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.
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Change history
03 June 2019
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
16 March 2018
A Correction to this paper has been published: https://doi.org/10.1038/s41588-018-0050-y
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Acknowledgements
A.P.R. was supported by R01DK089256. A.W.H. is supported by an NHMRC Practitioner Fellowship (APP1103329). A.K.M. received funding from NIH/NIDDK K01DK107836. A.T.H. is a Wellcome Trust Senior Investigator (WT098395) and an NIH Research Senior Investigator. A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (WT098017). A.R.W. is supported by the European Research Council (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). A.U.J. is supported by the American Heart Association (13POST16500011) and the NIH (R01DK089256, R01DK101855, K99HL130580). B.K. and E.K.S. were supported by the Doris Duke Medical Foundation, the NIH (R01DK106621), the University of Michigan Internal Medicine Department, Division of Gastroenterology, the University of Michigan Biological Sciences Scholars Program and the Central Society for Clinical Research. C.J.W. is supported by the NIH (HL094535, HL109946). D.J.L. is supported by R01HG008983 and R21DA040177. D.R.W. is supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. V. Salomaa has been supported by the Finnish Foundation for Cardiovascular Research. F.W.A. is supported by Dekker scholarship–Junior Staff Member 2014T001 Netherlands Heart Foundation and the UCL Hospitals NIHR Biomedical Research Centre. F.D. is supported by the UK MRC (MC_UU_12013/1-9). G.C.-P. received scholarship support from the University of Queensland and QIMR Berghofer. G.L. is funded by the Montreal Heart Institute Foundation and the Canada Research Chair program. H.Y. and T.M.F. are supported by the European Research Council (323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). I.M.H. is supported by BMBF (01ER1206) and BMBF (01ER1507m), the NIH and the Max Planck Society. J. Haessler was supported by NHLBI R21HL121422. J.N.H. is supported by NIH R01DK075787. K.E.N. was supported by the NIH (R01DK089256, R01HD057194, U01HG007416, R01DK101855) and the American Heart Association (13GRNT16490017). M.A.R. is supported by the Nuffield Department of Clinical Medicine Award, Clarendon Scholarship. M.I.M. is a Wellcome Trust Senior Investigator (WT098381) and an NIH Research Senior Investigator. M.D. is supported by the NCI (R25CA94880, P30CA008748). P.R.N. is supported by the European Research Council (AdG; 293574), the Research Council of Norway, the University of Bergen, the KG Jebsen Foundation and the Helse Vest, Norwegian Diabetes Association. P.T.E. is supported by the NIH (1R01HL092577, R01HL128914, K24HL105780), by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Foundation Leducq (14CVD01). P.L.A. was supported by NHLBI R21HL121422 and R01DK089256. P.L.H. is supported by the NIH (NS33335, HL57818). R.S.F. is supported by the NIH (T32GM096911). R.J.F.L. is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). S.A.L. is supported by the NIH (K23HL114724) and a Doris Duke Charitable Foundation Clinical Scientist Development Award. T.D.S. holds an ERC Advanced Principal Investigator award. T.A.M. is supported by an NHMRC Fellowship (APP1042255). T.H.P. received Lundbeck Foundation and Benzon Foundation support. V.T. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR). Z.K. is supported by the Leenaards Foundation, the Swiss National Science Foundation (31003A-143914) and SystemsX.ch (51RTP0_151019). Part of this work was conducted using the UK Biobank resource (project numbers 1251 and 9072). A full list of acknowledgments appears in the Supplementary Note.
