The University of Southampton
University of Southampton Institutional Repository

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

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
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.
1061-4036
26-41
Turcot, Valérie
083c1e73-4229-48c0-b1fc-b7f2029d6bf9
Lu, Yingchang
58bede2f-02f6-42c9-9eb1-cd1d030144aa
Highland, Heather M.
6c7e9658-11d8-4e28-b562-a36946f5668b
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Griffiths, Helen
a097fdaa-d3d6-49a9-9c69-0e6e5a5d518b
Understanding Society Scientific Group
Turcot, Valérie
083c1e73-4229-48c0-b1fc-b7f2029d6bf9
Lu, Yingchang
58bede2f-02f6-42c9-9eb1-cd1d030144aa
Highland, Heather M.
6c7e9658-11d8-4e28-b562-a36946f5668b
Gibson, Jane
855033a6-38f3-4853-8f60-d7d4561226ae
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Griffiths, Helen
a097fdaa-d3d6-49a9-9c69-0e6e5a5d518b

Turcot, Valérie, Lu, Yingchang and Highland, Heather M. , Understanding Society Scientific Group (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. (doi:10.1038/s41588-017-0011-x).

Record type: 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.

Text
NG-A46594R GIANT ExomeChip BMI - TEXT - REVISION - CLEAN v3 - Accepted Manuscript
Download (1MB)
Text
NG-A46594R GIANT ExomeChip BMI - SUPPLEMENTARY NOTE - REVISION v4
Restricted to Repository staff only
Request a copy
Spreadsheet
NG-A46594R GIANT ExomeChip BMI - SUPPLEMENTARY TABLES - REVISION
Restricted to Repository staff only
Request a copy

More information

Accepted/In Press date: 15 November 2017
e-pub ahead of print date: 22 December 2017
Published date: January 2018

Identifiers

Local EPrints ID: 418903
URI: http://eprints.soton.ac.uk/id/eprint/418903
ISSN: 1061-4036
PURE UUID: 6f651438-52c3-44b2-b319-dee55593ef40
ORCID for Jane Gibson: ORCID iD orcid.org/0000-0002-0973-8285
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305

Catalogue record

Date deposited: 23 Mar 2018 17:31
Last modified: 16 Mar 2024 06:04

Export record

Altmetrics

Contributors

Author: Valérie Turcot
Author: Yingchang Lu
Author: Heather M. Highland
Author: Jane Gibson ORCID iD
Author: Andrew Lotery ORCID iD
Author: Helen Griffiths
Corporate Author: Understanding Society Scientific Group

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×