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

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Title: Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
Authors: Justice, AE
Karaderi, T
Highland, HM
Young, KL
Graff, M
Lu, Y
Turcot, V
Auer, PL
Fine, RS
Guo, X
Schurmann, C
Lempradl, A
Marouli, E
Mahajan, A
Winkler, TW
Locke, AE
Medina-Gomez, C
Esko, T
Vedantam, S
Giri, A
Lo, KS
Alfred, T
Mudgal, P
Ng, MCY
Heard-Costa, NL
Feitosa, MF
Manning, AK
Willems, SM
Sivapalaratnam, S
Abecasis, G
Alam, DS
Allison, M
Amouyel, P
Arzumanyan, Z
Balkau, B
Bastarache, L
Bergmann, S
Bielak, LF
Blüher, M
Boehnke, M
Boeing, H
Boerwinkle, E
Böger, CA
Bork-Jensen, J
Bottinger, EP
Bowden, DW
Brandslund, I
Broer, L
Burt, AA
Butterworth, AS
Caulfield, MJ
Cesana, G
Chambers, JC
Chasman, DI
Chen, Y-DI
Chowdhury, R
Christensen, C
Chu, AY
Collins, FS
Cook, JP
Cox, AJ
Crosslin, DS
Danesh, J
De Bakker, PIW
Denus, SD
Mutsert, RD
Dedoussis, G
Demerath, EW
Dennis, JG
Denny, JC
Angelantonio, ED
Dörr, M
Drenos, F
Dubé, M-P
Dunning, AM
Easton, DF
Elliott, P
Evangelou, E
Farmaki, A-E
Feng, S
Ferrannini, E
Ferrieres, J
Florez, JC
Fornage, M
Fox, CS
Franks, PW
Friedrich, N
Gan, W
Gandin, I
Gasparini, P
Giedraitis, V
Girotto, G
Gorski, M
Grallert, H
Grarup, N
Grove, ML
Gustafsson, S
Haessler, J
Hansen, T
Hattersley, AT
Hayward, C
Heid, IM
Holmen, OL
Hovingh, GK
Howson, JMM
Hu, Y
Hung, Y-J
Hveem, K
Ikram, MA
Ingelsson, E
Jackson, AU
Jarvik, GP
Jia, Y
Jørgensen, T
Jousilahti, P
Justesen, JM
Kahali, B
Karaleftheri, M
Kardia, SLR
Karpe, F
Kee, F
Kitajima, H
Komulainen, P
Kooner, JS
Kovacs, P
Krämer, BK
Kuulasmaa, K
Kuusisto, J
Laakso, M
Lakka, TA
Lamparter, D
Lange, LA
Langenberg, C
Larson, EB
Lee, NR
Lee, W-J
Lehtimäki, T
Lewis, CE
Li, H
Li, J
Li-Gao, R
Lin, L-A
Lin, X
Lind, L
Lindström, J
Linneberg, A
Liu, C-T
Liu, DJ
Luan, J
Lyytikäinen, L-P
MacGregor, S
Mägi, R
Männistö, S
Marenne, G
Marten, J
Masca, NGD
McCarthy, MI
Meidtner, K
Mihailov, E
Moilanen, L
Moitry, M
Mook-Kanamori, DO
Morgan, A
Morris, AP
Müller-Nurasyid, M
Munroe, PB
Narisu, N
Nelson, CP
Neville, M
Ntalla, I
O'Connell, JR
Owen, KR
Pedersen, O
Peloso, GM
Pennell, CE
Perola, M
Perry, JA
Perry, JRB
Pers, TH
Ewing, A
Polasek, O
Raitakari, OT
Rasheed, A
Raulerson, CK
Rauramaa, R
Reilly, DF
Reiner, AP
Ridker, PM
Rivas, MA
Robertson, NR
Robino, A
Rudan, I
Ruth, KS
Saleheen, D
Salomaa, V
Samani, NJ
Schreiner, PJ
Schulze, MB
Scott, RA
Segura-Lepe, M
Sim, X
Slater, AJ
Small, KS
Smith, BH
Smith, JA
Southam, L
Spector, TD
Speliotes, EK
Stefansson, K
Steinthorsdottir, V
Stirrups, KE
Strauch, K
Stringham, HM
Stumvoll, M
Sun, L
Surendran, P
Swart, KMA
Tardif, J-C
Taylor, KD
Teumer, A
Thompson, DJ
Thorleifsson, G
Thorsteinsdottir, U
Thuesen, BH
Tönjes, A
Torres, M
Tsafantakis, E
Tuomilehto, J
Uitterlinden, AG
Uusitupa, M
Van Duijn, CM
Vanhala, M
Varma, R
Vermeulen, SH
Vestergaard, H
Vitart, V
Vogt, TF
Vuckovic, D
Wagenknecht, LE
Walker, M
Wallentin, L
Wang, F
Wang, CA
Wang, S
Wareham, NJ
Warren, HR
Waterworth, DM
Wessel, J
White, HD
Willer, CJ
Wilson, JG
Wood, AR
Wu, Y
Yaghootkar, H
Yao, J
Yerges-Armstrong, LM
Young, R
Zeggini, E
Zhan, X
Zhang, W
Zhao, JH
Zhao, W
Zheng, H
Zhou, W
Zillikens, MC
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
Rivadeneira, F
Borecki, IB
Pospisilik, JA
Deloukas, P
Frayling, TM
Lettre, G
Mohlke, KL
Rotter, JI
Kutalik, Z
Hirschhorn, JN
Cupples, LA
Loos, RJF
North, KE
Lindgren, CM
Item Type: Journal Article
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.
Issue Date: 1-Mar-2019
Date of Acceptance: 17-Dec-2018
URI: http://hdl.handle.net/10044/1/67523
DOI: https://dx.doi.org/10.1038/s41588-018-0334-2
ISSN: 1061-4036
Publisher: Nature Research
Start Page: 452
End Page: 469
Journal / Book Title: Nature Genetics
Volume: 51
Issue: 3
Copyright Statement: © 2019 Springer Nature Publishing AG
Sponsor/Funder: Home Office
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
UK DRI Ltd
Funder's Grant Number: PG0484
MR/L01632X/1
MR/L01632X/1
MR/L01341X/1
RTJ6219303-1
RDF03
N/A
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
11 Medical And Health Sciences
06 Biological Sciences
Developmental Biology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2019-02-18
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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