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Writing group (wrote and edited the manuscript): A.E.J., A.E.L., C.M.L., C.S., G.L., H.M.H., J.N.H., K.E.N., K.L.Y., M.F.F., M. Graff, P.D., R.J.F.L., T.M.F., V.T., Y. Lu. Data preparation group (program development and quality control of data from contributing cohorts for meta-analyses): A.E.J., A.E.L., C.M.-G., C.S., D.J.L., E.M., H.M.H., I.B.B., K.L.Y., K.E.S., K.S.L., M.A.R., M.C.Y.N., M. Graff, N.G.D.M., P. Mudgal, R.J.F.L., S. Feng, S.M.W., S.S., S.V., T.A., T.E., T. Karaderi, T.W.W., V.T., X.Z., Y. Lu. BMI meta-analyses (discovery and follow-up, single variant and gene based): A.E.J., C.S., C.-T.L., D.J.L., H.M.H., I.B.B., J.N.H., K.L.Y., R.J.F.L., T.M.F., V.T., Y. Lu. Childhood data (analyses and interpretation): A.E.H., G.M., H.H., I. Barroso, I.S.F., J.P.B., S.F.A.G., V.M. Pleiotropy working group: A.M., C.J.W., C.M.L., D.J.L., E.M., F.D., G.A., G.M., G.M.P., H. Kitajima, H.M.H., J.C.F., J.P.C., J.R.B.P., J.W., K.S.R., M. Boehnke, M.I.M., P.B.M., P.D., R.J.F.L., S. Kathiresan, S.M.W., S.W., T.F.V., X.S. Phenome-wide association studies: A.G., A.M., J.C.D., L. Bastarache, M.I.M., T.L.E. Gene set enrichment analyses: D.L., J.N.H., R.S.F., S.B., T.H.P., Z.K. Monogenic and syndromic gene enrichment analyses: A.K.M., H.M.H. Fly obesity screen: A. Lempradl, J.A. Pospisilik. Oversight of contributing studies: A. Linneberg, A. Peters, A. Tönjes, A.C.H., A.D.M., A.G.U., A.I.d.H., A.J.L., A.M.D., A.P.M., A.P.R., A.S.B., A.T.H., A.W.H., B.B., B.G.N., C.A.B., C.C., C.E.P., C.H., C.J.W., C.L., C.M.L., C.N.A.P., D.F.E., D.F.R., D.I.C., D.M.W., D.O.M.-K., D.R.N., D.R.W., D.S., D.W.B., E.B., E.B.L., E.D.A., E.F., E.I., E.K.S., E.P.B., E.Z., F. Karpe, F. Kee, F. Renström, F.W.A., G. Dedoussis, G. Tromp, G.B., G.B.J., G.K.H., G.L., G.P., G.P.J., G.W.M., H. Kuivaniemi, H.B., H.D.W., H.H., H.-J.G., H.M.d.R., H.R.W., I. Barroso, I. Brandslund, I.B.B., I.F., I.J.D., I.M.H., I.R., I.S.F., J. Kaprio, J.C.C., J.-C.T., J.D., J.D.R., J.F., J.G.W., J.I.R., J.M.M.H., J.M.S., J.R.O’C., J.S.K., J.T., K. Stefansson, K. Strauch, K.E.N., K.K., K.K.A., K.L.M., K.M.H., K.N., K.R.O., K.T.Z., L.E.W., L.L., L.W., M. Blüher, M. Kähönen, M.A.I., M.A.R., M.B.S., M.C.H.d.G., M.d.H., M.E.J., M.F., M.H.B., M.I.M., M.L.O’D., M.M., M.P., M.-P.D., M.S., M.U., M.V., M.W., N.D.P., N.J.S., N.J.W., N.S., N.v.L., O. Pedersen, O. Polasek, O.T.R., P. Kovacs, P.A., P.A.P., P.B.M., P.D., P.E., P.G., P.G.-L., P.J.S., P.L.A., P.L.H., P.L.P., P.M.R., P.R.N., P.T.C., P.W.F., R.A.O., R.A.S., R.C., R.E.S., R.J.F.L., R.V., S. Fauser, S. Kathiresan, S.E.M., S.F.A.G., S.J., S.L.R.K., S.M., S.P., S.H.S., T.A.M., T.B.H., T.D.S., T.E., T.H., T.J., T.L., T.L.E., T.M.F., U.T., V. Gudnason, V. Salomaa, V.V., W.H.