Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
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Version: Author's accepted manuscript
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State: Public
Version: Author's accepted manuscript
License: Not specified
Serval ID
serval:BIB_37FAA1DECECC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.
Journal
Nature genetics
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
50
Number
1
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
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
Pubmed
Web of science
Create date
13/01/2018 12:40
Last modification date
30/04/2021 7:09