A combined linkage and exome sequencing analysis for electrocardiogram parameters in the erasmus rucphen family study

Claudia T. Silva, Irina V. Zorkoltseva, Najaf Amin, Ayse Demirkan, Elisabeth M. van Leeuwen, Jan A. Kors, Marten van den Berg, Bruno H. Stricker, André G. Uitterlinden, Anatoly V. Kirichenko, Jacqueline C M Witteman, Rob Willemsen, Ben A. Oostra, Tatiana I. Axenovich, Cornelia M. van Duijn, Aaron Isaacs

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© 2016 Silva, Zorkoltseva, Amin, Demirkan, van Leeuwen, Kors, van den Berg, Stricker, Uitterlinden, Kirichenko, Witteman, Willemsen, Oostra, Axenovich, van Duijn and Isaacs.Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, QRS, and QT intervals, are known to be heritable and genome-wide association studies of these phenotypes have been successful in identifying common variants; however, a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing variance component linkage analysis in 1547 individuals from a large family-based study, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using exome sequencing. Five suggestive linkage peaks were identified: two for QT interval (1q24, LOD = 2.63; 2q34, LOD = 2.05), one for QRS interval (1p35, LOD = 2.52) and two for PR interval (9p22, LOD = 2.20; 14q11, LOD = 2.29). Fine-mapping using exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) in the FCRL2 gene associated with QT (rs74608430; P = 2.8 × 10-4, minor allele frequency = 0.019). Heritability analysis demonstrated that the SNP explained 2.42% of the trait's genetic variability in ERF (P = 0.02). Pathway analysis suggested that the gene is involved in cytosolic Ca2+ levels (P = 3.3 × 10-3) and AMPK stimulated fatty acid oxidation in muscle (P = 4.1 × 10-3). Look-ups in bioinformatics resources showed that expression of FCRL2 is associated with ARHGAP24 and SETBP1 expression. This finding was not replicated in the Rotterdam study. Combining the bioinformatics information with the association and linkage analyses, FCRL2 emerges as a strong candidate gene for QT interval.
Idioma originalEnglish (US)
PublicaciónFrontiers in Genetics
DOI
EstadoPublished - nov 8 2016

Huella dactilar

Exome
Electrocardiography
Computational Biology
Genes
AMP-Activated Protein Kinases
Genome-Wide Association Study
Sudden Cardiac Death
Gene Frequency
Single Nucleotide Polymorphism
Cardiac Arrhythmias
Fatty Acids
Phenotype
Muscles

Citar esto

Silva, Claudia T. ; Zorkoltseva, Irina V. ; Amin, Najaf ; Demirkan, Ayse ; van Leeuwen, Elisabeth M. ; Kors, Jan A. ; van den Berg, Marten ; Stricker, Bruno H. ; Uitterlinden, André G. ; Kirichenko, Anatoly V. ; Witteman, Jacqueline C M ; Willemsen, Rob ; Oostra, Ben A. ; Axenovich, Tatiana I. ; van Duijn, Cornelia M. ; Isaacs, Aaron. / A combined linkage and exome sequencing analysis for electrocardiogram parameters in the erasmus rucphen family study. En: Frontiers in Genetics. 2016.
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title = "A combined linkage and exome sequencing analysis for electrocardiogram parameters in the erasmus rucphen family study",
abstract = "{\circledC} 2016 Silva, Zorkoltseva, Amin, Demirkan, van Leeuwen, Kors, van den Berg, Stricker, Uitterlinden, Kirichenko, Witteman, Willemsen, Oostra, Axenovich, van Duijn and Isaacs.Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, QRS, and QT intervals, are known to be heritable and genome-wide association studies of these phenotypes have been successful in identifying common variants; however, a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing variance component linkage analysis in 1547 individuals from a large family-based study, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using exome sequencing. Five suggestive linkage peaks were identified: two for QT interval (1q24, LOD = 2.63; 2q34, LOD = 2.05), one for QRS interval (1p35, LOD = 2.52) and two for PR interval (9p22, LOD = 2.20; 14q11, LOD = 2.29). Fine-mapping using exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) in the FCRL2 gene associated with QT (rs74608430; P = 2.8 × 10-4, minor allele frequency = 0.019). Heritability analysis demonstrated that the SNP explained 2.42{\%} of the trait's genetic variability in ERF (P = 0.02). Pathway analysis suggested that the gene is involved in cytosolic Ca2+ levels (P = 3.3 × 10-3) and AMPK stimulated fatty acid oxidation in muscle (P = 4.1 × 10-3). Look-ups in bioinformatics resources showed that expression of FCRL2 is associated with ARHGAP24 and SETBP1 expression. This finding was not replicated in the Rotterdam study. Combining the bioinformatics information with the association and linkage analyses, FCRL2 emerges as a strong candidate gene for QT interval.",
author = "Silva, {Claudia T.} and Zorkoltseva, {Irina V.} and Najaf Amin and Ayse Demirkan and {van Leeuwen}, {Elisabeth M.} and Kors, {Jan A.} and {van den Berg}, Marten and Stricker, {Bruno H.} and Uitterlinden, {Andr{\'e} G.} and Kirichenko, {Anatoly V.} and Witteman, {Jacqueline C M} and Rob Willemsen and Oostra, {Ben A.} and Axenovich, {Tatiana I.} and {van Duijn}, {Cornelia M.} and Aaron Isaacs",
year = "2016",
month = "11",
day = "8",
doi = "10.3389/fgene.2016.00190",
language = "English (US)",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media S. A.",