-H.S., X.G., X.L., Y. Liu. Genotyping of contributing studies: A. Loukola, A.T.-H., A.S.B., A.D’E., A.G.U., A.I.d.H., A.J.L., A.L.M., A.M., A.M.D., A.P.G., A.P.M., A.P.R., A.R.H., A.S.B., A.V., A.W.H., A.Y.C., B.G.N., C.A.B., C.E.P., C.H., C.J.P., C.K., C.L., C.M., C.M.-G., C.M.L., C.M.v.D., C.N.A.P., C.S., D.F.R., D.I.C., D.J.C., D.J.R., D.M.W., D.R.N., E.D.A., E.E., E.I., E.K., E.M.L., E.P.B., E.W.D., F. Karpe, F. Rivadeneira, F.S.C., G. Davies, G. Tromp, G.P.J., G.W.M., H. Kuivaniemi, H.H., H.L.G., H. Li, H.V., I.G., J. Kuusisto, J.A. Perry, J.B.-J., J.C.C., J.D., J.D.F., J.G.D., J.I.R., J.M.M.H., J.S.K., J.T., K. Strauch, K.D.T., K.E.S., K.M., L. Milani, L. Southam, L.A.L., L.A.K., L.M.Y.-A., L.-P.L., M. Benn, M. Boehnke, M. Gorski, M. Kähönen, M.B.S., M.C.H.d.G., M.F., M.H.B., M.I.M., M.L., M.L.B., M.L.G., M.L.O’D., M.M.-N., M.-P.D., M.P.S.-L., N.D.P., N.G., N.J.S., N.J.W., N.v.L., Ø.H., P.B.M., P.G.-L., P.I.W.d.B., P.T.C., P.W.F., R.A.O., R.A.S., R.E.S., R.F.-S., R.J.F.L., R.L.-G., R.R., R.Y., S. Kanoni, S. Kathiresan, S.C., S.F.A.G., S.F.N., S.H.V., S.L.R.K., S.S., S.W.v.d.L., T.A.L., T.B.H., T.E., T.H., T.L., U.V., V.V., Wei Zhao, X.L., Y. Lu, Y.-D.I.C., Y.H., Y. Liu, Y. Wang. Phenotyping of contributing studies: A.A.B., A.-E.F., A.F., A.J. Swift, A. Pattie, A. Peters, A.R.H., A. Robino, A.S.B., A.T.H., A. Tönjes, A.T.-H., A.U.J., A.V., A.W.H., B.B., B.G.N., B.H.T., B.K., C.A.B., C.E.L., C.E.P., C.H., C.J.P., C.K., C.M., C.M.-G., C.M.L., C.N.A.P., C.S., D.E., D.F.R., D.I.C., D.J.R., D.R.N., D.R.V.E., D.R.W., E.C., E.D.A., E.E., E.F., E.I., E.P.B., E.R.B.P., E.T., E.W.D., F. Karpe, F. Kee, F. Renström, F. Rivadeneira, F.W., G.B.J., G.L., G.P.J., G. Tromp, G.W.M., H.B., H.D.W., H.H., H.L.G., H. Li, I.J.D., I.R., J.C., J.C.C., J.D., J.D.F., J.F., J.-H.J., J. Kaprio, J. Lindström, J.M.M.H., J.M.S., J.P.B., J.S.K., K.E.N., K.-H.L., K.K., K.K.A., K.M.H., K.N., K.R.O., K.S.L., K.S.S., K.T.Z., L.A.K., L.E.B., L.E.W., L.L., L.M.Y.-A., L. Southam, L. Sun, L.W., M.A., M.A.I., M. Blüher, M. Brumat, M.C.H.d.G., M.F.F., M.I.M., M.J.C., M. Kähönen, M. Karaleftheri, M.L.B., M.M., M.M.-N., M.N., M.R., M.S., N.D.P., N.F., N.G., N.J.S., N.J.W., N.N., N.R.L., Ø.H., O.H.F., O.L.H., O. Polasek, O.R., O.T.R., P.A., P.G.-L., P. Komulainen, P. Kovacs, P.L.P., P.M.R., P. Mitchell, P.R.K., P.R.N., P.T.C., P.T.E., R.d.M., R.E.S., R.F.-S., R.M.-C., R.R., R.S.K., R.V., R.Y., S.A.L., S.E.M., S.F.A.G., S. Fauser, S.H.S., S.H.V., S.L.R.K., S.M., S.S., S.T., T.A.L., T.A.M., T.B.H., T.D.S., T.E.G., T.J., T.J.P., T.L., T.L.E., T.N.P., V. Giedraitis, V. Salomaa, V.T., W.H.