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

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, P.I.W.; Denus, S.; Mutsert, R.; Dedoussis, G.; Demerath, E.W.; Dennis, J.G.; Denny, J.C.; Angelantonio, E.D.; 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.; Hovingh, G.K.; 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.; O’Connell, J.R.; Owen, K.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, 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, Hanieh; Yao, J.; Yerges-Armstrong, L.M.; Young, R.; Zeggini, E.; Zhan, X.; Zhang, W.; Zhao, J.H.; Zhao, W.; Zheng, H.; Zhou, W.; Zillikens, M.C.; 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.

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

journal contribution

posted on 2024-07-25, 15:48 authored by A.E. Justice, T. Karaderi, H.M. Highland, K.L. Young, M. Graff, Y. Lu, V. Turcot, P.L. Auer, R.S. Fine, X. Guo, C. Schurmann, A. Lempradl, E. Marouli, A. Mahajan, T.W. Winkler, A.E. Locke, C. Medina-Gomez, T. Esko, S. Vedantam, A. Giri, K.S. Lo, T. Alfred, P. Mudgal, M.C.Y. Ng, N.L. Heard-Costa, M.F. Feitosa, A.K. Manning, S.M. Willems, S. Sivapalaratnam, G. Abecasis, D.S. Alam, M. Allison, P. Amouyel, Z. Arzumanyan, B. Balkau, L. Bastarache, S. Bergmann, L.F. Bielak, M. Blüher, M. Boehnke, H. Boeing, E. Boerwinkle, C.A. Böger, J. Bork-Jensen, E.P. Bottinger, D.W. Bowden, I. Brandslund, L. Broer, A.A. Burt, A.S. Butterworth, M.J. Caulfield, G. Cesana, J.C. Chambers, D.I. Chasman, Y.-D.I. Chen, R. Chowdhury, C. Christensen, A.Y. Chu, F.S. Collins, J.P. Cook, A.J. Cox, D.S. Crosslin, J. Danesh, P.I.W. de, S. Denus, R. Mutsert, G. Dedoussis, E.W. Demerath, J.G. Dennis, J.C. Denny, E.D. Angelantonio, M. Dörr, F. Drenos, M.-P. Dubé, A.M. Dunning, D.F. Easton, P. Elliott, E. Evangelou, A.-E. Farmaki, S. Feng, E. Ferrannini, J. Ferrieres, J.C. Florez, M. Fornage, C.S. Fox, P.W. Franks, N. Friedrich, W. Gan, I. Gandin, P. Gasparini, V. Giedraitis, G. Girotto, M. Gorski, H. Grallert, N. Grarup, M.L. Grove, S. Gustafsson, J. Haessler, T. Hansen, A.T. Hattersley, C. Hayward, I.M. Heid, O.L. Holmen, G.K. Hovingh, J.M.M. Howson, Y. Hu, Y.-J. Hung, K. Hveem, M.A. Ikram, E. Ingelsson, A.U. Jackson, G.P. Jarvik, Y. Jia, T. Jørgensen, P. Jousilahti, J.M. Justesen, B. Kahali, M. Karaleftheri, S.L.R. Kardia, F. Karpe, F. Kee, H. Kitajima, P. Komulainen, J.S. Kooner, P. Kovacs, B.K. Krämer, K. Kuulasmaa, J. Kuusisto, M. Laakso, T.A. Lakka, D. Lamparter, L.A. Lange, C. Langenberg, E.B. Larson, N.R. Lee, W.-J. Lee, T. Lehtimäki, C.E. Lewis, H. Li, J. Li, R. Li-Gao, L.-A. Lin, X. Lin, L. Lind, J. Lindström, A. Linneberg, C.-T. Liu, D.J. Liu, J. Luan, L.-P. Lyytikäinen, S. MacGregor, R. Mägi, S. Männistö, G. Marenne, J. Marten, N.G.D. Masca, M.I. McCarthy, K. Meidtner, E. Mihailov, L. Moilanen, M. Moitry, D.O. Mook-Kanamori, A. Morgan, A.P. Morris, M. Müller-Nurasyid, P.B. Munroe, N. Narisu, C.P. Nelson, M. Neville, I. Ntalla, J.R. O’Connell, K.R. Owen, O. Pedersen, G.M. Peloso, C.E. Pennell, M. Perola, J.A. Perry, J.R.B. Perry, T.H. Pers, A. Ewing, O. Polasek, O.T. Raitakari, A. Rasheed, C.K. Raulerson, R. Rauramaa, D.F. Reilly, A.P. Reiner, P.M. Ridker, M.A. Rivas, N.R. Robertson, A. Robino, I. Rudan, K.S. Ruth, D. Saleheen, V. Salomaa, N.J. Samani, P.J. Schreiner, M.B. Schulze, R.A. Scott, M. Segura-Lepe, X. Sim, A.J. Slater, K.S. Small, B.H. Smith, J.A. Smith, L. Southam, T.D. Spector, E.K. Speliotes, K. Stefansson, V. Steinthorsdottir, K.E. Stirrups, K. Strauch, H.M. Stringham, M. Stumvoll, L. Sun, P. Surendran, K.M.A. Swart, J.-C. Tardif, K.D. Taylor, A. Teumer, D.J. Thompson, G. Thorleifsson, U. Thorsteinsdottir, B.H. Thuesen, A. Tönjes, M. Torres, E. Tsafantakis, J. Tuomilehto, A.G. Uitterlinden, M. Uusitupa, C.M. van, M. Vanhala, R. Varma, S.H. Vermeulen, H. Vestergaard, V. Vitart, T.F. Vogt, D. Vuckovic, L.E. Wagenknecht, M. Walker, L. Wallentin, F. Wang, C.A. Wang, S. Wang, N.J. Wareham, H.R. Warren, D.M. Waterworth, J. Wessel, H.D. White, C.J. Willer, J.G. Wilson, A.R. Wood, Y. Wu, Hanieh YaghootkarHanieh Yaghootkar, J. Yao, L.M. Yerges-Armstrong, R. Young, E. Zeggini, X. Zhan, W. Zhang, J.H. Zhao, W. Zhao, H. Zheng, W. Zhou, M.C. Zillikens, F. Rivadeneira, I.B. Borecki, J.A. Pospisilik, P. Deloukas, T.M. Frayling, G. Lettre, K.L. Mohlke, J.I. Rotter, Z. Kutalik, J.N. Hirschhorn, L.A. Cupples, R.J.F. Loos, K.E. North, C.M. Lindgren

