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

Citation

Turcot, V and Lu, Y and Highland, HM and Schurmann, C and Justice, AE and Hewitt, AW and Loos, RJF, et al, Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity, Nature Genetics, 50, (1) pp. 26-41. ISSN 1061-4036 (2018) [Refereed Article]


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2018 Nature America Inc., part of Springer Nature

DOI: doi:10.1038/s41588-017-0011-x

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Ophthalmology and Optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Hearing, Vision, Speech and Their Disorders
Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:127115
Year Published:2018
Web of Science® Times Cited:14
Deposited By:Menzies Institute for Medical Research
Deposited On:2018-07-11
Last Modified:2018-08-01
Downloads:3 View Download Statistics

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