}

Silva, CT, Zorkoltseva, IV, Amin, N, Demirkan, A, van Leeuwen, EM, Kors, JA, van den Berg, M, Stricker, BH, Uitterlinden, AG, Kirichenko, AV, Witteman, JCM, Willemsen, R, Oostra, BA, Axenovich, TI, van Duijn, CM & Isaacs, A 2016, 'A combined linkage and exome sequencing analysis for electrocardiogram parameters in the erasmus rucphen family study', Frontiers in Genetics. https://doi.org/10.3389/fgene.2016.00190

A combined linkage and exome sequencing analysis for electrocardiogram parameters in the erasmus rucphen family study. / Silva, Claudia T.; Zorkoltseva, Irina V.; Amin, Najaf; Demirkan, Ayse; van Leeuwen, Elisabeth M.; Kors, Jan A.; van den Berg, Marten; Stricker, Bruno H.; Uitterlinden, André G.; Kirichenko, Anatoly V.; Witteman, Jacqueline C M; Willemsen, Rob; Oostra, Ben A.; Axenovich, Tatiana I.; van Duijn, Cornelia M.; Isaacs, Aaron.

En: Frontiers in Genetics, 08.11.2016.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - A combined linkage and exome sequencing analysis for electrocardiogram parameters in the erasmus rucphen family study

AU - Silva, Claudia T.

AU - Zorkoltseva, Irina V.

AU - Amin, Najaf

AU - Demirkan, Ayse

AU - van Leeuwen, Elisabeth M.

AU - Kors, Jan A.

AU - van den Berg, Marten

AU - Stricker, Bruno H.

AU - Uitterlinden, André G.

AU - Kirichenko, Anatoly V.

AU - Witteman, Jacqueline C M

AU - Willemsen, Rob

AU - Oostra, Ben A.

AU - Axenovich, Tatiana I.

AU - van Duijn, Cornelia M.

AU - Isaacs, Aaron

PY - 2016/11/8

Y1 - 2016/11/8

N2 - © 2016 Silva, Zorkoltseva, Amin, Demirkan, van Leeuwen, Kors, van den Berg, Stricker, Uitterlinden, Kirichenko, Witteman, Willemsen, Oostra, Axenovich, van Duijn and Isaacs.Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, QRS, and QT intervals, are known to be heritable and genome-wide association studies of these phenotypes have been successful in identifying common variants; however, a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing variance component linkage analysis in 1547 individuals from a large family-based study, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using exome sequencing. Five suggestive linkage peaks were identified: two for QT interval (1q24, LOD = 2.63; 2q34, LOD = 2.05), one for QRS interval (1p35, LOD = 2.52) and two for PR interval (9p22, LOD = 2.20; 14q11, LOD = 2.29). Fine-mapping using exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) in the FCRL2 gene associated with QT (rs74608430; P = 2.8 × 10-4, minor allele frequency = 0.019). Heritability analysis demonstrated that the SNP explained 2.42% of the trait's genetic variability in ERF (P = 0.02). Pathway analysis suggested that the gene is involved in cytosolic Ca2+ levels (P = 3.3 × 10-3) and AMPK stimulated fatty acid oxidation in muscle (P = 4.1 × 10-3). Look-ups in bioinformatics resources showed that expression of FCRL2 is associated with ARHGAP24 and SETBP1 expression. This finding was not replicated in the Rotterdam study. Combining the bioinformatics information with the association and linkage analyses, FCRL2 emerges as a strong candidate gene for QT interval.

AB - © 2016 Silva, Zorkoltseva, Amin, Demirkan, van Leeuwen, Kors, van den Berg, Stricker, Uitterlinden, Kirichenko, Witteman, Willemsen, Oostra, Axenovich, van Duijn and Isaacs.Electrocardiogram (ECG) measurements play a key role in the diagnosis and prediction of cardiac arrhythmias and sudden cardiac death. ECG parameters, such as the PR, QRS, and QT intervals, are known to be heritable and genome-wide association studies of these phenotypes have been successful in identifying common variants; however, a large proportion of the genetic variability of these traits remains to be elucidated. The aim of this study was to discover loci potentially harboring rare variants utilizing variance component linkage analysis in 1547 individuals from a large family-based study, the Erasmus Rucphen Family Study (ERF). Linked regions were further explored using exome sequencing. Five suggestive linkage peaks were identified: two for QT interval (1q24, LOD = 2.63; 2q34, LOD = 2.05), one for QRS interval (1p35, LOD = 2.52) and two for PR interval (9p22, LOD = 2.20; 14q11, LOD = 2.29). Fine-mapping using exome sequence data identified a C > G missense variant (c.713C > G, p.Ser238Cys) in the FCRL2 gene associated with QT (rs74608430; P = 2.8 × 10-4, minor allele frequency = 0.019). Heritability analysis demonstrated that the SNP explained 2.42% of the trait's genetic variability in ERF (P = 0.02). Pathway analysis suggested that the gene is involved in cytosolic Ca2+ levels (P = 3.3 × 10-3) and AMPK stimulated fatty acid oxidation in muscle (P = 4.1 × 10-3). Look-ups in bioinformatics resources showed that expression of FCRL2 is associated with ARHGAP24 and SETBP1 expression. This finding was not replicated in the Rotterdam study. Combining the bioinformatics information with the association and linkage analyses, FCRL2 emerges as a strong candidate gene for QT interval.

U2 - 10.3389/fgene.2016.00190

DO - 10.3389/fgene.2016.00190

M3 - Article

C2 - 27877193

JO - Frontiers in Genetics

JF - Frontiers in Genetics

SN - 1664-8021

ER -