Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

Philipp S. Wild, Janine F. Felix, Arne Schillert, Alexander Teumer, Ming Huei Chen, Maarten J.G. Leening, Uwe Völker, Vera Großmann, Jennifer A. Brody, Marguerite R. Irvin, Sanjiv J. Shah, Setia Pramana, Wolfgang Lieb, Reinhold Schmidt, Alice V. Stanton, Dörthe Malzahn, Albert Vernon Smith, Johan Sundström, Cosetta Minelli, Daniela Ruggiero & 103 others Leo Pekka Lyytikäinen, Daniel Tiller, J. Gustav Smith, Claire Monnereau, Marco R. Di Tullio, Solomon K. Musani, Alanna C. Morrison, Tune H. Pers, Michael Morley, Marcus E. Kleber, Jayashri Aragam, Emelia J. Benjamin, Joshua C. Bis, Egbert Bisping, Ulrich Broeckel, Susan Cheng, Jaap W. Deckers, Fabiola Del Greco M, Frank Edelmann, Myriam Fornage, Lude Franke, Nele Friedrich, Tamara B. Harris, Edith Hofer, Albert Hofman, Jie Huang, Alun D. Hughes, Mika Kähönen, Jochen Kruppa, Karl J. Lackner, Lars Lannfelt, Rafael Laskowski, Lenore J. Launer, Margrét Leosdottir, Honghuang Lin, Cecilia M. Lindgren, Christina Loley, Calum A. MacRae, Deborah Mascalzoni, Jamil Mayet, Daniel Medenwald, Andrew P. Morris, Christian Müller, Martina Müller-Nurasyid, Stefania Nappo, Peter M. Nilsson, Sebastian Nuding, Teresa Nutile, Annette Peters, Arne Pfeufer, Diana Pietzner, Peter P. Pramstaller, Olli T. Raitakari, Kenneth M. Rice, Fernando Rivadeneira, Jerome I. Rotter, Saku T. Ruohonen, Ralph L Sacco, Tandaw E. Samdarshi, Helena Schmidt, Andrew S.P. Sharp, Denis C. Shields, Rossella Sorice, Nona Sotoodehnia, Bruno H. Stricker, Praveen Surendran, Simon Thom, Anna M. Töglhofer, André G. Uitterlinden, Rolf Wachter, Henry Völzke, Andreas Ziegler, Thomas Münzel, Winfried März, Thomas P. Cappola, Joel N. Hirschhorn, Gary F. Mitchell, Nicholas L. Smith, Ervin R. Fox, Nicole D. Dueker, Vincent W.V. Jaddoe, Olle Melander, Martin Russ, Terho Lehtimäki, Marina Ciullo, Andrew A. Hicks, Lars Lind, Vilmundur Gudnason, Burkert Pieske, Anthony J. Barron, Robert Zweiker, Heribert Schunkert, Erik Ingelsson, Kiang Liu, Donna K. Arnett, Bruce M. Psaty, Stefan Blankenberg, Martin G. Larson, Stephan B. Felix, Oscar H. Franco, Tanja Zeller, Ramachandran S. Vasan, Marcus Dörr

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

Original languageEnglish (US)
Pages (from-to)1798-1812
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number5
DOIs
StatePublished - May 1 2017

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Meta-Analysis
Genetic Loci
Genome-Wide Association Study
Genome
Single Nucleotide Polymorphism
Monocytes
Heart Diseases
Gene Expression
perflenapent

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wild, P. S., Felix, J. F., Schillert, A., Teumer, A., Chen, M. H., Leening, M. J. G., ... Dörr, M. (2017). Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. Journal of Clinical Investigation, 127(5), 1798-1812. https://doi.org/10.1172/JCI84840

