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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

Yoneyama, Sachiko; Guo, Yiran; Lanktree, Matthew B.; Barnes, Michael R.; Elbers, Clara C.; Karczewski, Konrad J.; Padmanabhan, Sandosh; Bauer, Florianne; Baumert, Jens and Beitelshees, Amber, et al. (2014) In Human Molecular Genetics 23(9). p.2498-2510
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... (More)
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. (Less)
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Human Molecular Genetics
volume
23
issue
9
pages
2498 - 2510
publisher
Oxford University Press
external identifiers
  • wos:000334359100023
  • scopus:84897479338
ISSN
0964-6906
DOI
10.1093/hmg/ddt626
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English
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yes
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9d8b966d-69bf-40d7-a746-5f32ac5c71e7 (old id 4488050)
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2014-06-23 14:22:43
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@article{9d8b966d-69bf-40d7-a746-5f32ac5c71e7,
  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.},
  author       = {Yoneyama, Sachiko and Guo, Yiran and Lanktree, Matthew B. and Barnes, Michael R. and Elbers, Clara C. and Karczewski, Konrad J. and Padmanabhan, Sandosh and Bauer, Florianne and Baumert, Jens and Beitelshees, Amber and Berenson, Gerald S. and Boer, Jolanda M. A. and Burke, Gregory and Cade, Brian and Chen, Wei and Cooper-Dehoff, Rhonda M. and Gaunt, Tom R. and Gieger, Christian and Gong, Yan and Gorski, Mathias and Heard-Costa, Nancy and Johnson, Toby and Lamonte, Michael J. and Mcdonough, Caitrin and Monda, Keri L. and Onland-Moret, N. Charlotte and Nelson, Christopher P. and O'Connell, Jeffrey R. and Ordovas, Jose and Peter, Inga and Peters, Annette and Shaffer, Jonathan and Shen, Haiqinq and Smith, Erin and Speilotes, Liz and Thomas, Fridtjof and Thorand, Barbara and Verschuren, W. M. Monique and Anand, Sonia S. and Dominiczak, Anna and Davidson, Karina W. and Hegele, Robert A. and Heid, Iris and Hofker, Marten H. and Huggins, Gordon S. and Illig, Thomas and Johnson, Julie A. and Kirkland, Susan and Koenig, Wolfgang and Langaee, Taimour Y. and Mccaffery, Jeanne and Melander, Olle and Mitchell, Braxton D. and Munroe, Patricia and Murray, Sarah S. and Papanicolaou, George and Redline, Susan and Reilly, Muredach and Samani, Nilesh J. and Schork, Nicholas J. and Van der Schouw, Yvonne T. and Shimbo, Daichi and Shuldiner, Alan R. and Tobin, Martin D. and Wijmenga, Cisca and Yusuf, Salim and Hakonarson, Hakon and Lange, Leslie A. and Demerath, Ellen W. and Fox, Caroline S. and North, Kari E. and Reiner, Alex P. and Keating, Brendan and Taylor, Kira C.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {9},
  pages        = {2498--2510},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {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},
  url          = {http://dx.doi.org/10.1093/hmg/ddt626},
  volume       = {23},
  year         = {2014},
}