Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data

RS Vasan; NL Glazer; Janine Felix; W Lieb; PS Wild; SB Felix; N Watzinger; MG Larson; NL Smith; Abbas Dehghan; A Grosshennig; A Schillert; A Teumer; R Schmidt; S Kathiresan; T Lumley; YS Aulchenko; IR Konig; T Zeller; G Homuth; Maksim Struchalin; J Aragam; JC Bis; Fernando Rivadeneira; J Erdmann; RB Schnabel; M Dorr; R Zweiker; L Lind; RJ Rodeheffer; KH Greiser; D Levy; T Haritunians; Jaap Deckers; J Stritzke; KJ Lackner; U Volker; E Ingelsson; CJ O'Donnell; SR Heckbert; Bruno Stricker; I Kullo; A Ziegler; T Reffelmann; MM Redfield; K Werdan; GF Mitchell; K Rice; DK Arnett; Bert Hofman; JS Gottdiener; André Uitterlinden; T Meitinger; M Blettner; N Friedrich; TJ Wang; BM Psaty; Cornelia Duijn; HE Wichmann; TF Munzel; HK Kroemer; E Benjamin; JI Rotter; JCM Witteman; H Schunkert; Heléna Schmidt; H Volzke; S Blankenberg

doi:10.1001/jama.2009.978-a

Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data

RS Vasan, NL Glazer, Janine Felix, W Lieb, PS Wild, SB Felix, N Watzinger, MG Larson, NL Smith, Abbas Dehghan, A Grosshennig, A Schillert, A Teumer, R Schmidt, S Kathiresan, T Lumley, YS Aulchenko, IR Konig, T Zeller, G HomuthMaksim Struchalin, J Aragam, JC Bis, Fernando Rivadeneira, J Erdmann, RB Schnabel, M Dorr, R Zweiker, L Lind, RJ Rodeheffer, KH Greiser, D Levy, T Haritunians, Jaap Deckers, J Stritzke, KJ Lackner, U Volker, E Ingelsson, CJ O'Donnell, SR Heckbert, Bruno Stricker, I Kullo, A Ziegler, T Reffelmann, MM Redfield, K Werdan, GF Mitchell, K Rice, DK Arnett, Bert Hofman, JS Gottdiener, André Uitterlinden, T Meitinger, M Blettner, N Friedrich, TJ Wang, BM Psaty, Cornelia Duijn, HE Wichmann, TF Munzel, HK Kroemer, E Benjamin, JI Rotter, JCM Witteman, H Schunkert, Heléna Schmidt, H Volzke, S Blankenberg

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

192 Citations (Scopus)

Abstract

Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms ( SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. Main Outcome Measures Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. Results In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining < 1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). Conclusions We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease. JAMA. 2009;302(2):168-178 www.jama.com

Original language	Undefined/Unknown
Pages (from-to)	168-178
Number of pages	11
Journal	JAMA - Journal of the American Medical Association
Volume	302
Issue number	2
DOIs	https://doi.org/10.1001/jama.2009.978-a
Publication status	Published - 2009

Research programs

EMC COEUR-09
EMC MM-01-39-02
EMC NIHES-01-64-01
EMC NIHES-03-77-02

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1001/jama.2009.978-a

http://hdl.handle.net/1765/25173

Cite this

Vasan, RS., Glazer, NL., Felix, J., Lieb, W., Wild, PS., Felix, SB., Watzinger, N., Larson, MG., Smith, NL., Dehghan, A., Grosshennig, A., Schillert, A., Teumer, A., Schmidt, R., Kathiresan, S., Lumley, T., Aulchenko, YS., Konig, IR., Zeller, T., ... Blankenberg, S. (2009). Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data. JAMA - Journal of the American Medical Association, 302(2), 168-178. https://doi.org/10.1001/jama.2009.978-a

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title = "Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data",

abstract = "Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms ( SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. Main Outcome Measures Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. Results In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining < 1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). Conclusions We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease. JAMA. 2009;302(2):168-178 www.jama.com",

author = "RS Vasan and NL Glazer and Janine Felix and W Lieb and PS Wild and SB Felix and N Watzinger and MG Larson and NL Smith and Abbas Dehghan and A Grosshennig and A Schillert and A Teumer and R Schmidt and S Kathiresan and T Lumley and YS Aulchenko and IR Konig and T Zeller and G Homuth and Maksim Struchalin and J Aragam and JC Bis and Fernando Rivadeneira and J Erdmann and RB Schnabel and M Dorr and R Zweiker and L Lind and RJ Rodeheffer and KH Greiser and D Levy and T Haritunians and Jaap Deckers and J Stritzke and KJ Lackner and U Volker and E Ingelsson and CJ O'Donnell and SR Heckbert and Bruno Stricker and I Kullo and A Ziegler and T Reffelmann and MM Redfield and K Werdan and GF Mitchell and K Rice and DK Arnett and Bert Hofman and JS Gottdiener and Andr{\'e} Uitterlinden and T Meitinger and M Blettner and N Friedrich and TJ Wang and BM Psaty and Cornelia Duijn and HE Wichmann and TF Munzel and HK Kroemer and E Benjamin and JI Rotter and JCM Witteman and H Schunkert and Hel{\'e}na Schmidt and H Volzke and S Blankenberg",