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. / Wild, Philipp S.; Felix, Janine F.; Schillert, Arne; Teumer, Alexander; Chen, Ming Huei; Leening, Maarten J.G.; Völker, Uwe; Großmann, Vera; Brody, Jennifer A.; Irvin, Marguerite R.; Shah, Sanjiv J.; Pramana, Setia; Lieb, Wolfgang; Schmidt, Reinhold; Stanton, Alice V.; Malzahn, Dörthe; Smith, Albert Vernon; Sundström, Johan; Minelli, Cosetta; Ruggiero, Daniela; Lyytikäinen, Leo Pekka; Tiller, Daniel; Smith, J. Gustav; Monnereau, Claire; Di Tullio, Marco R.; Musani, Solomon K.; Morrison, Alanna C.; Pers, Tune H.; Morley, Michael; Kleber, Marcus E.; Aragam, Jayashri; Benjamin, Emelia J.; Bis, Joshua C.; Bisping, Egbert; Broeckel, Ulrich; Cheng, Susan; Deckers, Jaap W.; Del Greco M, Fabiola; Edelmann, Frank; Fornage, Myriam; Franke, Lude; Friedrich, Nele; Harris, Tamara B.; Hofer, Edith; Hofman, Albert; Huang, Jie; Hughes, Alun D.; Kähönen, Mika; Kruppa, Jochen; Lackner, Karl J.; Lannfelt, Lars; Laskowski, Rafael; Launer, Lenore J.; Leosdottir, Margrét; Lin, Honghuang; Lindgren, Cecilia M.; Loley, Christina; MacRae, Calum A.; Mascalzoni, Deborah; Mayet, Jamil; Medenwald, Daniel; Morris, Andrew P.; Müller, Christian; Müller-Nurasyid, Martina; Nappo, Stefania; Nilsson, Peter M.; Nuding, Sebastian; Nutile, Teresa; Peters, Annette; Pfeufer, Arne; Pietzner, Diana; Pramstaller, Peter P.; Raitakari, Olli T.; Rice, Kenneth M.; Rivadeneira, Fernando; Rotter, Jerome I.; Ruohonen, Saku T.; Sacco, Ralph L; Samdarshi, Tandaw E.; Schmidt, Helena; Sharp, Andrew S.P.; Shields, Denis C.; Sorice, Rossella; Sotoodehnia, Nona; Stricker, Bruno H.; Surendran, Praveen; Thom, Simon; Töglhofer, Anna M.; Uitterlinden, André G.; Wachter, Rolf; Völzke, Henry; Ziegler, Andreas; Münzel, Thomas; März, Winfried; Cappola, Thomas P.; Hirschhorn, Joel N.; Mitchell, Gary F.; Smith, Nicholas L.; Fox, Ervin R.; Dueker, Nicole D.; Jaddoe, Vincent W.V.; Melander, Olle; Russ, Martin; Lehtimäki, Terho; Ciullo, Marina; Hicks, Andrew A.; Lind, Lars; Gudnason, Vilmundur; Pieske, Burkert; Barron, Anthony J.; Zweiker, Robert; Schunkert, Heribert; Ingelsson, Erik; Liu, Kiang; Arnett, Donna K.; Psaty, Bruce M.; Blankenberg, Stefan; Larson, Martin G.; Felix, Stephan B.; Franco, Oscar H.; Zeller, Tanja; Vasan, Ramachandran S.; Dörr, Marcus.

In: Journal of Clinical Investigation, Vol. 127, No. 5, 01.05.2017, p. 1798-1812.

