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 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 König; Taimour Y. Langaee; Jeanne Mccaffery; Olle Melander; 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

doi:10.1093/hmg/ddt626

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 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 König, Taimour Y. Langaee, Jeanne Mccaffery, Olle Melander, 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

Department of Epidemiology and Environmental Health

University of North Carolina at Chapel Hill
Children's Hospital of Philadelphia
BGI-Shenzhen
McMaster University
Queen Mary University of London
Utrecht University
Stanford University
University of Glasgow
Helmholtz Zentrum München - German Research Center for Environmental Health
University of Maryland, Baltimore
Tulane University
National Institute of Public Health and the Environment
Wake Forest University
Harvard University
Brigham and Women’s Hospital
University of Florida
University of Bristol
University of Regensburg
Boston University
Amgen Incorporated
University of Leicester
University Hospitals of Leicester NHS Trust
Tufts University
Icahn School of Medicine at Mount Sinai
Columbia University
Rady Children's Hospital
Massachusetts General Hospital
University of Michigan, Ann Arbor
The Broad Institute of MIT and Harvard
University of Tennessee Health Science Center
Population Health Research Institute, Ontario
Western University
University of Groningen
Tufts-New England Medical Center
Hannover Medical School
Dalhousie University
Ulm University
Lifespan
Brown University
Lund University
Scripps Research Institute
National Institutes of Health
University of Pennsylvania
Scripps Research Translational Institute
Department of Veterans Affairs
University of Minnesota Twin Cities
Carolina Center for Genome Sciences
University of Washington
University of Louisville School of Public Health & Information Sciences

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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 across̃2100cardiovascular-related genes. Eachtraitwasmodeled asa function of age, study siteandprincipal components to control for population stratification, andweconducted a fixed-effectsmeta-analysis. Nonewloci 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 language	English
Article number	ddt626
Pages (from-to)	2498-2510
Number of pages	13
Journal	Human Molecular Genetics
Volume	23
Issue number	9
DOIs	https://doi.org/10.1093/hmg/ddt626
State	Published - May 2014

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10.1093/hmg/ddt626

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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., ... Taylor, K. C. (2014). 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. Human Molecular Genetics, 23(9), 2498-2510. Article ddt626. https://doi.org/10.1093/hmg/ddt626

@article{91908817f9124de9a4ecb7652084aa4d,

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",

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 acros{\~s}2100cardiovascular-related genes. Eachtraitwasmodeled asa function of age, study siteandprincipal components to control for population stratification, andweconducted a fixed-effectsmeta-analysis. Nonewloci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 {\texttimes}10-6). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β±SE, 0.048±0.008, P=7.7{\texttimes}10-9) as was rs7302703-G in HOXC10 (β=0.044±0.008, P=2.9{\texttimes}10-7) and rs936108-C in PEMT (β-0.035±0.007, P=1.9{\texttimes}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{\texttimes}10-6) and rs1037575-A in ATBDB4 (β=0.046±0.01, P=2.2{\texttimes}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 = "Sachiko Yoneyama and Yiran Guo and Lanktree, \{Matthew B.\} and Barnes, \{Michael R.\} and Elbers, \{Clara C.\} and Karczewski, \{Konrad J.\} and Sandosh Padmanabhan and Florianne Bauer and Jens Baumert and Amber Beitelshees and Berenson, \{Gerald S.\} and Boer, \{Jolanda M.A.\} and Gregory Burke and Brian Cade and Wei Chen and Cooper-Dehoff, \{Rhonda M.\} and Gaunt, \{Tom R.\} and Christian Gieger and Yan Gong and Mathias Gorski and Nancy Heard-Costa and Toby Johnson and Lamonte, \{Michael J.\} and Caitrin Mcdonough and Monda, \{Keri L.\} and Onland-Moret, \{N. Charlotte\} and Nelson, \{Christopher P.\} and O'Connell, \{Jeffrey R.\} and Jose Ordovas and Inga Peter and Annette Peters and Jonathan Shaffer and Haiqinq Shen and Erin Smith and Liz Speilotes and Fridtjof Thomas and Barbara Thorand and Verschuren, \{W. M.Monique\} and Anand, \{Sonia S.\} and Anna Dominiczak and Davidson, \{Karina W.\} and Hegele, \{Robert A.\} and Iris Heid and Hofker, \{Marten H.\} and Huggins, \{Gordon S.\} and Thomas Illig and Johnson, \{Julie A.\} and Susan Kirkland and Wolfgang K{\"o}nig and Langaee, \{Taimour Y.\} and Jeanne Mccaffery and Olle Melander and Mitchell, \{Braxton D.\} and Patricia Munroe and Murray, \{Sarah S.\} and George Papanicolaou and Susan Redline and Muredach Reilly and Samani, \{Nilesh J.\} and Schork, \{Nicholas J.\} and \{Van Der Schouw\}, \{Yvonne T.\} and Daichi Shimbo and Shuldiner, \{Alan R.\} and Tobin, \{Martin D.\} and Cisca Wijmenga and Salim Yusuf and Hakon Hakonarson and Lange, \{Leslie A.\} and Demerath, \{Ellen W.\} and Fox, \{Caroline S.\} and North, \{Kari E.\} and Reiner, \{Alex P.\} and Brendan Keating and Taylor, \{Kira C.\}",

