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

被引：269

作者：

Turcot, Valerie ^{[1
]}

Lu, Yingchang ^{[2
,3
,4
]}

Highland, Heather M. ^{[5
,6
]}

Schurmann, Claudia ^{[3
,4
]}

Justice, Anne E. ^{[5
]}

Fine, Rebecca S. ^{[7
,8
,9
,10
]}

Bradfield, Jonathan P. ^{[11
,12
]}

Esko, Tonu ^{[7
,9
,10
,13
]}

Giri, Ayush ^{[14
]}

Graff, Mariaelisa ^{[5
]}

Guo, Xiuqing ^{[15
]}

Hendricks, Audrey E. ^{[16
,17
]}

Karaderi, Tugce ^{[18
,19
]}

Lempradl, Adelheid ^{[20
]}

Locke, Adam E. ^{[21
,22
,23
]}

Mahajan, Anubha ^{[18
]}

Marouli, Eirini ^{[24
]}

Sivapalaratnam, Suthesh ^{[25
,26
,27
]}

Young, Kristin L. ^{[5
]}

Alfred, Tamuno ^{[3
]}

Feitosa, Mary F. ^{[28
]}

Masca, Nicholas G. D. ^{[29
,30
]}

Manning, Alisa K. ^{[7
,26
,31
,32
]}

Medina-Gomez, Carolina ^{[33
,34
]}

Mudgal, Poorva ^{[35
]}

Ng, Maggie C. Y. ^{[35
,36
]}

Reiner, Alex P. ^{[37
,38
]}

Vedantam, Sailaja ^{[7
,8
,9
,10
]}

Willems, Sara M. ^{[39
]}

Winkler, Thomas W. ^{[40
]}

Abecasis, Goncalo ^{[21
,22
]}

Aben, Katja K. ^{[41
,42
]}

Alam, Dewan S. ^{[43
]}

Alharthi, Sameer E. ^{[24
,44
]}

Allison, Matthew ^{[45
]}

Amouyel, Philippe ^{[46
,47
,48
]}

Asselbergs, Folkert W. ^{[49
,50
,51
]}

Auer, Paul L. ^{[52
]}

Balkau, Beverley ^{[53
]}

Bang, Lia E. ^{[54
]}

Barroso, Ines ^{[16
,55
,56
]}

Bastarache, Lisa ^{[57
]}

Benn, Marianne ^{[58
,59
]}

Bergmann, Sven ^{[60
,61
]}

Bielak, Lawrence F. ^{[62
]}

Blueher, Matthias ^{[63
,64
]}

Boehnke, Michael ^{[21
,22
]}

Boeing, Heiner ^{[65
]}

Boerwinkle, Eric ^{[4
,6
,67
]}

Boeger, Carsten A. ^{[68
]}

机构：

[1] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada

[2] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Ingram Canc Ctr,Vanderbilt Ep, Nashville, TN 37212 USA

[3] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

[5] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[6] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Univ Texas Sch Publ Hlth, Univ Texas MD Anderson Canc Ctr,UTHealth Grad Sch, Houston, TX 77030 USA

[7] Broad Inst & MIT Harvard, Cambridge, MA 02142 USA

[8] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[9] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[10] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA

[11] Childrens Hosp Philadelphia, Div Human Genet, Ctr Appl Gen, Philadelphia, PA 19104 USA

[12] Quantinuum Res LLC, San Diego, CA USA

[13] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia

[14] Vanderbilt Univ, Dept Med, Div Epidemiol, Inst Med & Publ Hlth,Vanderbilt Genet Inst, Nashville, TN USA

[15] LABioMed Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA USA

[16] Wellcome Trust Sanger Inst, Hinxton, England

[17] Univ Colorado, Dept Math & Stat Sci, Denver, CO 80202 USA

[18] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[19] Eastern Mediterranean Univ, Fac Arts & Sci, Dept Biol Sci, Gazimagusa, Cyprus

[20] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany

[21] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[22] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[23] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO USA

[24] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England

[25] AMC, Dept Vasc Med, Amsterdam, Netherlands

[26] Massachusetts Gen Hosp, Boston, MA 02114 USA

[27] Univ Cambridge, Dept Haematol, Cambridge, England

[28] Washington Univ, Sch Med, Dept Genet, Div Stat Gen, St Louis, MO 63110 USA

[29] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England

[30] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England

[31] Harvard Med Sch, Dept Med, Boston, MA USA

[32] Broad Inst, Med & Populat Genet Program, Cambridge, MA USA

[33] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[34] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[35] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA

[36] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA

[37] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[38] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[39] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England

[40] Univ Regensburg, Dept Genet Epidemiol, Regensburg, Germany

[41] Netherlands Comprehens Canc Org, Utrecht, Netherlands

[42] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands

[43] York Univ, Sch Kinesiol & Hlth Sci, Fac Hlth, Toronto, ON, Canada

[44] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia

[45] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA

[46] INSERM, U1167, Lille, France

[47] Inst Pasteur, U1167, Lille, France

[48] Univ Lille, U1167, RID AGE Risk Factors & Mol Determinants Aging Rel, Lille, France

[49] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[50] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands

来源：

NATURE GENETICS | 2018年 / 50卷 / 01期

基金：

瑞士国家科学基金会; 澳大利亚国家健康与医学研究理事会; 加拿大健康研究院; 英国生物技术与生命科学研究理事会; 英国惠康基金; 欧洲研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; MELANOCORTIN-4 RECEPTOR GENE; DONEPEZIL; 23; MG; FRAMESHIFT MUTATION; GLUCOSE-HOMEOSTASIS; HYPOTHALAMIC AMPK; CODING VARIANTS; BLOOD-PRESSURE; RARE; LOCI;

D O I：

10.1038/s41588-017-0011-x

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 similar to 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 similar to 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.

引用

页码：26 / +

页数：19

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