Research output: Contribution to journalArticle

Wild, PS, Felix, JF, Schillert, A, Teumer, A, Chen, MH, Leening, MJG, Völker, U, Großmann, V, Brody, JA, Irvin, MR, Shah, SJ, Pramana, S, Lieb, W, Schmidt, R, Stanton, AV, Malzahn, D, Smith, AV, Sundström, J, Minelli, C, Ruggiero, D, Lyytikäinen, LP, Tiller, D, Smith, JG, Monnereau, C, Di Tullio, MR, Musani, SK, Morrison, AC, Pers, TH, Morley, M, Kleber, ME, Aragam, J, Benjamin, EJ, Bis, JC, Bisping, E, Broeckel, U, Cheng, S, Deckers, JW, Del Greco M, F, Edelmann, F, Fornage, M, Franke, L, Friedrich, N, Harris, TB, Hofer, E, Hofman, A, Huang, J, Hughes, AD, Kähönen, M, Kruppa, J, Lackner, KJ, Lannfelt, L, Laskowski, R, Launer, LJ, Leosdottir, M, Lin, H, Lindgren, CM, Loley, C, MacRae, CA, Mascalzoni, D, Mayet, J, Medenwald, D, Morris, AP, Müller, C, Müller-Nurasyid, M, Nappo, S, Nilsson, PM, Nuding, S, Nutile, T, Peters, A, Pfeufer, A, Pietzner, D, Pramstaller, PP, Raitakari, OT, Rice, KM, Rivadeneira, F, Rotter, JI, Ruohonen, ST, Sacco, RL, Samdarshi, TE, Schmidt, H, Sharp, ASP, Shields, DC, Sorice, R, Sotoodehnia, N, Stricker, BH, Surendran, P, Thom, S, Töglhofer, AM, Uitterlinden, AG, Wachter, R, Völzke, H, Ziegler, A, Münzel, T, März, W, Cappola, TP, Hirschhorn, JN, Mitchell, GF, Smith, NL, Fox, ER, Dueker, ND, Jaddoe, VWV, Melander, O, Russ, M, Lehtimäki, T, Ciullo, M, Hicks, AA, Lind, L, Gudnason, V, Pieske, B, Barron, AJ, Zweiker, R, Schunkert, H, Ingelsson, E, Liu, K, Arnett, DK, Psaty, BM, Blankenberg, S, Larson, MG, Felix, SB, Franco, OH, Zeller, T, Vasan, RS & Dörr, M 2017, 'Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function', Journal of Clinical Investigation, vol. 127, no. 5, pp. 1798-1812. https://doi.org/10.1172/JCI84840
Wild, Philipp S. ; Felix, Janine F. ; Schillert, Arne ; Teumer, Alexander ; Chen, Ming Huei ; Leening, Maarten J.G. ; Völker, Uwe ; Großmann, Vera ; Brody, Jennifer A. ; Irvin, Marguerite R. ; Shah, Sanjiv J. ; Pramana, Setia ; Lieb, Wolfgang ; Schmidt, Reinhold ; Stanton, Alice V. ; Malzahn, Dörthe ; Smith, Albert Vernon ; Sundström, Johan ; Minelli, Cosetta ; Ruggiero, Daniela ; Lyytikäinen, Leo Pekka ; Tiller, Daniel ; Smith, J. Gustav ; Monnereau, Claire ; Di Tullio, Marco R. ; Musani, Solomon K. ; Morrison, Alanna C. ; Pers, Tune H. ; Morley, Michael ; Kleber, Marcus E. ; Aragam, Jayashri ; Benjamin, Emelia J. ; Bis, Joshua C. ; Bisping, Egbert ; Broeckel, Ulrich ; Cheng, Susan ; Deckers, Jaap W. ; Del Greco M, Fabiola ; Edelmann, Frank ; Fornage, Myriam ; Franke, Lude ; Friedrich, Nele ; Harris, Tamara B. ; Hofer, Edith ; Hofman, Albert ; Huang, Jie ; Hughes, Alun D. ; Kähönen, Mika ; Kruppa, Jochen ; Lackner, Karl J. ; Lannfelt, Lars ; Laskowski, Rafael ; Launer, Lenore J. ; Leosdottir, Margrét ; Lin, Honghuang ; Lindgren, Cecilia M. ; Loley, Christina ; MacRae, Calum A. ; Mascalzoni, Deborah ; Mayet, Jamil ; Medenwald, Daniel ; Morris, Andrew P. ; Müller, Christian ; Müller-Nurasyid, Martina ; Nappo, Stefania ; Nilsson, Peter M. ; Nuding, Sebastian ; Nutile, Teresa ; Peters, Annette ; Pfeufer, Arne ; Pietzner, Diana ; Pramstaller, Peter P. ; Raitakari, Olli T. ; Rice, Kenneth M. ; Rivadeneira, Fernando ; Rotter, Jerome I. ; Ruohonen, Saku T. ; Sacco, Ralph L ; Samdarshi, Tandaw E. ; Schmidt, Helena ; Sharp, Andrew S.P. ; Shields, Denis C. ; Sorice, Rossella ; Sotoodehnia, Nona ; Stricker, Bruno H. ; Surendran, Praveen ; Thom, Simon ; Töglhofer, Anna M. ; Uitterlinden, André G. ; Wachter, Rolf ; Völzke, Henry ; Ziegler, Andreas ; Münzel, Thomas ; März, Winfried ; Cappola, Thomas P. ; Hirschhorn, Joel N. ; Mitchell, Gary F. ; Smith, Nicholas L. ; Fox, Ervin R. ; Dueker, Nicole D. ; Jaddoe, Vincent W.V. ; Melander, Olle ; Russ, Martin ; Lehtimäki, Terho ; Ciullo, Marina ; Hicks, Andrew A. ; Lind, Lars ; Gudnason, Vilmundur ; Pieske, Burkert ; Barron, Anthony J. ; Zweiker, Robert ; Schunkert, Heribert ; Ingelsson, Erik ; Liu, Kiang ; Arnett, Donna K. ; Psaty, Bruce M. ; Blankenberg, Stefan ; Larson, Martin G. ; Felix, Stephan B. ; Franco, Oscar H. ; Zeller, Tanja ; Vasan, Ramachandran S. ; Dörr, Marcus. / Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 5. pp. 1798-1812.
