Prolonged Signal-Averaged P-Wave Duration as an Intermediate Phenotype for Familial Atrial Fibrillation

Abstract

This study sought to perform a genome-wide linkage analysis in a large atrial fibrillation (AF) kindred using AF and abnormally prolonged signal-averaged (SA) P-wave duration as the phenotype. Although inherited forms of AF exist, phenotypic complexity has limited efforts to ascertain mutation carriers and thus identify causal genes. The identification of intermediate or endophenotypes may accelerate this effort. A genome-wide linkage analysis was performed in a 4-generation AF kindred of 27 individuals, 8 with AF documented by electrocardiogram. The analysis was performed using AF as the phenotype, and repeated using an abnormally prolonged SA P-wave duration as the phenotype. Linkage analysis and fine mapping generated a maximum multipoint logarithm of the odds (LOD) score of 3.0 at chromosome 5p15 between markers D5S406 and D5S635. Importantly, 8 heterozygous carriers had a prolonged SA P-wave (203 +/- 21 ms) compared with 17 noncarriers (116 +/- 12 ms, p < 0.00001). Using prolonged SA P-wave (conventionally defined as >155 ms) as an endophenotype, a maximum LOD score of 3.6 was obtained in the same region of chromosome 5p15, a span of 5.75 centi-Morgans. In a large AF kindred, we have identified a novel AF locus on chromosome 5p15 and shown that affected individuals with AF and mutation carriers can be identified by a prolonged SA P-wave duration. Importantly, identification of an endophenotype in this kindred not only aided ascertainment of additional family members but also increased the LOD score, providing increased support for linkage at this locus. Identification of the causal gene, mapped to chromosome 5p15, will advance our understanding of the molecular basis of AF.