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

CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetics Consortium, GoT2D Genes Consortium, EPIC-InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, The MAGIC Investigators, Understanding Society Scientific Group, Valérie Turcot, Yingchang Lu, Heather M Highland, Claudia Schurmann, Anne E Justice, Rebecca S Fine, Jonathan P Bradfield, Tõnu Esko, Ayush GiriMariaelisa Graff, Xiuqing Guo, Audrey E Hendricks, Tugce Karaderi, Adelheid Lempradl, Adam E Locke, Anubha Mahajan, Eirini Marouli, Suthesh Sivapalaratnam, Kristin L Young, Tamuno Alfred, Mary F Feitosa, Nicholas G D Masca, Alisa K Manning, Carolina Medina-Gomez, Poorva Mudgal, Maggie C Y Ng, Alex P Reiner, Sailaja Vedantam, Sara M Willems, Thomas W Winkler, Gonçalo Abecasis, Linda Broer, Rajiv Chowdhury, Amanda J Cox, Paul I W Bakker, Mark C H Groot, Anneke I Hollander, Torben Hansen, Yongmei Liu, Roel A Ophoff, John R B Perry, Tinca J Polderman, Alexander Teumer, André G Uitterlinden, Sander W Laan, Cornelia M Duijn, Jing Hua Zhao, Wei Zhao, Fernando Rivadeneira, Ingrid B. Borecki, Panos Deloukas, Timothy Frayling, Guillaume Lettre, Kari E. North, Cecilia M. Lindgren, Joel N. Hirschorn*, Ruth J.F. Loos*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

243 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)26-41
Number of pages16
JournalNature Genetics
Volume50
Issue number1
DOIs
Publication statusPublished - Jan 2018

Research programs

  • EMC MM-01-39-09-A
  • EMC MM-03-86-01
  • EMC NIHES-01-64-02
  • EMC NIHES-02-65-02
  • EMC NIHES-03-30-02

Fingerprint

Dive into the research topics of 'Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity'. Together they form a unique fingerprint.

Cite this