@article{2019a52e70504dc3bc502b7049e98264,
title = "Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function",
abstract = "BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.",
author = "Wild, {Philipp S.} and Felix, {Janine F.} and Arne Schillert and Alexander Teumer and Chen, {Ming Huei} and Leening, {Maarten J.G.} and Uwe V{\"o}lker and Vera Gro{\ss}mann and Brody, {Jennifer A.} and Irvin, {Marguerite R.} and Shah, {Sanjiv J.} and Setia Pramana and Wolfgang Lieb and Reinhold Schmidt and Stanton, {Alice V.} and D{\"o}rthe Malzahn and Smith, {Albert Vernon} and Johan Sundstr{\"o}m and Cosetta Minelli and Daniela Ruggiero and Lyytik{\"a}inen, {Leo Pekka} and Daniel Tiller and Smith, {J. Gustav} and Claire Monnereau and {Di Tullio}, {Marco R.} and Musani, {Solomon K.} and Morrison, {Alanna C.} and Pers, {Tune H.} and Michael Morley and Kleber, {Marcus E.} and Jayashri Aragam and Benjamin, {Emelia J.} and Bis, {Joshua C.} and Egbert Bisping and Ulrich Broeckel and Susan Cheng and Deckers, {Jaap W.} and {Del Greco M}, Fabiola and Frank Edelmann and Myriam Fornage and Lude Franke and Nele Friedrich and Harris, {Tamara B.} and Edith Hofer and Albert Hofman and Jie Huang and Hughes, {Alun D.} and Mika K{\"a}h{\"o}nen and Jochen Kruppa and Lackner, {Karl J.} and Lars Lannfelt and Rafael Laskowski and Launer, {Lenore J.} and Margr{\'e}t Leosdottir and Honghuang Lin and Lindgren, {Cecilia M.} and Christina Loley and MacRae, {Calum A.} and Deborah Mascalzoni and Jamil Mayet and Daniel Medenwald and Morris, {Andrew P.} and Christian M{\"u}ller and Martina M{\"u}ller-Nurasyid and Stefania Nappo and Nilsson, {Peter M.} and Sebastian Nuding and Teresa Nutile and Annette Peters and Arne Pfeufer and Diana Pietzner and Pramstaller, {Peter P.} and Raitakari, {Olli T.} and Rice, {Kenneth M.} and Fernando Rivadeneira and Rotter, {Jerome I.} and Ruohonen, {Saku T.} and Sacco, {Ralph L} and Samdarshi, {Tandaw E.} and Helena Schmidt and Sharp, {Andrew S.P.} and Shields, {Denis C.} and Rossella Sorice and Nona Sotoodehnia and Stricker, {Bruno H.} and Praveen Surendran and Simon Thom and T{\"o}glhofer, {Anna M.} and Uitterlinden, {Andr{\'e} G.} and Rolf Wachter and Henry V{\"o}lzke and Andreas Ziegler and Thomas M{\"u}nzel and Winfried M{\"a}rz and Cappola, {Thomas P.} and Hirschhorn, {Joel N.} and Mitchell, {Gary F.} and Smith, {Nicholas L.} and Fox, {Ervin R.} and Dueker, {Nicole D.} and Jaddoe, {Vincent W.V.} and Olle Melander and Martin Russ and Terho Lehtim{\"a}ki and Marina Ciullo and Hicks, {Andrew A.} and Lars Lind and Vilmundur Gudnason and Burkert Pieske and Barron, {Anthony J.} and Robert Zweiker and Heribert Schunkert and Erik Ingelsson and Kiang Liu and Arnett, {Donna K.} and Psaty, {Bruce M.} and Stefan Blankenberg and Larson, {Martin G.} and Felix, {Stephan B.} and Franco, {Oscar H.} and Tanja Zeller and Vasan, {Ramachandran S.} and Marcus D{\"o}rr",
year = "2017",
month = "5",
day = "1",
doi = "10.1172/JCI84840",
language = "English (US)",
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pages = "1798--1812",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
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}

