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

Valérie Turcot; Yingchang Lu; Heather M. Highland; Claudia Schurmann; Anne E. Justice; Rebecca S. Fine; Jonathan P. Bradfield; Tõnu Esko; Ayush Giri; Mariaelisa Graff; Xiuqing Guo; Audrey E. Hendricks; Tugce Karaderi; Adelheid Lempradl; Adam E. Locke; Anubha Mahajan; Eirini Marouli; Suthesh Sivapalaratnam; Kristin L. Young; Tamuno Alfred; Mary F. Feitosa; Nicholas G.D. Masca; Alisa K. Manning; Carolina Medina-Gomez; Poorva Mudgal; Maggie C.Y. Ng; Alex P. Reiner; Sailaja Vedantam; Sara M. Willems; Thomas W. Winkler; Gonçalo Abecasis; Katja K. Aben; Dewan S. Alam; Sameer E. Alharthi; Matthew Allison; Philippe Amouyel; Folkert W. Asselbergs; Paul L. Auer; Beverley Balkau; Lia E. Bang; Inês Barroso; Lisa Bastarache; Marianne Benn; Sven Bergmann; Lawrence F. Bielak; Matthias Blüher; Michael Boehnke; Heiner Boeing; Anke R. Hammerschlag; Tinca J. Polderman

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

Valérie Turcot
, Yingchang Lu
, Heather M. Highland
, Claudia Schurmann
, Anne E. Justice
, Rebecca S. Fine
, Jonathan P. Bradfield
, Tõnu Esko
, Ayush Giri
, Mariaelisa Graff
, Xiuqing Guo
, Audrey E. Hendricks
, Tugce Karaderi
, Adelheid Lempradl
, Adam E. Locke
, Anubha Mahajan
, Eirini Marouli
, Suthesh Sivapalaratnam
, Kristin L. Young
, Tamuno Alfred

Mary F. Feitosa, Nicholas G.D. Masca, Alisa K. Manning, Carolina Medina-Gomez, Poorva Mudgal, Maggie C.Y. Ng, Alex P. Reiner, Sailaja Vedantam, Sara M. Willems, Thomas W. Winkler, Gonçalo Abecasis, Katja K. Aben, Dewan S. Alam, Sameer E. Alharthi, Matthew Allison, Philippe Amouyel, Folkert W. Asselbergs, Paul L. Auer, Beverley Balkau, Lia E. Bang, Inês Barroso, Lisa Bastarache, Marianne Benn, Sven Bergmann, Lawrence F. Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Anke R. Hammerschlag, Tinca J. Polderman

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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.

Original language	English
Pages (from-to)	26-41
Number of pages	22
Journal	Nature Genetics
Volume	50
Issue number	1
Early online date	22 Dec 2017
DOIs	https://doi.org/10.1038/s41588-017-0011-x
Publication status	Published - Jan 2018

Funding

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.

Funders	Funder number
Nuffield Department of Clinical Medicine
Fondation Leenaards
UCL Hospitals NIHR Biomedical Research Centre
Stiftelsen Kristian Gerhard Jebsen
Norges Forskningsråd
Max-Planck-Gesellschaft
National Institutes of Health
University of Queensland
Fondation Institut de Cardiologie de Montréal
Danish Diabetes Academy
Universitetet i Bergen
Sydäntutkimussäätiö
Canadian Institutes of Health Research
Novo Nordisk Fonden
University of Michigan
Helse Vest
National Heart, Lung, and Blood Institute	R01HL109946, R01HL092577, K24HL105780, K23HL114724, R01HL117078, R00HL130580, R01HL128914, 13GRNT16490017, R21HL121422, T32HL007055, R00HL094535, R01HL057818
National Institute of Child Health and Human Development	R01HD073342
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK107904, R01DK106621, R01DK106236, P30DK020572, R01DK089256, R01DK075787, R01DK107786, K01DK107836, R01DK093757, R01DK072193, R01DK110113, U01DK062370, P30DK063491, R01DK101855
National Center for Advancing Translational Sciences	UL1TR001881, KL2TR001109
European Research Council	SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC
National Human Genome Research Institute	U01HG007416, F31HG009850, R01HG008983, ZIAHG000024, U01HG007417
Medical Research Council	MC_PC_13046, MR/N01104X/2, MC_PC_13048, MR/P013880/1, MC_PC_13040, MR/K026992/1, MR/L01341X/1, MC_UU_12015/2, MC_UU_12015/1, MR/L003120/1, G9521010, MR/K007017/1, G0601966, G0600237, G1001799, MR/K006584/1, MR/L01632X/1, MC_PC_U127561128, MR/P02811X/1, MR/M501633/1, MR/M501633/2
Biotechnology and Biological Sciences Research Council	BB/F019394/1
Doris Duke Medical Foundation	R01DK106621
Diabetesforbundet	K24HL105780, 1R01HL092577, 13EIA14220013, R01HL128914
National Cancer Institute	R25CA094880, P30CA008748, 293574, T32CA009156
Bundesministerium für Bildung und Forschung	01ER1507m, 01ER1206
Canada Research Chairs	323195
National Health and Medical Research Council	454382, APP1103329, 1042255, 1103329
Fondation Leducq	K23HL114724, R01DK110113, T32GM096911, R01DK107786, 14CVD01, U01HG007417
National Institute of Neurological Disorders and Stroke	R01NS033335
Horizon 2020 Framework Programme	669026, 692145
American Heart Association	K99HL130580, R01DK101855, 13POST16500011
National Institute on Drug Abuse	R21DA040177
European Commission	603091
National Institute of General Medical Sciences	T32GM096911
Doris Duke Charitable Foundation	APP1042255
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R01HD057194
UK MRC	MC_UU_12013/1-9
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	31003A-143914, 51RTP0_151019
NIH Office of the Director	S10OD018522
Central Society for Clinical Research	R21DA040177, HL094535, R01HG008983

