A Combined Linkage and Exome Sequencing Analysis for Electrocardiogram Parameters in the Erasmus Rucphen Family Study

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Electrocardiogram (ECG) parameters like PR, QRS, and QT intervals are crucial for diagnosing cardiac arrhythmias and predicting sudden cardiac death.
• While genome-wide association studies have identified common variants, a significant portion of genetic variability in these ECG traits remains unexplained.
• Identifying rare variants is essential for a comprehensive understanding of the genetic architecture of cardiac electrical activity.

Purpose of the Study:

• To discover novel genetic loci harboring rare variants influencing ECG parameters using variance component linkage analysis.
• To explore linked regions identified through linkage analysis with exome sequencing.
• To identify specific genetic variants associated with ECG traits and elucidate their functional implications.

Main Methods:

• Variance component linkage analysis was performed on 1547 individuals from the Erasmus Rucphen Family (ERF) study.
• Exome sequencing was used to fine-map regions identified by linkage analysis.
• Association analyses, heritability estimations, and pathway analyses were conducted to evaluate identified variants and genes.

Main Results:

• Five suggestive linkage peaks were identified for QT, QRS, and PR intervals.
• A rare C > G missense variant (p.Ser238Cys) in the FCRL2 gene was significantly associated with QT interval (rs74608430; P = 2.8 × 10⁻⁴).
• This FCRL2 variant explained 2.42% of the genetic variability in QT interval and was implicated in cytosolic Ca²+ levels and AMPK-stimulated fatty acid oxidation.

Conclusions:

• The FCRL2 gene, particularly the identified rare variant, is a strong candidate for influencing QT interval duration.
• This study highlights the importance of investigating rare variants for understanding the genetic basis of ECG phenotypes.
• Further research into FCRL2's role in cardiac electrophysiology may provide new insights into arrhythmia mechanisms.