Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Turcot, V.; Lu, Y.; Highland, H.M.; Schurmann, C.; Justice, A.E.; Fine, R.S.; Bradfield, J.P.; Esko, T.; Giri, A.; Graff, M.; Guo, X.; Hendricks, A.E.; Karaderi, T.; Lempradl, A.; Locke, A.E.; Mahajan, A.; Marouli, E.; Sivapalaratnam, S.; Young, K.L.; Alfred, T.; Feitosa, M.F.; Masca, NGD; Manning, A.K.; Medina-Gomez, C.; Mudgal, P.; Ng, MCY; Reiner, A.P.; Vedantam, S.; Willems, S.M.; Winkler, T.W.; Abecasis, G.; Aben, K.K.; Alam, D.S.; Alharthi, S.E.; Allison, M.; Amouyel, P.; Asselbergs, F.W.; Auer, P.L.; Balkau, B.; Bang, L.E.; Barroso, I.; Bastarache, L.; Benn, M.; Bergmann, S.; Bielak, L.F.; Blüher, M.; Boehnke, M.; Boeing, H.; Boerwinkle, E.; Böger, C.A.; Bork-Jensen, J.; Bots, M.L.; Bottinger, E.P.; Bowden, D.W.; Brandslund, I.; Breen, G.; Brilliant, M.H.; Broer, L.; Brumat, M.; Burt, A.A.; Butterworth, A.S.; Campbell, P.T.; Cappellani, S.; Carey, D.J.; Catamo, E.; Caulfield, M.J.; Chambers, J.C.; Chasman, D.I.; Chen, Y.I.; Chowdhury, R.; Christensen, C.; Chu, A.Y.; Cocca, M.; Collins, F.S.; Cook, J.P.; Corley, J.; Corominas Galbany, J.; Cox, A.J.; Crosslin, D.S.; Cuellar-Partida, G.; D'Eustacchio, A.; Danesh, J.; Davies, G.; Bakker, PIW; Groot, MCH; Mutsert, R.; Deary, I.J.; Dedoussis, G.; Demerath, E.W.; Heijer, M.; Hollander, A.I.; Ruijter, H.M.; Dennis, J.G.; Denny, J.C.; Di Angelantonio, E.; Drenos, F.; Du, M.; Dubé, M.P.; Dunning, A.M.; Easton, D.F.; Edwards, T.L.; Ellinghaus, D.; Ellinor, P.T.; Elliott, P.; Evangelou, E.; Farmaki, A.E.; Farooqi, I.S.; Faul, J.D.; Fauser, S.; Feng, S.; Ferrannini, E.; Ferrieres, J.; Florez, J.C.; Ford, I.; Fornage, M.; Franco, O.H.; Franke, A.; Franks, P.W.; Friedrich, N.; Frikke-Schmidt, R.; Galesloot, T.E.; Gan, W.; Gandin, I.; Gasparini, P.; Gibson, J.; Giedraitis, V.; Gjesing, A.P.; Gordon-Larsen, P.; Gorski, M.; Grabe, H.J.; Grant, SFA; Grarup, N.; Griffiths, H.L.; Grove, M.L.; Gudnason, V.; Gustafsson, S.; Haessler, J.; Hakonarson, H.; Hammerschlag, A.R.; Hansen, T.; Harris, K.M.; Harris, T.B.; Hattersley, A.T.; Have, C.T.; Hayward, C.; He, L.; Heard-Costa, N.L.; Heath, A.C.; Heid, I.M.; Helgeland, Ø.; Hernesniemi, J.; Hewitt, A.W.; Holmen, O.L.; Hovingh, G.K.; Howson, JMM; Hu, Y.; Huang, P.L.; Huffman, J.E.; Ikram, M.A.; Ingelsson, E.; Jackson, A.U.; Jansson, J.H.; Jarvik, G.P.; Jensen, G.B.; Jia, Y.; Johansson, S.; Jørgensen, M.E.; Jørgensen, T.; Jukema, J.W.; Kahali, B.; Kahn, R.S.; Kähönen, M.; Kamstrup, P.R.; Kanoni, S.; Kaprio, J.; Karaleftheri, M.; Kardia, SLR; Karpe, F.; Kathiresan, S.; Kee, F.; Kiemeney, L.A.; Kim, E.; Kitajima, H.; Komulainen, P.; Kooner, J.S.; Kooperberg, C.; Korhonen, T.; Kovacs, P.; Kuivaniemi, H.; Kutalik, Z.; Kuulasmaa, K.; Kuusisto, J.; Laakso, M.; Lakka, T.A.; Lamparter, D.; Lange, E.M.; Lange, L.A.; Langenberg, C.; Larson, E.B.; Lee, N.R.; Lehtimäki, T.; Lewis, C.E.; Li, H.; Li, J.; Li-Gao, R.; Lin, H.; Lin, K.H.; Lin, L.A.; Lin, X.; Lind, L.; Lindström, J.; Linneberg, A.; Liu, C.T.; Liu, D.J.; Liu, Y.; Lo, K.S.; Lophatananon, A.; Lotery, A.J.; Loukola, A.; Luan, J.; Lubitz, S.A.; Lyytikäinen, L.P.; Männistö, S.; Marenne, G.; Mazul, A.L.; McCarthy, M.I.; McKean-Cowdin, R.; Medland, S.E.; Meidtner, K.; Milani, L.; Mistry, V.; Mitchell, P.; Mohlke, K.L.; Moilanen, L.; Moitry, M.; Montgomery, G.W.; Mook-Kanamori, D.O.; Moore, C.; Mori, T.A.; Morris, A.D.; Morris, A.P.; Müller-Nurasyid, M.; Munroe, P.B.; Nalls, M.A.; Narisu, N.; Nelson, C.P.; Neville, M.; Nielsen, S.F.; Nikus, K.; Njølstad, P.R.; Nordestgaard, B.G.; Nyholt, D.R.; O'Connel, J.R.; O'Donoghue, M.L.; Olde Loohuis, L.M.; Ophoff, R.A.; Owen, K.R.; Packard, C.J.; Padmanabhan, S.; Palmer, CNA; Palmer, N.D.; Pasterkamp, G.; Patel, A.P.; Pattie, A.; Pedersen, O.; Peissig, P.L.; Peloso, G.M.; Pennell, C.E.; Perola, M.; Perry, J.A.; Perry, JRB; Pers, T.H.; Person, T.N.; Peters, A.; Petersen, ERB; Peyser, P.A.; Pirie, A.; Polasek, O.; Polderman, T.J.; Puolijoki, H.; Raitakari, O.T.; Rasheed, A.; Rauramaa, R.; Reilly, D.F.; Renström, F.; Rheinberger, M.; Ridker, P.M.; Rioux, J.D.; Rivas, M.A.; Roberts, D.J.; Robertson, N.R.; Robino, A.; Rolandsson, O.; Rudan, I.; Ruth, K.S.; Saleheen, D.; Salomaa, V.; Samani, N.J.; Sapkota, Y.; Sattar, N.; Schoen, R.E.; Schreiner, P.J.; Schulze, M.B.; Scott, R.A.; Segura-Lepe, M.P.; Shah, S.H.; Sheu, W.H.; Sim, X.; Slater, A.J.; Small, K.S.; Smith, A.V.; Southam, L.; Spector, T.D.; Speliotes, E.K.; Starr, J.M.; Stefansson, K.; Steinthorsdottir, V.; Stirrups, K.E.; Strauch, K.; Stringham, H.M.; Stumvoll, M.; Sun, L.; Surendran, P.; Swift, A.J.; Tada, H.; Tansey, K.E.; Tardif, J.C.; Taylor, K.D.; Teumer, A.; Thompson, D.J.; Thorleifsson, G.; Thorsteinsdottir, U.; Thuesen, B.H.; Tönjes, A.; Tromp, G.; Trompet, S.; Tsafantakis, E.; Tuomilehto, J.; Tybjaerg-Hansen, A.; Tyrer, J.P.; Uher, R.; Uitterlinden, A.G.; Uusitupa, M.; Laan, S.W.; Duijn, C.M.; Leeuwen, N.; van Setten, J.; Vanhala, M.; Varbo, A.; Varga, T.V.; Varma, R.; Velez Edwards, D.R.; Vermeulen, S.H.; Veronesi, G.; Vestergaard, H.; Vitart, V.; Vogt, T.F.; Völker, U.; Vuckovic, D.; Wagenknecht, L.E.; Walker, M.; Wallentin, L.; Wang, F.; Wang, C.A.; Wang, S.; Wang, Y.; Ware, E.B.; Wareham, N.J.; Warren, H.R.; Waterworth, D.M.; Wessel, J.; White, H.D.; Willer, C.J.; Wilson, J.G.; Witte, D.R.; Wood, A.R.; Wu, Y.; Yaghootkar, H.; Yao, J.; Yao, P.; Yerges-Armstrong, L.M.; Young, R.; Zeggini, E.; Zhan, X.; Zhang, W.; Zhao, J.H.; Zhao, W.; Zhao, W.; Zhou, W.; Zondervan, K.T.; Rotter, J.I.; Pospisilik, J.A.; Rivadeneira, F.; Borecki, I.B.; Deloukas, P.; Frayling, T.M.; Lettre, G.; North, K.E.; Lindgren, C.M.; Hirschhorn, J.N.; Loos, RJF