UN SDGs

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SDG 3 Good Health and Well-being

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10.1038/s41588-017-0011-x

Proteinaltering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesityFinal published version, 2.72 MBLicence: Article 25fa Dutch Copyright Act

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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., ... Polderman, T. J. (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics, 50(1), 26-41. https://doi.org/10.1038/s41588-017-0011-x

@article{f6943b66034f48db9e6dae8ea047329d,

title = "Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity",

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 \textasciitilde{}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 \textasciitilde{}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.",

author = "Val{\'e}rie Turcot and Yingchang Lu and Highland, \{Heather M.\} and Claudia Schurmann and Justice, \{Anne E.\} and Fine, \{Rebecca S.\} and Bradfield, \{Jonathan P.\} and T{\~o}nu Esko and Ayush Giri and Mariaelisa Graff and Xiuqing Guo and Hendricks, \{Audrey E.\} and Tugce Karaderi and Adelheid Lempradl and Locke, \{Adam E.\} and Anubha Mahajan and Eirini Marouli and Suthesh Sivapalaratnam and Young, \{Kristin L.\} and Tamuno Alfred and Feitosa, \{Mary F.\} and Masca, \{Nicholas G.D.\} and Manning, \{Alisa K.\} and Carolina Medina-Gomez and Poorva Mudgal and Ng, \{Maggie C.Y.\} and Reiner, \{Alex P.\} and Sailaja Vedantam and Willems, \{Sara M.\} and Winkler, \{Thomas W.\} and Gon{\c c}alo Abecasis and Aben, \{Katja K.\} and Alam, \{Dewan S.\} and Alharthi, \{Sameer E.\} and Matthew Allison and Philippe Amouyel and Asselbergs, \{Folkert W.\} and Auer, \{Paul L.\} and Beverley Balkau and Bang, \{Lia E.\} and In{\^e}s Barroso and Lisa Bastarache and Marianne Benn and Sven Bergmann and Bielak, \{Lawrence F.\} and Matthias Bl{\"u}her and Michael Boehnke and Heiner Boeing and Hammerschlag, \{Anke R.\} and Polderman, \{Tinca J.\}",

year = "2018",

month = jan,

doi = "10.1038/s41588-017-0011-x",

language = "English",

volume = "50",

pages = "26--41",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

}

Turcot, V, Lu, Y, Highland, HM, Schurmann, C, Justice, AE, Fine, RS, Bradfield, JP, Esko, T, Giri, A, Graff, M, Guo, X, Hendricks, AE, Karaderi, T, Lempradl, A, Locke, AE, Mahajan, A, Marouli, E, Sivapalaratnam, S, Young, KL, Alfred, T, Feitosa, MF, Masca, NGD, Manning, AK, Medina-Gomez, C, Mudgal, P, Ng, MCY, Reiner, AP, Vedantam, S, Willems, SM, Winkler, TW, Abecasis, G, Aben, KK, Alam, DS, Alharthi, SE, Allison, M, Amouyel, P, Asselbergs, FW, Auer, PL, Balkau, B, Bang, LE, Barroso, I, Bastarache, L, Benn, M, Bergmann, S, Bielak, LF, Blüher, M, Boehnke, M, Boeing, H, Hammerschlag, AR & Polderman, TJ 2018, 'Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity', Nature Genetics, vol. 50, no. 1, pp. 26-41. https://doi.org/10.1038/s41588-017-0011-x

TY - JOUR

T1 - Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

AU - Turcot, Valérie

AU - Lu, Yingchang

AU - Highland, Heather M.

AU - Schurmann, Claudia

AU - Justice, Anne E.

AU - Fine, Rebecca S.

AU - Bradfield, Jonathan P.

AU - Esko, Tõnu

AU - Giri, Ayush

AU - Graff, Mariaelisa

AU - Guo, Xiuqing

AU - Hendricks, Audrey E.

AU - Karaderi, Tugce

AU - Lempradl, Adelheid

AU - Locke, Adam E.

AU - Mahajan, Anubha

AU - Marouli, Eirini

AU - Sivapalaratnam, Suthesh

AU - Young, Kristin L.

AU - Alfred, Tamuno

AU - Feitosa, Mary F.

AU - Masca, Nicholas G.D.

AU - Manning, Alisa K.

AU - Medina-Gomez, Carolina

AU - Mudgal, Poorva

AU - Ng, Maggie C.Y.

AU - Reiner, Alex P.

AU - Vedantam, Sailaja

AU - Willems, Sara M.

AU - Winkler, Thomas W.

AU - Abecasis, Gonçalo

AU - Aben, Katja K.

AU - Alam, Dewan S.

AU - Alharthi, Sameer E.

AU - Allison, Matthew

AU - Amouyel, Philippe

AU - Asselbergs, Folkert W.

AU - Auer, Paul L.

AU - Balkau, Beverley

AU - Bang, Lia E.

AU - Barroso, Inês

AU - Bastarache, Lisa

AU - Benn, Marianne

AU - Bergmann, Sven

AU - Bielak, Lawrence F.

AU - Blüher, Matthias

AU - Boehnke, Michael

AU - Boeing, Heiner

AU - Hammerschlag, Anke R.

AU - Polderman, Tinca J.

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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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UR - https://www.scopus.com/pages/publications/85039153797#tab=citedBy

U2 - 10.1038/s41588-017-0011-x

DO - 10.1038/s41588-017-0011-x

M3 - Article

AN - SCOPUS:85039153797

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VL - 50

SP - 26

EP - 41

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

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