-H.S., X.L., X.S., Y. Liu, Y. Lu. Data analysis of contributing studies: A.E.H., A.E.J., A.E.L., A.G., A.J.C., A.J. Slater, A. Lophatananon, A.M., A.P.M., A.P.P., A. Pirie, A.R.W., A. Rasheed, A. Robino, A.S.B., A. Teumer, A.V.S., A.Y.C., B.K., C.A.B., C.A.W., C.H., C.M.-G., C.P.N., C.S., C.T.H., C.-T.L., D.F.R., D.I.C., D.J.T., D.M.W., D.S.A., D.S.C., D.V., E.B.W., E.E., F. Rivadeneira, G.C.-P., G. Davies, G.L., G.M., G. Thorleifsson, G. Tromp, G.V., H. Li, H. Lin, H.M.S., H.P., H.R.W., H.T., H.Y., I.F., I.G., J.A. Perry, J.B.-J., J.C.C., J.C.G., J.E.H., J.G., J.G.D., J.H.Z., J. Haessler, J. Hernesniemi, J.I.R., J. Kuusisto, J. Li, J. Luan, J.M.M.H., J.P.B., J.P.T., J.R.O’C., J.S.K., J.v.S., J.W.J., J.Y., K.E.N., K.E.S., K.E.T., K.L.Y., K.M., K.S.L., L.-A.L., L.A.L., L. Broer, L.F.B., L.H., L.M.O.L., L.M.Y.-A., L. Moilanen, L.-P.L., L. Southam, M.A.N., M.C., M.C.H.d.G., M.C.Y.N., M.D., M.F., M.F.F., M. Gorski, M. Graff, M.L., M.P.S.-L., M.R., M.U., M.V., N.D.P., N.G., N.G.D.M., N.J.S., N.L.H.-C., N.R.R., N.v.L., Ø.H., P.L.A., P. Mudgal, P.S., P.Y., R.A.S., R.C., R.L.-G., R.U., R.Y., S.A.L., S.E.A., S.G., S.J., S.M., S.M.W., S.P., S.S., S.V., S.W.v.d.L., T.E., T. Karaderi, T. Korhonen, T.L.E., T.M.F., T.V.V., T.W.W., V.M., V. Steinthorsdottir, V.T., V.V., W.G., W. Zhang, W. Zhou, Wei Zhao, X.G., X.L., X.S., Y.H., Y.J., Y. Lu, Y.S., Y. Wu.
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G. Thorleifsson, V. Steinthorsdottir, U.T. and K. Stefansson are employed by deCODE Genetics/Amgen, Inc.I. Barroso and spouse own stock in GlaxoSmithKline and Incyte, Ltd.S. Kathiresan has received grant support from Bayer Healthcare and Amarin; holds equity in San Therapeutics and Catabasis; and has received personal fees for participation in scientific advisory boards for Bayer Healthcare, Catabasis, Regeneron Genetics Center, Merck, Celera, Genomics PLC, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly Company, Leerink Partners, Noble Insights and Ionis Pharmaceuticals. A.Y.C., D.F.R. and T.F.V. are employees of Merck Sharp Dohme Corp., New Jersey, USA. D.I.C. receives genotyping and collaborative scientific support from Amgen and receives support for genetic analysis from AstraZeneca. P.M.R. receives genotyping and collaborative scientific support from Amgen and receives support for genetic analysis from AstraZeneca. M.J.C. is Chief Scientist for Genomics England, a UK government company.
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Turcot, V., Lu, Y., Highland, H.M. et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 50, 26–41 (2018). https://doi.org/10.1038/s41588-017-0011-x
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DOI: https://doi.org/10.1038/s41588-017-0011-x
