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

Accepted version
Peer-reviewed

Change log

Authors

Turcot, Valérie 
Lu, Yingchang 
Highland, Heather M 

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.

Description

Keywords

Adult, Animals, Body Mass Index, Drosophila, Energy Intake, Energy Metabolism, Female, Gene Frequency, Genetic Variation, Humans, Male, Obesity, Proteins, Syndrome

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

50

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_UU_12015/1)
British Heart Foundation (None)
British Heart Foundation (None)
Cancer Research Uk (None)
Medical Research Council (MC_UU_12015/2)
Medical Research Council (MR/P02811X/1)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (116074)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
British Heart Foundation (CH/12/2/29428)
Medical Research Council (MR/P013880/1)
Ume� University (unknown)
NHS Blood and Transplant (NHSBT) (WP12-01)
European Commission (279143)
NHS Blood and Transplant (NHSBT) (11-01-GEN)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Medical Research Council (MR/L003120/1)
European Commission (279233)
European Research Council (268834)
MRC (MR/J015709/1)
MRC (MR/J006602/1)
MRC (MR/J006599/1)
Medical Research Council (MR/M012816/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
British Heart Foundation (RG/16/4/32218)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-25)
Department of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10024)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1516-29)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
MRC (MC_PC_13046)
MRC (MC_PC_13048)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
Medical Research Council (MC_UU_12015/7)
Medical Research Council (MR/S003746/1)
Cancer Research UK (16563)