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, MCY; 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.I.; Chowdhury, R.; Christensen, C.; Chu, A.Y.; Collins, F.S.; Cook, J.P.; Cox, A.J.; Crosslin, D.S.; Danesh, J.; de Bakker, PIW; 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, JMM; 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, SLR; 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, NGD; 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, JRB; 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, KMA; 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.; 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, RJF; North, K.E.; Lindgren, C.M.

doi:10.1038/s41588-018-0334-2

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

Details

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Serval ID

serval:BIB_3FE73F14651D

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Nature genetics

Author(s)

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 MCY, 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.I., Chowdhury R., Christensen C., Chu A.Y., Collins F.S., Cook J.P., Cox A.J., Crosslin D.S., Danesh J., de Bakker PIW, 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 JMM, 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 SLR, 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 NGD, 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 JRB, 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 KMA, 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., 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 RJF, North K.E., Lindgren C.M.

Working group(s)

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

ISSN

1546-1718 (Electronic)

ISSN-L

1061-4036

Publication state

Published

Issued date

03/2019

Peer-reviewed

Oui

Volume

Number

Pages

452-469

Language

english

Notes

Publication types: Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

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

Animals, Body Fat Distribution/methods, Body Mass Index, Case-Control Studies, Drosophila/genetics, Exome/genetics, Female, Gene Frequency/genetics, Genetic Predisposition to Disease/genetics, Genetic Variation/genetics, Genome-Wide Association Study/methods, Homeostasis/genetics, Humans, Lipids/genetics, Male, Proteins/genetics, Risk Factors, Waist-Hip Ratio/methods

URN

urn:nbn:ch:serval-BIB_3FE73F14651D2

OAI-PMH

oai:serval.unil.ch:BIB_3FE73F14651D

DOI

10.1038/s41588-018-0334-2

Pubmed

30778226

Web of science

000459947200014

Create date

28/02/2019 14:52