doi:10.1038/s41588-017-0011-x

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

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Serval ID

serval:BIB_37FAA1DECECC

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Journal

Nature genetics

Author(s)

Turcot V., Lu Y., Highland H.M., Schurmann C., Justice A.E., Fine R.S., Bradfield J.P., Esko T., Giri A., Graff M., Guo X., Hendricks A.E., Karaderi T., Lempradl A., Locke A.E., Mahajan A., Marouli E., Sivapalaratnam S., Young K.L., Alfred T., Feitosa M.F., Masca NGD, Manning A.K., Medina-Gomez C., Mudgal P., Ng MCY, Reiner A.P., Vedantam S., Willems S.M., Winkler T.W., Abecasis G., Aben K.K., Alam D.S., Alharthi S.E., Allison M., Amouyel P., Asselbergs F.W., Auer P.L., Balkau B., Bang L.E., Barroso I., Bastarache L., Benn M., Bergmann S., Bielak L.F., Blüher M., Boehnke M., Boeing H., Boerwinkle E., Böger C.A., Bork-Jensen J., Bots M.L., Bottinger E.P., Bowden D.W., Brandslund I., Breen G., Brilliant M.H., Broer L., Brumat M., Burt A.A., Butterworth A.S., Campbell P.T., Cappellani S., Carey D.J., Catamo E., Caulfield M.J., Chambers J.C., Chasman D.I., Chen Y.I., Chowdhury R., Christensen C., Chu A.Y., Cocca M., Collins F.S., Cook J.P., Corley J., Corominas Galbany J., Cox A.J., Crosslin D.S., Cuellar-Partida G., D'Eustacchio A., Danesh J., Davies G., Bakker PIW, Groot MCH, Mutsert R., Deary I.J., Dedoussis G., Demerath E.W., Heijer M., Hollander A.I., Ruijter H.M., Dennis J.G., Denny J.C., Di Angelantonio E., Drenos F., Du M., Dubé M.P., Dunning A.M., Easton D.F., Edwards T.L., Ellinghaus D., Ellinor P.T., Elliott P., Evangelou E., Farmaki A.E., Farooqi I.S., Faul J.D., Fauser S., Feng S., Ferrannini E., Ferrieres J., Florez J.C., Ford I., Fornage M., Franco O.H., Franke A., Franks P.W., Friedrich N., Frikke-Schmidt R., Galesloot T.E., Gan W., Gandin I., Gasparini P., Gibson J., Giedraitis V., Gjesing A.P., Gordon-Larsen P., Gorski M., Grabe H.J., Grant SFA, Grarup N., Griffiths H.L., Grove M.L., Gudnason V., Gustafsson S., Haessler J., Hakonarson H., Hammerschlag A.R., Hansen T., Harris K.M., Harris T.B., Hattersley A.T., Have C.T., Hayward C., He L., Heard-Costa N.L., Heath A.C., Heid I.M., Helgeland Ø., Hernesniemi J., Hewitt A.W., Holmen O.L., Hovingh G.K., Howson JMM, Hu Y., Huang P.L., Huffman J.E., Ikram M.A., Ingelsson E., Jackson A.U., Jansson J.H., Jarvik G.P., Jensen G.B., Jia Y., Johansson S., Jørgensen M.E., Jørgensen T., Jukema J.W., Kahali B., Kahn R.S., Kähönen M., Kamstrup P.R., Kanoni S., Kaprio J., Karaleftheri M., Kardia SLR, Karpe F., Kathiresan S., Kee F., Kiemeney L.A., Kim E., Kitajima H., Komulainen P., Kooner J.S., Kooperberg C., Korhonen T., Kovacs P., Kuivaniemi H., Kutalik Z., Kuulasmaa K., Kuusisto J., Laakso M., Lakka T.A., Lamparter D., Lange E.M., Lange L.A., Langenberg C., Larson E.B., Lee N.R., Lehtimäki T., Lewis C.E., Li H., Li J., Li-Gao R., Lin H., Lin K.H., Lin L.A., Lin X., Lind L., Lindström J., Linneberg A., Liu C.T., Liu D.J., Liu Y., Lo K.S., Lophatananon A., Lotery A.J., Loukola A., Luan J., Lubitz S.A., Lyytikäinen L.P., Männistö S., Marenne