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

Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E.; Fine, Rebecca S.; Franks, Paul LU ; Renström, Frida LU and V Varga, Tibor LU (2018) In Nature Genetics 50(1). p.26-35
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... (More)
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. © 2017 The Author(s). (Less)
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organization
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Contribution to journal
publication status
published
subject
in
Nature Genetics
volume
50
issue
1
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85039153797
ISSN
1546-1718
DOI
10.1038/s41588-017-0011-x
language
English
LU publication?
yes
id
7c44c0fc-fda1-475e-8dc7-5c961a231af6
date added to LUP
2018-01-05 10:32:33
date last changed
2018-05-13 04:37:51
@article{7c44c0fc-fda1-475e-8dc7-5c961a231af6,
  abstract     = {Genome-wide association studies (GWAS) have identified &gt;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) &lt;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. © 2017 The Author(s).},
  author       = {Turcot, Valérie and Lu, Yingchang and Highland, Heather M and Schurmann, Claudia and Justice, Anne E. and Fine, Rebecca S. and Franks, Paul and Renström, Frida and V Varga, Tibor},
  issn         = {1546-1718},
  language     = {eng},
  number       = {1},
  pages        = {26--35},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity},
  url          = {http://dx.doi.org/10.1038/s41588-017-0011-x},
  volume       = {50},
  year         = {2018},
}