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. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

History

School affiliated with

School of Chemistry (Research Outputs)

Publication Title

Nature Genetics

Volume

51

Issue

3

Pages/Article Number

452-469

Publisher

Nature Publishing Group

External DOI

https://www.doi.org/10.1038/s41588-018-0334-2

ISSN

10614036

Date Accepted

2018-12-17

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Keywords

Animals Body Fat Distribution Body Mass Index Case-Control Studies Drosophila Exome Female Gene Frequency Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Homeostasis Humans Lipids Male Proteins Risk Factors Waist-Hip Ratio adiponectin protein lipid ACVR1C gene adipogenesis African angiogenesis ANGPTL4 gene Article bioinformatics body fat distribution body mass bone development coding DAGLB gene DNAH10 gene East Asian European exome expression quantitative trait locus FGFR2 gene gene gene frequency gene knockdown genetic trait genetic variability genotype glucose homeostasis Hispanic human insulin blood level lipid homeostasis meta analysis MLXIPL gene nonhuman phenotype PLXND1 gene priority journal RAPGEF3 gene recessive inheritance RNA splicing RREB1 gene sex difference South Asian TBX15 gene triacylglycerol level waist hip ratio white adipose tissue animal case control study female genetic predisposition genetic variation genetics genome-wide association study homeostasis male procedures risk factor

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

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