year = "2014",

month = may,

doi = "10.1093/hmg/ddt626",

language = "English",

volume = "23",

pages = "2498--2510",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

Yoneyama, S, Guo, Y, Lanktree, MB, Barnes, MR, Elbers, CC, Karczewski, KJ, Padmanabhan, S, Bauer, F, Baumert, J, Beitelshees, A, Berenson, GS, Boer, JMA, Burke, G, Cade, B, Chen, W, Cooper-Dehoff, RM, Gaunt, TR, Gieger, C, Gong, Y, Gorski, M, Heard-Costa, N, Johnson, T, Lamonte, MJ, Mcdonough, C, Monda, KL, Onland-Moret, NC, Nelson, CP, O'Connell, JR, Ordovas, J, Peter, I, Peters, A, Shaffer, J, Shen, H, Smith, E, Speilotes, L, Thomas, F, Thorand, B, Verschuren, WMM, Anand, SS, Dominiczak, A, Davidson, KW, Hegele, RA, Heid, I, Hofker, MH, Huggins, GS, Illig, T, Johnson, JA, Kirkland, S, König, W, Langaee, TY, Mccaffery, J, Melander, O, Mitchell, BD, Munroe, P, Murray, SS, Papanicolaou, G, Redline, S, Reilly, M, Samani, NJ, Schork, NJ, Van Der Schouw, YT, Shimbo, D, Shuldiner, AR, Tobin, MD, Wijmenga, C, Yusuf, S, Hakonarson, H, Lange, LA, Demerath, EW, Fox, CS, North, KE, Reiner, AP, Keating, B & Taylor, KC 2014, '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', Human Molecular Genetics, vol. 23, no. 9, ddt626, pp. 2498-2510. https://doi.org/10.1093/hmg/ddt626

TY - JOUR

T1 - 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

AU - Yoneyama, Sachiko

AU - Guo, Yiran

AU - Lanktree, Matthew B.

AU - Barnes, Michael R.

AU - Elbers, Clara C.

AU - Karczewski, Konrad J.

AU - Padmanabhan, Sandosh

AU - Bauer, Florianne

AU - Baumert, Jens

AU - Beitelshees, Amber

AU - Berenson, Gerald S.

AU - Boer, Jolanda M.A.

AU - Burke, Gregory

AU - Cade, Brian

AU - Chen, Wei

AU - Cooper-Dehoff, Rhonda M.

AU - Gaunt, Tom R.

AU - Gieger, Christian

AU - Gong, Yan

AU - Gorski, Mathias

AU - Heard-Costa, Nancy

AU - Johnson, Toby

AU - Lamonte, Michael J.

AU - Mcdonough, Caitrin

AU - Monda, Keri L.

AU - Onland-Moret, N. Charlotte

AU - Nelson, Christopher P.

AU - O'Connell, Jeffrey R.

AU - Ordovas, Jose

AU - Peter, Inga

AU - Peters, Annette

AU - Shaffer, Jonathan

AU - Shen, Haiqinq

AU - Smith, Erin

AU - Speilotes, Liz

AU - Thomas, Fridtjof

AU - Thorand, Barbara

AU - Verschuren, W. M.Monique

AU - Anand, Sonia S.

AU - Dominiczak, Anna

AU - Davidson, Karina W.

AU - Hegele, Robert A.

AU - Heid, Iris

AU - Hofker, Marten H.

AU - Huggins, Gordon S.

AU - Illig, Thomas

AU - Johnson, Julie A.

AU - Kirkland, Susan

AU - König, Wolfgang

AU - Langaee, Taimour Y.

AU - Mccaffery, Jeanne

AU - Melander, Olle

AU - Mitchell, Braxton D.

AU - Munroe, Patricia

AU - Murray, Sarah S.

AU - Papanicolaou, George

AU - Redline, Susan

AU - Reilly, Muredach

AU - Samani, Nilesh J.

AU - Schork, Nicholas J.

AU - Van Der Schouw, Yvonne T.

AU - Shimbo, Daichi

AU - Shuldiner, Alan R.

AU - Tobin, Martin D.

AU - Wijmenga, Cisca

AU - Yusuf, Salim

AU - Hakonarson, Hakon

AU - Lange, Leslie A.

AU - Demerath, Ellen W.

AU - Fox, Caroline S.

AU - North, Kari E.

AU - Reiner, Alex P.

AU - Keating, Brendan

AU - Taylor, Kira C.

PY - 2014/5

Y1 - 2014/5

N2 - 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 across̃2100cardiovascular-related genes. Eachtraitwasmodeled asa function of age, study siteandprincipal components to control for population stratification, andweconducted a fixed-effectsmeta-analysis. Nonewloci 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.

AB - 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 across̃2100cardiovascular-related genes. Eachtraitwasmodeled asa function of age, study siteandprincipal components to control for population stratification, andweconducted a fixed-effectsmeta-analysis. Nonewloci 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.

UR - https://www.scopus.com/pages/publications/84897479338

U2 - 10.1093/hmg/ddt626

DO - 10.1093/hmg/ddt626

M3 - Article

C2 - 24345515

AN - SCOPUS:84897479338

SN - 0964-6906

VL - 23

SP - 2498

EP - 2510

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 9

M1 - ddt626

ER -

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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