Journal
FRONTIERS IN GENETICS
Volume 7, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2016.00190
Keywords
genetics; epidemiology; electrocardiography; linkage; exome
Categories
Funding
- European Commission [018947, LSHG-CL-2006-01947]
- European Community's Seventh Framework Programme [HEALTH-F4-2007-201413]
- European Commission under the programme
- 5th Framework Programme [QLG2-CT-2002-01254]
- Netherlands Organization for Scientific Research
- Russian Foundation for Basic Research [NWO-REBR 047.017.043]
- Russian Federal Agency of Scientific Organizations projects [VI.53.2.2, 0324-2015-0003]
- Netherlands Organization for the Health Research and Development grant [91111025]
- Erasmus Medical Center (MC) and Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- Municipality of Rotterdam
- Federal Agency of Scientific Organizations [0324-2015-0003]
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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 x 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 x 10(-3)) and AMPK stimulated fatty acid oxidation in muscle (P = 4.1 x 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.
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