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
Renström, Frida
V Varga, Tibor

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Publication date

January 2018

DOI

10.1038/s41588-017-0011-x

Publisher

Springer Science and Business Media LLC

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 variant...