title: A Combined Linkage and Exome Sequencing Analysis for Electrocardiogram Parameters in the Erasmus Rucphen Family Study.
abstract: 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 theFCRL2gene 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 ofFCRL2is associated withARHGAP24andSETBP1expression. This finding was not replicated in the Rotterdam study. Combining the bioinformatics information with the association and linkage analyses,FCRL2emerges as a strong candidate gene for QT interval.
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterRotterdam, Netherlands; Doctoral Program in Biomedical Sciences, Universidad del RosarioBogotá, Colombia; GENIUROS Group, Genetics and Genomics Research Center CIGGUR, School of Medicine and Health Sciences, Universidad del RosarioBogotá, Colombia.
authors.forename: Claudia T
authors.initials: CT
authors.lastname: Silva
authors.affiliation: Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences Novosibirsk, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Zorkoltseva
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterRotterdam, Netherlands; Department of Human Genetics, Leiden University Medical CenterLeiden, Netherlands.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Demirkan
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Kors
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: van den Berg
authors.affiliation: Department of Epidemiology, Erasmus University Medical CenterRotterdam, Netherlands; Department of Internal Medicine, Erasmus University Medical CenterRotterdam, Netherlands; Inspectorate of Health CareThe Hague, Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences Novosibirsk, Russia.
authors.forename: Anatoly V
authors.initials: AV
authors.lastname: Kirichenko
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center Rotterdam, Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterRotterdam, Netherlands; Center for Medical Systems BiologyLeiden, Netherlands.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.affiliation: Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences Novosibirsk, Russia.
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Axenovich
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterRotterdam, Netherlands; Center for Medical Systems BiologyLeiden, Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterRotterdam, Netherlands; Center for Medical Systems BiologyLeiden, Netherlands.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
keywords: electrocardiography; epidemiology; exome; genetics; linkage