Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data

Ramachandran S. Vasan; Nicole L. Glazer; Janine F. Felix; Wolfgang Lieb; Philipp S. Wild; Stephan B. Felix; Norbert Watzinger; Martin G. Larson; Nicholas L. Smith; Abbas Dehghan; Anika Großhennig; Arne Schillert; Alexander Teumer; Reinhold Schmidt; Sekar Kathiresan; Thomas Lumley; Yurii S. Aulchenko; Inke R. König; Tanja Zeller; Georg Homuth; Maksim Struchalin; Jayashri Aragam; Joshua C. Bis; Fernando Rivadeneira; Jeanette Erdmann; Renate B. Schnabel; Marcus Dörr; Robert Zweiker; Lars Lind; Richard J. Rodeheffer; Karin Halina Greiser; Daniel Levy; Talin Haritunians; Jaap W. Deckers; Jan Stritzke; Karl J. Lackner; Uwe Völker; Erik Ingelsson; Iftikhar Kullo; Johannes Haerting; Christopher J. O'Donnell; Susan R. Heckbert; Bruno H. Stricker; Andreas Ziegler; Thorsten Reffelmann; Margaret M. Redfield; Karl Werdan; Gary F. Mitchell; Kenneth Rice; Donna K. Arnett; Albert Hofman; John S. Gottdiener; Andre G. Uitterlinden; Thomas Meitinger; Maria Blettner; Nele Friedrich; Thomas J. Wang; Bruce M. Psaty; Cornelia M. Van Duijn; H. Erich Wichmann; Thomas F. Munzel; Heyo K. Kroemer; Emelia J. Benjamin; Jerome I. Rotter; Jacqueline C. Witteman; Heribert Schunkert; Helena Schmidt; Henry Völzke; Stefan 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

Ramachandran S. Vasan, Nicole L. Glazer, Janine F. Felix, Wolfgang Lieb, Philipp S. Wild, Stephan B. Felix, Norbert Watzinger, Martin G. Larson, Nicholas L. Smith, Abbas Dehghan, Anika Großhennig, Arne Schillert, Alexander Teumer, Reinhold Schmidt, Sekar Kathiresan, Thomas Lumley, Yurii S. Aulchenko, Inke R. König, Tanja Zeller, Georg HomuthMaksim Struchalin, Jayashri Aragam, Joshua C. Bis, Fernando Rivadeneira, Jeanette Erdmann, Renate B. Schnabel, Marcus Dörr, Robert Zweiker, Lars Lind, Richard J. Rodeheffer, Karin Halina Greiser, Daniel Levy, Talin Haritunians, Jaap W. Deckers, Jan Stritzke, Karl J. Lackner, Uwe Völker, Erik Ingelsson, Iftikhar Kullo, Johannes Haerting, Christopher J. O'Donnell, Susan R. Heckbert, Bruno H. Stricker, Andreas Ziegler, Thorsten Reffelmann, Margaret M. Redfield, Karl Werdan, Gary F. Mitchell, Kenneth Rice, Donna K. Arnett, Albert Hofman, John S. Gottdiener, Andre G. Uitterlinden, Thomas Meitinger, Maria Blettner, Nele Friedrich, Thomas J. Wang, Bruce M. Psaty, Cornelia M. Van Duijn, H. Erich Wichmann, Thomas F. Munzel, Heyo K. Kroemer, Emelia J. Benjamin, Jerome I. Rotter, Jacqueline C. Witteman, Heribert Schunkert, Helena Schmidt, Henry Völzke, Stefan Blankenberg

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

187 Scopus citations

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.

Original language	English (US)
Pages (from-to)	168-178
Number of pages	11
Journal	JAMA
Volume	302
Issue number	2
DOIs	https://doi.org/10.1001/jama.2009.978-a
State	Published - Jul 8 2009
Externally published	Yes

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General Medicine

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Vasan, R. S., Glazer, N. L., Felix, J. F., Lieb, W., Wild, P. S., Felix, S. B., Watzinger, N., Larson, M. G., Smith, N. L., Dehghan, A., Großhennig, A., Schillert, A., Teumer, A., Schmidt, R., Kathiresan, S., Lumley, T., Aulchenko, Y. S., König, I. R., Zeller, T., ... Blankenberg, S. (2009). Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data. JAMA, 302(2), 168-178. https://doi.org/10.1001/jama.2009.978-a

Vasan, RS, Glazer, NL, Felix, JF, 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, König, IR, Zeller, T, Homuth, G, Struchalin, M, Aragam, J, Bis, JC, Rivadeneira, F, Erdmann, J, Schnabel, RB, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, RJ, Greiser, KH, Levy, D, Haritunians, T, Deckers, JW, Stritzke, J, Lackner, KJ, Völker, U, Ingelsson, E, Kullo, I, Haerting, J, O'Donnell, CJ, Heckbert, SR, Stricker, BH, Ziegler, A, Reffelmann, T, Redfield, MM, Werdan, K, Mitchell, GF, Rice, K, Arnett, DK, Hofman, A, Gottdiener, JS, Uitterlinden, AG, Meitinger, T, Blettner, M, Friedrich, N, Wang, TJ, Psaty, BM, Van Duijn, CM, Wichmann, HE, Munzel, TF, Kroemer, HK, Benjamin, EJ, Rotter, JI, Witteman, JC, Schunkert, H, Schmidt, H, Völzke, H & Blankenberg, S 2009, 'Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data', JAMA, vol. 302, no. 2, pp. 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.",

