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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- Source :
- Nature Genetics, 51, 3, pp. 452-469, Nature Genetics, 51, 452-469, Nature genetics, 51(3), 452-469. Nature Publishing Group, Nature Genetics, Nature genetics, Nature Genetics, 51(3), 452-469. Nature Publishing Group, Nature genetics, vol. 51, no. 3, pp. 452-469, Nat. Genet. 51, 452–469 (2019), Justice, A E, Karaderi, T, Highland, H M, Young, K L, Graff, M, Lu, Y, Turcot, V, Auer, P L, Fine, R S, Guo, X, Schurmann, C, Lempradl, A, Marouli, E, Mahajan, A, Winkler, T W, Locke, A E, Medina-Gomez, C, Esko, T N, Vedantam, S, Giri, A, Lo, K S, Alfred, T, Mudgal, P, Ng, M C Y, Heard-Costa, N L, Feitosa, M F, Manning, A K, Willems, S M, Sivapalaratnam, S, Abecasis, G, Alam, D S, Allison, M, Amouyel, P, Arzumanyan, Z, Balkau, B, Bastarache, L, Bergmann, S, Bielak, L F, Blüher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Böger, C A, Bork-Jensen, J, Bottinger, E P, Bowden, D W, Brandslund, I, Li, J, Swart, K M A, Vermeulen, S H, CHD Exome+ Consortium, Frayling, T M, Lettre, G, Mohlke, K L, Rotter, J I, Kutalik, Z, Hirschhorn, J N, Cupples, L A, Loos, R J F, North, K E & Lindgren, C M 2019, ' Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution ', Nature Genetics, vol. 51, pp. 452–469 . https://doi.org/10.1038/s41588-018-0334-2, Justice, A E, Karaderi, T, Highland, H M, Young, K L, Graff, M, Lu, Y, Turcot, V, Auer, P L, Fine, R S, Guo, X, Schurmann, C, Lempradl, A, Marouli, E, Mahajan, A, Winkler, T W, Locke, A E, Medina-Gomez, C, Esko, T, Vedantam, S, Giri, A, Lo, K S, Alfred, T, Mudgal, P, Ng, M C Y, Heard-Costa, N L, Feitosa, M F, Manning, A K, Willems, S M, Sivapalaratnam, S, Abecasis, G, Alam, D S, Allison, M, Amouyel, P, Arzumanyan, Z, Balkau, B, Bastarache, L, Bergmann, S, Bielak, L F, Blüher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Böger, C A, Bork-Jensen, J, Bottinger, E P, Bowden, D W, Brandslund, I, Broer, L, Burt, A A, Butterworth, A S, Caulfield, M J, Cesana, G, Chambers, J C, Chasman, D I, Chen, Y-D I, Chowdhury, R, Christensen, C, Chu, A Y, Collins, F S, Cook, J P, Cox, A J, Crosslin, D S, Danesh, J, de Bakker, P I W, de Denus, S, de Mutsert, R, Dedoussis, G, Demerath, E W, Dennis, J G, Denny, J C, Di Angelantonio, E, Dörr, M, Drenos, F, Dubé, M-P, Dunning, A M, Easton, D F, Elliott, P, Evangelou, E, Farmaki, A-E, Feng, S, Ferrannini, E, Ferrieres, J, Florez, J C, Fornage, M, Fox, C S, Franks, P W, Friedrich, N, Gan, W, Gandin, I, Gasparini, P, Giedraitis, V, Girotto, G, Gorski, M, Grallert, H, Grarup, N, Grove, M L, Gustafsson, S, Haessler, J, Hansen, T, Hattersley, A T, Hayward, C, Heid, I M, Holmen, O L, Kees Hovingh, G, Howson, J M M, Hu, Y, Hung, Y-J, Hveem, K, Ikram, M A, Ingelsson, E, Jackson, A U, Jarvik, G P, Jia, Y, Jørgensen, T, Jousilahti, P, Justesen, J M, Kahali, B, Karaleftheri, M, Kardia, S L R, Karpe, F, Kee, F, Kitajima, H, Komulainen, P, Kooner, J S, Kovacs, P, Krämer, B K, Kuulasmaa, K, Kuusisto, J, Laakso, M, Lakka, T A, Lamparter, D, Lange, L A, Langenberg, C, Larson, E B, Lee, N R, Lee, W-J, Lehtimäki, T, Lewis, C E, Li, H, Li, J, Li-Gao, R, Lin, L-A, Lin, X, Lind, L, Lindström, J, Linneberg, A, Liu, C-T, Liu, D J, Luan, J, Lyytikäinen, L-P, MacGregor, S, Mägi, R, Männistö, S, Marenne, G, Marten, J, Masca, N G D, McCarthy, M I, Meidtner, K, Mihailov, E, Moilanen, L, Moitry, M, Mook-Kanamori, D O, Morgan, A, Morris, A P, Müller-Nurasyid, M, Munroe, P B, Narisu, N, Nelson, C P, Neville, M, Ntalla, I, Owen, K R, O'Connell, J R, Pedersen, O, Peloso, G M, Pennell, C E, Perola, M, Perry, J A, Perry, J R B, Pers, T H, Ewing, A, Polasek, O, Raitakari, O T, Rasheed, A, Raulerson, C K, Rauramaa, R, Reilly, D F, Reiner, A P, Ridker, P M, Rivas, M A, Robertson, N R, Robino, A, Rudan, I, Ruth, K S, Saleheen, D, Salomaa, V, Samani, N J, Schreiner, P J, Schulze, M B, Scott, R A, Segura-Lepe, M, Sim, X, Slater, A J, Small, K S, Smith, B H, Smith, J A, Southam, L, Spector, T D, Speliotes, E K, Stefansson, K, Steinthorsdottir, V, Stirrups, K E, Strauch, K, Stringham, H M, Stumvoll, M, Sun, L, Surendran, P, Swart, K M A, Tardif, J-C, Taylor, K D, Teumer, A, Thompson, D J, Thorleifsson, G, Thorsteinsdottir, U, Thuesen, B H, Tönjes, A, Torres, M, Tsafantakis, E, Tuomilehto, J, Uitterlinden, A G, Uusitupa, M, van Duijn, C M, Vanhala, M, Varma, R, Vermeulen, S H, Vestergaard, H, Vitart, V, Vogt, T F, Vuckovic, D, Wagenknecht, L E, Walker, M, Wallentin, L, Wang, F, Wang, C A, Wang, S, Wareham, N J, Warren, H R, Waterworth, D