TY - JOUR

T1 - Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

AU - Wild, Philipp S.

AU - Felix, Janine F.

AU - Schillert, Arne

AU - Teumer, Alexander

AU - Chen, Ming Huei

AU - Leening, Maarten J.G.

AU - Völker, Uwe

AU - Großmann, Vera

AU - Brody, Jennifer A.

AU - Irvin, Marguerite R.

AU - Shah, Sanjiv J.

AU - Pramana, Setia

AU - Lieb, Wolfgang

AU - Schmidt, Reinhold

AU - Stanton, Alice V.

AU - Malzahn, Dörthe

AU - Smith, Albert Vernon

AU - Sundström, Johan

AU - Minelli, Cosetta

AU - Ruggiero, Daniela

AU - Lyytikäinen, Leo Pekka

AU - Tiller, Daniel

AU - Smith, J. Gustav

AU - Monnereau, Claire

AU - Di Tullio, Marco R.

AU - Musani, Solomon K.

AU - Morrison, Alanna C.

AU - Pers, Tune H.

AU - Morley, Michael

AU - Kleber, Marcus E.

AU - Aragam, Jayashri

AU - Benjamin, Emelia J.

AU - Bis, Joshua C.

AU - Bisping, Egbert

AU - Broeckel, Ulrich

AU - Cheng, Susan

AU - Deckers, Jaap W.

AU - Del Greco M, Fabiola

AU - Edelmann, Frank

AU - Fornage, Myriam

AU - Franke, Lude

AU - Friedrich, Nele

AU - Harris, Tamara B.

AU - Hofer, Edith

AU - Hofman, Albert

AU - Huang, Jie

AU - Hughes, Alun D.

AU - Kähönen, Mika

AU - Kruppa, Jochen

AU - Lackner, Karl J.

AU - Lannfelt, Lars

AU - Laskowski, Rafael

AU - Launer, Lenore J.

AU - Leosdottir, Margrét

AU - Lin, Honghuang

AU - Lindgren, Cecilia M.

AU - Loley, Christina

AU - MacRae, Calum A.

AU - Mascalzoni, Deborah

AU - Mayet, Jamil

AU - Medenwald, Daniel

AU - Morris, Andrew P.

AU - Müller, Christian

AU - Müller-Nurasyid, Martina

AU - Nappo, Stefania

AU - Nilsson, Peter M.

AU - Nuding, Sebastian

AU - Nutile, Teresa

AU - Peters, Annette

AU - Pfeufer, Arne

AU - Pietzner, Diana

AU - Pramstaller, Peter P.

AU - Raitakari, Olli T.

AU - Rice, Kenneth M.

AU - Rivadeneira, Fernando

AU - Rotter, Jerome I.

AU - Ruohonen, Saku T.

AU - Sacco, Ralph L

AU - Samdarshi, Tandaw E.

AU - Schmidt, Helena

AU - Sharp, Andrew S.P.

AU - Shields, Denis C.

AU - Sorice, Rossella

AU - Sotoodehnia, Nona

AU - Stricker, Bruno H.

AU - Surendran, Praveen

AU - Thom, Simon

AU - Töglhofer, Anna M.

AU - Uitterlinden, André G.

AU - Wachter, Rolf

AU - Völzke, Henry

AU - Ziegler, Andreas

AU - Münzel, Thomas

AU - März, Winfried

AU - Cappola, Thomas P.

AU - Hirschhorn, Joel N.

AU - Mitchell, Gary F.

AU - Smith, Nicholas L.

AU - Fox, Ervin R.

AU - Dueker, Nicole D.

AU - Jaddoe, Vincent W.V.

AU - Melander, Olle

AU - Russ, Martin

AU - Lehtimäki, Terho

AU - Ciullo, Marina

AU - Hicks, Andrew A.

AU - Lind, Lars

AU - Gudnason, Vilmundur

AU - Pieske, Burkert

AU - Barron, Anthony J.

AU - Zweiker, Robert

AU - Schunkert, Heribert

AU - Ingelsson, Erik

AU - Liu, Kiang

AU - Arnett, Donna K.

AU - Psaty, Bruce M.

AU - Blankenberg, Stefan

AU - Larson, Martin G.

AU - Felix, Stephan B.

AU - Franco, Oscar H.

AU - Zeller, Tanja

AU - Vasan, Ramachandran S.

AU - Dörr, Marcus

PY - 2017/5/1

Y1 - 2017/5/1

N2 - BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

AB - BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

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U2 - 10.1172/JCI84840

DO - 10.1172/JCI84840

M3 - Article

VL - 127

SP - 1798

EP - 1812

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -