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

CHD Exome+ Consortium; EPIC-CVD Consortium; ExomeBP Consortium; Global Lipids Genetics Consortium; GoT2D Genes Consortium; EPIC-InterAct Consortium; INTERVAL Study; ReproGen Consortium; T2D-Genes Consortium; The MAGIC Investigators; Understanding Society Scientific Group; 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; Linda Broer; Rajiv Chowdhury; Amanda J Cox; Paul I W Bakker; Mark C H Groot; Anneke I Hollander; Torben Hansen; Yongmei Liu; Roel A Ophoff; John R B Perry; Tinca J Polderman; Alexander Teumer; André G Uitterlinden; Sander W Laan; Cornelia M Duijn; Jing Hua Zhao; Wei Zhao; Fernando Rivadeneira; Ingrid B. Borecki; Panos Deloukas; Timothy Frayling; Guillaume Lettre; Kari E. North; Cecilia M. Lindgren; Joel N. Hirschorn; Ruth J.F. Loos

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

CHD Exome+ Consortium
, EPIC-CVD Consortium
, ExomeBP Consortium
, Global Lipids Genetics Consortium
, GoT2D Genes Consortium
, EPIC-InterAct Consortium
, INTERVAL Study
, ReproGen Consortium
, T2D-Genes Consortium
, The MAGIC Investigators
, Understanding Society Scientific Group
, 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, Linda Broer, Rajiv Chowdhury, Amanda J Cox, Paul I W Bakker, Mark C H Groot, Anneke I Hollander, Torben Hansen, Yongmei Liu, Roel A Ophoff, John R B Perry, Tinca J Polderman, Alexander Teumer, André G Uitterlinden, Sander W Laan, Cornelia M Duijn, Jing Hua Zhao, Wei Zhao, Fernando Rivadeneira, Ingrid B. Borecki, Panos Deloukas, Timothy Frayling, Guillaume Lettre, Kari E. North, Cecilia M. Lindgren, Joel N. Hirschorn^*, Ruth J.F. Loos^*

^*Corresponding author for this work

Montreal Heart Institute
Vanderbilt University School of Medicine
University of North Carolina at Chapel Hill
Charles Bronfman Institute for Personalized Medicine
Broad Institute of MIT and Harvard
Center for Applied Genomics (Philadelphia)
Vanderbilt University
The Institute for Translational Genomics and Population Sciences
Wellcome Trust Sanger Institute
University of Oxford
Max Planck Institute of Immunobiology and Epigenetics
University of Michigan, Ann Arbor
Queen Mary University of London
Department of Vascular Medicine
University of Washington School of Medicine
University of Leicester
Wake Forest University School of Medicine
Washington College of Law, American University, Washington DC, United States of America (Sep 2014-Jan 2015)
University of Cambridge School of Clinical Medicine
University of Regensburg
University of Cambridge
Griffith University Queensland
University Medical Centre Utrecht
Radboud University Medical Center
University of Copenhagen
University of California
Vrije Universiteit Amsterdam
University Medicine Greifswald
University of Pennsylvania
Harvard Medical School
Boston Children's Hospital
Barts and The London School of Medicine and Dentistry
King Abdulaziz University
University of Exeter Medical School
University of Montreal
Icahn School of Medicine at Mount Sinai

Research output: Contribution to journal › Article › Academic › peer-review

335 Citations (Scopus)

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	16
Journal	Nature Genetics
Volume	50
Issue number	1
DOIs	https://doi.org/10.1038/s41588-017-0011-x
Publication status	Published - Jan 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research programs

EMC MM-01-39-09-A
EMC MM-03-86-01
EMC NIHES-01-64-02
EMC NIHES-02-65-02
EMC NIHES-03-30-02

Access to Document

10.1038/s41588-017-0011-x

http://hdl.handle.net/1765/103760

Cite this

CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetics Consortium, GoT2D Genes Consortium, EPIC-InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, The MAGIC Investigators, Understanding Society Scientific Group, Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., Bradfield, J. P., Esko, T., ... Loos, R. J. F. (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{e8214cf204654d6b892749ac07b97f8f,

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 = "\{CHD Exome+ Consortium\} and \{EPIC-CVD Consortium\} and \{ExomeBP Consortium\} and \{Global Lipids Genetics Consortium\} and \{GoT2D Genes Consortium\} and \{EPIC-InterAct Consortium\} and \{INTERVAL Study\} and \{ReproGen Consortium\} and \{T2D-Genes Consortium\} and \{The MAGIC Investigators\} and \{Understanding Society Scientific Group\} and 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 Linda Broer and Rajiv Chowdhury and Cox, \{Amanda J\} and Bakker, \{Paul I W\} and Groot, \{Mark C H\} and Hollander, \{Anneke I\} and Torben Hansen and Yongmei Liu and Ophoff, \{Roel A\} and Perry, \{John R B\} and Polderman, \{Tinca J\} and Alexander Teumer and Uitterlinden, \{Andr{\'e} G\} and Laan, \{Sander W\} and Duijn, \{Cornelia M\} and Zhao, \{Jing Hua\} and Wei Zhao and Fernando Rivadeneira and Borecki, \{Ingrid B.\} and Panos Deloukas and Timothy Frayling and Guillaume Lettre and North, \{Kari E.\} and Lindgren, \{Cecilia M.\} and Hirschorn, \{Joel N.\} and Loos, \{Ruth J.F.\} and Lisette Stolk and Visser, \{Jenny A.\} and \{van Meurs\}, Joyce and Bert Hofman and Joop Laven and \{Franco Duran\}, \{OH (Oscar)\} and Arfan Ikram",

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",

}

CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetics Consortium, GoT2D Genes Consortium, EPIC-InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, The MAGIC Investigators, Understanding Society Scientific Group, 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, Broer, L, Chowdhury, R, Cox, AJ, Bakker, PIW, Groot, MCH, Hollander, AI, Hansen, T, Liu, Y, Ophoff, RA, Perry, JRB, Polderman, TJ, Teumer, A, Uitterlinden, AG, Laan, SW, Duijn, CM, Zhao, JH, Zhao, W, Rivadeneira, F, Borecki, IB, Deloukas, P, Frayling, T, Lettre, G, North, KE, Lindgren, CM, Hirschorn, JN & Loos, RJF 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 - CHD Exome+ Consortium

AU - EPIC-CVD Consortium

AU - ExomeBP Consortium

AU - Global Lipids Genetics Consortium

AU - GoT2D Genes Consortium

AU - EPIC-InterAct Consortium

AU - INTERVAL Study

AU - ReproGen Consortium

AU - T2D-Genes Consortium

AU - The MAGIC Investigators

AU - Understanding Society Scientific Group

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 - Broer, Linda

AU - Chowdhury, Rajiv

AU - Cox, Amanda J

AU - Bakker, Paul I W

AU - Groot, Mark C H

AU - Hollander, Anneke I

AU - Hansen, Torben

AU - Liu, Yongmei

AU - Ophoff, Roel A

AU - Perry, John R B

AU - Polderman, Tinca J

AU - Teumer, Alexander

AU - Uitterlinden, André G

AU - Laan, Sander W

AU - Duijn, Cornelia M

AU - Zhao, Jing Hua

AU - Zhao, Wei

AU - Rivadeneira, Fernando

AU - Borecki, Ingrid B.

AU - Deloukas, Panos

AU - Frayling, Timothy

AU - Lettre, Guillaume

AU - North, Kari E.

AU - Lindgren, Cecilia M.

AU - Hirschorn, Joel N.

AU - Loos, Ruth J.F.

AU - Stolk, Lisette

AU - Visser, Jenny A.

AU - van Meurs, Joyce

AU - Hofman, Bert

AU - Laven, Joop

AU - Franco Duran, OH (Oscar)

AU - Ikram, Arfan

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.

U2 - 10.1038/s41588-017-0011-x

DO - 10.1038/s41588-017-0011-x

M3 - Article

C2 - 29273807

SN - 1061-4036

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

Abstract

UN SDGs

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