year = "2009",

doi = "10.1001/jama.2009.978-a",

language = "Undefined/Unknown",

volume = "302",

pages = "168--178",

journal = "JAMA - Journal of the American Medical Association",

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Vasan, RS, Glazer, NL, Felix, J, Lieb, W, Wild, PS, Felix, SB, Watzinger, N, Larson, MG, Smith, NL, Dehghan, A, Grosshennig, A, Schillert, A, Teumer, A, Schmidt, R, Kathiresan, S, Lumley, T, Aulchenko, YS, Konig, IR, Zeller, T, Homuth, G, Struchalin, M, Aragam, J, Bis, JC, Rivadeneira, F, Erdmann, J, Schnabel, RB, Dorr, M, Zweiker, R, Lind, L, Rodeheffer, RJ, Greiser, KH, Levy, D, Haritunians, T, Deckers, J, Stritzke, J, Lackner, KJ, Volker, U, Ingelsson, E, O'Donnell, CJ, Heckbert, SR, Stricker, B, Kullo, I, Ziegler, A, Reffelmann, T, Redfield, MM, Werdan, K, Mitchell, GF, Rice, K, Arnett, DK, Hofman, B, Gottdiener, JS, Uitterlinden, A, Meitinger, T, Blettner, M, Friedrich, N, Wang, TJ, Psaty, BM, Duijn, C, Wichmann, HE, Munzel, TF, Kroemer, HK, Benjamin, E, Rotter, JI, Witteman, JCM, Schunkert, H, Schmidt, H, Volzke, H & Blankenberg, S 2009, 'Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data', JAMA - Journal of the American Medical Association, vol. 302, no. 2, pp. 168-178. https://doi.org/10.1001/jama.2009.978-a

TY - JOUR

T1 - Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis and Replication of Genome-wide Association Data

AU - Vasan, RS

AU - Glazer, NL

AU - Felix, Janine

AU - Lieb, W

AU - Wild, PS

AU - Felix, SB

AU - Watzinger, N

AU - Larson, MG

AU - Smith, NL

AU - Dehghan, Abbas

AU - Grosshennig, A

AU - Schillert, A

AU - Teumer, A

AU - Schmidt, R

AU - Kathiresan, S

AU - Lumley, T

AU - Aulchenko, YS

AU - Konig, IR

AU - Zeller, T

AU - Homuth, G

AU - Struchalin, Maksim

AU - Aragam, J

AU - Bis, JC

AU - Rivadeneira, Fernando

AU - Erdmann, J

AU - Schnabel, RB

AU - Dorr, M

AU - Zweiker, R

AU - Lind, L

AU - Rodeheffer, RJ

AU - Greiser, KH

AU - Levy, D

AU - Haritunians, T

AU - Deckers, Jaap

AU - Stritzke, J

AU - Lackner, KJ

AU - Volker, U

AU - Ingelsson, E

AU - O'Donnell, CJ

AU - Heckbert, SR

AU - Stricker, Bruno

AU - Kullo, I

AU - Ziegler, A

AU - Reffelmann, T

AU - Redfield, MM

AU - Werdan, K

AU - Mitchell, GF

AU - Rice, K

AU - Arnett, DK

AU - Hofman, Bert

AU - Gottdiener, JS

AU - Uitterlinden, André

AU - Meitinger, T

AU - Blettner, M

AU - Friedrich, N

AU - Wang, TJ

AU - Psaty, BM

AU - Duijn, Cornelia

AU - Wichmann, HE

AU - Munzel, TF

AU - Kroemer, HK

AU - Benjamin, E

AU - Rotter, JI

AU - Witteman, JCM

AU - Schunkert, H

AU - Schmidt, Heléna

AU - Volzke, H

AU - Blankenberg, S

PY - 2009

Y1 - 2009

N2 - Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms ( SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. Main Outcome Measures Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. Results In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining < 1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). Conclusions We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease. JAMA. 2009;302(2):168-178 www.jama.com

AB - Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms ( SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. Main Outcome Measures Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. Results In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining < 1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). Conclusions We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease. JAMA. 2009;302(2):168-178 www.jama.com

U2 - 10.1001/jama.2009.978-a

DO - 10.1001/jama.2009.978-a

M3 - Article

C2 - 19584346

SN - 0098-7484

VL - 302

SP - 168

EP - 178

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

IS - 2

ER -