author = "Vasan, {Ramachandran S.} and Glazer, {Nicole L.} and Felix, {Janine F.} and Wolfgang Lieb and Wild, {Philipp S.} and Felix, {Stephan B.} and Norbert Watzinger and Larson, {Martin G.} and Smith, {Nicholas L.} and Abbas Dehghan and Anika Gro{\ss}hennig and Arne Schillert and Alexander Teumer and Reinhold Schmidt and Sekar Kathiresan and Thomas Lumley and Aulchenko, {Yurii S.} and K{\"o}nig, {Inke R.} and Tanja Zeller and Georg Homuth and Maksim Struchalin and Jayashri Aragam and Bis, {Joshua C.} and Fernando Rivadeneira and Jeanette Erdmann and Schnabel, {Renate B.} and Marcus D{\"o}rr and Robert Zweiker and Lars Lind and Rodeheffer, {Richard J.} and Greiser, {Karin Halina} and Daniel Levy and Talin Haritunians and Deckers, {Jaap W.} and Jan Stritzke and Lackner, {Karl J.} and Uwe V{\"o}lker and Erik Ingelsson and Iftikhar Kullo and Johannes Haerting and O'Donnell, {Christopher J.} and Heckbert, {Susan R.} and Stricker, {Bruno H.} and Andreas Ziegler and Thorsten Reffelmann and Redfield, {Margaret M.} and Karl Werdan and Mitchell, {Gary F.} and Kenneth Rice and Arnett, {Donna K.} and Albert Hofman and Gottdiener, {John S.} and Uitterlinden, {Andre G.} and Thomas Meitinger and Maria Blettner and Nele Friedrich and Wang, {Thomas J.} and Psaty, {Bruce M.} and {Van Duijn}, {Cornelia M.} and Wichmann, {H. Erich} and Munzel, {Thomas F.} and Kroemer, {Heyo K.} and Benjamin, {Emelia J.} and Rotter, {Jerome I.} and Witteman, {Jacqueline C.} and Heribert Schunkert and Helena Schmidt and Henry V{\"o}lzke and Stefan Blankenberg",

year = "2009",

month = jul,

day = "8",

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

language = "English (US)",

volume = "302",

pages = "168--178",

journal = "JAMA",

issn = "0098-7484",

publisher = "American Medical Association",

number = "2",

}

TY - JOUR

T1 - Genetic variants associated with cardiac structure and function

T2 - A meta-analysis and replication of genome-wide association data

AU - Vasan, Ramachandran S.

AU - Glazer, Nicole L.

AU - Felix, Janine F.

AU - Lieb, Wolfgang

AU - Wild, Philipp S.

AU - Felix, Stephan B.

AU - Watzinger, Norbert

AU - Larson, Martin G.

AU - Smith, Nicholas L.

AU - Dehghan, Abbas

AU - Großhennig, Anika

AU - Schillert, Arne

AU - Teumer, Alexander

AU - Schmidt, Reinhold

AU - Kathiresan, Sekar

AU - Lumley, Thomas

AU - Aulchenko, Yurii S.

AU - König, Inke R.

AU - Zeller, Tanja

AU - Homuth, Georg

AU - Struchalin, Maksim

AU - Aragam, Jayashri

AU - Bis, Joshua C.

AU - Rivadeneira, Fernando

AU - Erdmann, Jeanette

AU - Schnabel, Renate B.

AU - Dörr, Marcus

AU - Zweiker, Robert

AU - Lind, Lars

AU - Rodeheffer, Richard J.

AU - Greiser, Karin Halina

AU - Levy, Daniel

AU - Haritunians, Talin

AU - Deckers, Jaap W.

AU - Stritzke, Jan

AU - Lackner, Karl J.

AU - Völker, Uwe

AU - Ingelsson, Erik

AU - Kullo, Iftikhar

AU - Haerting, Johannes

AU - O'Donnell, Christopher J.

AU - Heckbert, Susan R.

AU - Stricker, Bruno H.

AU - Ziegler, Andreas

AU - Reffelmann, Thorsten

AU - Redfield, Margaret M.

AU - Werdan, Karl

AU - Mitchell, Gary F.

AU - Rice, Kenneth

AU - Arnett, Donna K.

AU - Hofman, Albert

AU - Gottdiener, John S.

AU - Uitterlinden, Andre G.

AU - Meitinger, Thomas

AU - Blettner, Maria

AU - Friedrich, Nele

AU - Wang, Thomas J.

AU - Psaty, Bruce M.

AU - Van Duijn, Cornelia M.

AU - Wichmann, H. Erich

AU - Munzel, Thomas F.

AU - Kroemer, Heyo K.

AU - Benjamin, Emelia J.

AU - Rotter, Jerome I.

AU - Witteman, Jacqueline C.

AU - Schunkert, Heribert

AU - Schmidt, Helena

AU - Völzke, Henry

AU - Blankenberg, Stefan

PY - 2009/7/8

Y1 - 2009/7/8

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.

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.

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Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data

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