M, Wessel, J, White, H D, Willer, C J, Wilson, J G, Wood, A R, Wu, Y, Yaghootkar, H, Yao, J, Yerges-Armstrong, L M, Young, R, Zeggini, E, Zhan, X, Zhang, W, Hua Zhao, J, Zhao, W, Zheng, H, Zhou, W, Zillikens, M C, 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, The MAGIC Investigators, Rivadeneira, F, Borecki, I B, Pospisilik, J A, Deloukas, P, Frayling, T M, Lettre, G, Mohlke, K L, Rotter, J I, Kutalik, Z, Hirschhorn, J N, Cupples, L A, Loos, R J F, North, K E & Lindgren, C M 2019, ' Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution ', Nature Genetics, vol. 51, no. 3, pp. 452-469 . https://doi.org/10.1038/s41588-018-0334-2, CHD Exome+ Consortium 2019, ' Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution ', Nature Genetics, vol. 51, no. 3, pp. 452-469 . https://doi.org/10.1038/s41588-018-0334-2, Nature Genetics, 51(3), 452, T2D-Genes Consortium, The MAGIC Investigators, 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 2019, ' Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution ', Nature Genetics, vol. 51, no. 3, pp. 452-469 . https://doi.org/10.1038/s41588-018-0334-2, 2019, ' Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution ', Nature Genetics . https://doi.org/10.1038/s41588-018-0334-2, CHD Exome+ Consortium 2019, ' Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body fat distribution ', Nature Genetics, vol. xx, no. xx, xx, pp. xx . https://doi.org/10.1038/s41588-018-0334-2, Nature Genetics, 51. Nature Publishing Group, Justice, A E, Karaderi, T, Highland, H M, Young, K L, Graff, M, Lu, Y, Turcot, V, Auer, P L, Fine, R S, Guo, X, Schurmann, C, Lempradl, A, Marouli, E, Mahajan, A, Winkler, T W, Locke, A E, Medina-Gomez, C, Esko, T, Vedantam, S, Giri, A, Lo, K S, Alfred, T, Mudgal, P, Ng, M C Y, Heard-Costa, N L, Feitosa, M F, Manning, A K, Willems, S M, Sivapalaratnam, S, Abecasis, G, Alam, D S, Allison, M, Amouyel, P, Arzumanyan, Z, Balkau, B, Bastarache, L, Bergmann, S, Bielak, L F, Blüher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Böger, C A, Bork-Jensen, J, Bottinger, E P, Bowden, D W, Brandslund, I, Christensen, C, Hansen, T, Thuesen, B H & CHD Exome+ Consortium 2019, ' Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution ', Nature Genetics, vol. 51, no. 3, pp. 452-469 . https://doi.org/10.1038/s41588-018-0334-2
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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 9 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.<br />Editorial summary: A trans-ethnic exome-wide association study for body fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.
- Subjects :
- Exome/genetics
Male
ReproGen Consortium
Adipose tissue
Genome-wide association study
Type 2 diabetes
White adipose tissue
Body Mass Index
Animals
Body Fat Distribution
Case-Control Studies
Drosophila
Exome
Female
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Homeostasis
Humans
Lipids
Proteins
Risk Factors
Waist-Hip Ratio
0302 clinical medicine
Hyperlipidemia
Body fat distribution
2. Zero hunger
Genetics
0303 health sciences
INSULIN-RESISTANCE
ADIPOCYTE DIFFERENTIATION
CHD Exome+ Consortium
Genetic Predisposition to Disease/genetics
Drosophila/genetics
RS11209026 POLYMORPHISM
KINASE 7
1184 Genetics, developmental biology, physiology
T2D-Genes Consortium
11 Medical And Health Sciences
Body Fat Distribution/methods
RECEPTOR ALK7
ADIPOSE-TISSUE
Gene Frequency/genetics
Genetic Variation/genetics
InterAct
Urological cancers Radboud Institute for Health Sciences [Radboudumc 15]
genetic association study
RNA splicing
Proteins/genetics
Genome-Wide Association Study/methods
Lipid particle
ExomeBP Consortium
WAIST CIRCUMFERENCE
Waist-Hip Ratio/methods
Biology
EPIC-CVD Consortium
Article
MAGIC Investigators
03 medical and health sciences
Homeostasis/genetics
Lipids/genetics
All institutes and research themes of the Radboud University Medical Center
medicine
Global Lipids Genetic Consortium
Risk factor
GENOME-WIDE ASSOCIATION
ABDOMINAL ADIPOSITY
Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
Gene
030304 developmental biology
06 Biological Sciences
medicine.disease
Minor allele frequency
GoT2D Genes Consortium
genetics research
TYPE-2 DIABETES SUSCEPTIBILITY
3111 Biomedicine
Body mass index
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 15461718 and 10614036
- Volume :
- 51
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Nature Genetics
- Accession number :
- edsair.doi.dedup.....223a107b9051e5f9a6274fac650ecff4
- Full Text :
- https://doi.org/10.1038/s41588-018-0334-2