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

Title: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity.
Authors: Turcot, V
Chambers, J
Elliott, P
Evangelou, E
Kooner, J
Zhang, W
Loos, R
Item Type: Journal Article
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.
Issue Date: 22-Dec-2017
Date of Acceptance: 15-Nov-2017
URI: http://hdl.handle.net/10044/1/55169
DOI: https://dx.doi.org/10.1038/s41588-017-0011-x
ISSN: 1061-4036
Publisher: Nature Publishing Group
Start Page: 26
End Page: 41
Journal / Book Title: Nature Genetics
Volume: 50
Copyright Statement: Copyright © 2017, Springer Nature
Sponsor/Funder: British Heart Foundation
Wellcome Trust
Medical Research Council (MRC)
National Institute for Health Research
Home Office
National Institutes of Health
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: SP/04/02
084723/Z/08/Z
G0601966
NF-SI-0611-10136
7370192
1 U01 DK085545-01
MR/L01632X/1
MR/L01341X/1
RTJ6219303-1
RDF03
Keywords: 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
11 Medical And Health Sciences
06 Biological Sciences
Developmental Biology
Publication Status: Published
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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