G., Mazul A.L., McCarthy M.I., McKean-Cowdin R., Medland S.E., Meidtner K., Milani L., Mistry V., Mitchell P., Mohlke K.L., Moilanen L., Moitry M., Montgomery G.W., Mook-Kanamori D.O., Moore C., Mori T.A., Morris A.D., Morris A.P., Müller-Nurasyid M., Munroe P.B., Nalls M.A., Narisu N., Nelson C.P., Neville M., Nielsen S.F., Nikus K., Njølstad P.R., Nordestgaard B.G., Nyholt D.R., O'Connel J.R., O'Donoghue M.L., Olde Loohuis L.M., Ophoff R.A., Owen K.R., Packard C.J., Padmanabhan S., Palmer CNA, Palmer N.D., Pasterkamp G., Patel A.P., Pattie A., Pedersen O., Peissig P.L., Peloso G.M., Pennell C.E., Perola M., Perry J.A., Perry JRB, Pers T.H., Person T.N., Peters A., Petersen ERB, Peyser P.A., Pirie A., Polasek O., Polderman T.J., Puolijoki H., Raitakari O.T., Rasheed A., Rauramaa R., Reilly D.F., Renström F., Rheinberger M., Ridker P.M., Rioux J.D., Rivas M.A., Roberts D.J., Robertson N.R., Robino A., Rolandsson O., Rudan I., Ruth K.S., Saleheen D., Salomaa V., Samani N.J., Sapkota Y., Sattar N., Schoen R.E., Schreiner P.J., Schulze M.B., Scott R.A., Segura-Lepe M.P., Shah S.H., Sheu W.H., Sim X., Slater A.J., Small K.S., Smith A.V., Southam L., Spector T.D., Speliotes E.K., Starr J.M., Stefansson K., Steinthorsdottir V., Stirrups K.E., Strauch K., Stringham H.M., Stumvoll M., Sun L., Surendran P., Swift A.J., Tada H., Tansey K.E., Tardif J.C., Taylor K.D., Teumer A., Thompson D.J., Thorleifsson G., Thorsteinsdottir U., Thuesen B.H., Tönjes A., Tromp G., Trompet S., Tsafantakis E., Tuomilehto J., Tybjaerg-Hansen A., Tyrer J.P., Uher R., Uitterlinden A.G., Uusitupa M., Laan S.W., Duijn C.M., Leeuwen N., van Setten J., Vanhala M., Varbo A., Varga T.V., Varma R., Velez Edwards D.R., Vermeulen S.H., Veronesi G., Vestergaard H., Vitart V., Vogt T.F., Völker U., Vuckovic D., Wagenknecht L.E., Walker M., Wallentin L., Wang F., Wang C.A., Wang S., Wang Y., Ware E.B., Wareham N.J., Warren H.R., Waterworth D.M., Wessel J., White H.D., Willer C.J., Wilson J.G., Witte D.R., Wood A.R., Wu Y., Yaghootkar H., Yao J., Yao P., Yerges-Armstrong L.M., Young R., Zeggini E., Zhan X., Zhang W., Zhao J.H., Zhao W., Zhao W., Zhou W., Zondervan K.T., Rotter J.I., Pospisilik J.A., Rivadeneira F., Borecki I.B., Deloukas P., Frayling T.M., Lettre G., North K.E., Lindgren C.M., Hirschhorn J.N., Loos RJF

Working group(s)

CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group

ISSN

1546-1718 (Electronic)

ISSN-L

1061-4036

Publication state

Published

Issued date

01/2018

Peer-reviewed

Oui

Volume

Number

Pages

26-41

Language

english

Notes

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

Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Keywords

Adult, Animals, Body Mass Index, Drosophila/genetics, Energy Intake/genetics, Energy Metabolism/genetics, Female, Gene Frequency, Genetic Variation, Humans, Male, Obesity/genetics, Proteins/genetics, Syndrome

URN

urn:nbn:ch:serval-BIB_37FAA1DECECC7

OAI-PMH

oai:serval.unil.ch:BIB_37FAA1DECECC

DOI

10.1038/s41588-017-0011-x

Pubmed

29273807

Web of science

000423157400007

Create date

13/01/2018 12:40