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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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Overview

authors

  • Yoneyama, S.
  • Guo, Y.
  • Lanktree, M. B.
  • Barnes, M. R.
  • Elbers, C. C.
  • Karczewski, K. J.
  • Padmanabhan, S.
  • Bauer, F.
  • Baumert, J.
  • Beitelshees, A.
  • Berenson, G. S.
  • Boer, J. M. A.
  • Burke, G.
  • Cade, B.
  • Chen, W.
  • Cooper-Dehoff, R. M.
  • Gaunt, T. R.
  • Gieger, C.
  • Gong, Y.
  • Gorski, M.
  • Heard-Costa, N.
  • Johnson, T.
  • Lamonte, M. J.
  • McDonough, C.
  • Monda, K. L.
  • Onland-Moret, N. C.
  • Nelson, C. P.
  • O'Connell, J. R.
  • Ordovas, J.
  • Peter, I.
  • Peters, A.
  • Shaffer, J.
  • Shen, H.
  • Smith, E.
  • Speilotes, L.
  • Thomas, F.
  • Thorand, B.
  • Verschuren, W. M. M.
  • Anand, S. S.
  • Dominiczak, A.
  • Davidson, K. W.
  • Hegele, R. A.
  • Heid, I.
  • Hofker, M. H.
  • Huggins, G. S.
  • Illig, T.
  • Johnson, J. A.
  • Kirkland, S.
  • Look AHEAD Research Group
  • Konig, W.
  • Langaee, T. Y.
  • McCaffery, J.
  • Melander, O.
  • Mitchell, B. D.
  • Munroe, P.
  • Murray, Sarah
  • Papanicolaou, G.
  • Redline, S.
  • Reilly, M.
  • Samani, N. J.
  • Schork, Nicholas
  • Van der Schouw, Y. T.
  • Shimbo, D.
  • Shuldiner, A. R.
  • Tobin, M. D.
  • Wijmenga, C.
  • Yusuf, S.
  • GIANT Consortium
  • CARe IBC Consortium
  • Hakonarson, H.
  • Lange, L. A.
  • Demerath, E. W.
  • Fox, C. S.
  • North, K. E.
  • Reiner, A. P.
  • Keating, B.
  • Taylor, K. C.

publication date

  • May 2014

journal

  • Human Molecular Genetics  Journal

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 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 (? � 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.
  • 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.

subject areas

  • 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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Identity

PubMed Central ID

  • PMC3988452

International Standard Serial Number (ISSN)

  • 0964-6906

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddt626

PubMed ID

  • 24345515
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Additional Document Info

start page

  • 2498

end page

  • 2510

volume

  • 23

issue

  • 9

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