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

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 GorskiNancy 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 König, Martin D Tobin, Look AHEAD Research Group

Research output: Contribution to journalArticle (Academic Journal)peer-review

24 Citations (Scopus)


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 NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 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 (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 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.

Original languageEnglish
Pages (from-to)2498-510
Number of pages13
JournalHuman Molecular Genetics
Issue number9
Publication statusPublished - 1 May 2014


  • Adiposity
  • Adult
  • Aged
  • Aged, 80 and over
  • Body Mass Index
  • European Continental Ancestry Group
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Waist Circumference
  • Waist-Hip Ratio
  • Young Adult


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