Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations

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Abstract

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 2080 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes 50 000 cosmopolitan tagged SNPs across 2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P 2.4 10(6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR ( SE, 0.048 0.008, P 7.7 10(9)) as was rs7302703-G in HOXC10 ( 0.044 0.008, P 2.9 10(7)) and rs936108-C in PEMT ( 0.035 0.007, P 1.9 10(6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 ( 0.10 0.02, P 1.9 10(6)) and rs1037575-A in ATBDB4 ( 0.046 0.01, P 2.2 10(6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

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Authors
  • Sachiko Yoneyama
  • Yiran Guo
  • Matthew B. Lanktree
  • Michael R. Barnes
  • Clara C. Elbers
  • Konrad J. Karczewski
  • Sandosh Padmanabhan
  • Florianne Bauer
  • Jens Baumert
  • Amber Beitelshees
  • Gerald S. Berenson
  • Jolanda M. A. Boer
  • Gregory Burke
  • Brian Cade
  • Wei Chen
  • Rhonda M. Cooper-Dehoff
  • Tom R. Gaunt
  • Christian Gieger
  • Yan Gong
  • Mathias Gorski
  • Nancy Heard-Costa
  • Toby Johnson
  • Michael J. Lamonte
  • Caitrin Mcdonough
  • Keri L. Monda
  • N. Charlotte Onland-Moret
  • Christopher P. Nelson
  • Jeffrey R. O'Connell
  • Jose Ordovas
  • Inga Peter
  • Annette Peters
  • Jonathan Shaffer
  • Haiqinq Shen
  • Erin Smith
  • Liz Speilotes
  • Fridtjof Thomas
  • Barbara Thorand
  • W. M. Monique Verschuren
  • Sonia S. Anand
  • Anna Dominiczak
  • Karina W. Davidson
  • Robert A. Hegele
  • Iris Heid
  • Marten H. Hofker
  • Gordon S. Huggins
  • Thomas Illig
  • Julie A. Johnson
  • Susan Kirkland
  • Wolfgang Koenig
  • Taimour Y. Langaee
  • Jeanne Mccaffery
  • Braxton D. Mitchell
  • Patricia Munroe
  • Sarah S. Murray
  • George Papanicolaou
  • Susan Redline
  • Muredach Reilly
  • Nilesh J. Samani
  • Nicholas J. Schork
  • Yvonne T. Van der Schouw
  • Daichi Shimbo
  • Alan R. Shuldiner
  • Martin D. Tobin
  • Cisca Wijmenga
  • Salim Yusuf
  • Hakon Hakonarson
  • Leslie A. Lange
  • Ellen W. Demerath
  • Caroline S. Fox
  • Kari E. North
  • Alex P. Reiner
  • Brendan Keating
  • Kira C. Taylor
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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)2498-2510
JournalHuman Molecular Genetics
Volume23
Issue number9
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes