Consortium,
Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium,
EPIC-CVD Consortium,
ExomeBP Consortium,
Global Lipids Genetics Consortium,
GoT2D Genes Consortium,
InterAct,
ReproGen Consortium,
T2D-Genes Consortium,
MAGIC Investigators,
Rivadeneira, Fernando
Borecki, Ingrid B.
Pospisilik, J. Andrew
Deloukas, Panos
Frayling, Timothy M.
Lettre, Guillaume
Mohlke, Karen L.
Rotter, Jerome I.
Kutalik, Zoltan
Hirschhorn, Joel N.
Cupples, L. Adrienne
Loos, Ruth J. F.
North, Kari E.
Lindgren, Cecilia M.

PMCID

PMC6560635

ORCiD

Highland - 000-0002-3583-8239
Graff - 0000-0001-6380-1735