Mapping A Novel Locus For Familial Atrial Fibrillation

Objective The purpose of this study was to identify the novel causative locus forhuman familial atrial fibrillation (AF) and to investigate the molecular basis of AF.Background AF is the most common clinically significant arrhythmia, whoseprevalence increases sharply with age. As an independent risk factor, AF can lead tosevere complications such as stroke and heart failure. A recent survey in a largecohort of lone AF demonstrated that 39％of individuals had a positive family history.The latest epidemiological data from the Framingham study in an unselectedpopulation-based sample showed that 30％of AF patients had a genetic background.Up to now, three chromosomal loci (10q22-24, 6q14-16 and 5p13) and threepotassium ion channel genes (KCNQ1, KCNE2 and KCNJ2) have been found to beassociated with familial AF. However, in most other AF cases the genetic basis is stillpoorly understood.Methods In the present study, we analyzed a four-generation Dutch family in whichAF segregated as an autosomal dominant trait. After the exclusion of linkage to10q22-24, 6q14-16, 5p13, KCNQ1, KCNE2, KCNJ2, and some ionchannel-associated candidate genes, a genome-wide linkage scan using 398microsatellite markers was performed.Results After genome-wide scanning at a density of 10cM, a two-point LOD score of3.9645 ([θ]=0.00) at D10S1652 and a haplotype segregating with the disorder weredemonstrated only across regions of chromosome 10. Subsequent fine mapping gavea maximum two-point LOD score of 4.1982 ([θ]=0.00) at D10S568. Distinctrecombination in several individuals narrowed the shared region among all affectedindividuals to 16.4cM on the Genethon map (flanking markers: D10S578 andD10S1652), corresponding to chromosome 10p11-q21. Thirteen candidate genesresiding in this region, which could be associated with AF, were screened. Nomutation has been found in their coding regions including the intron splice regions.Conclusions We identify a novel locus for AF on chromosome 10p11-q21, whichprovides further evidence of genetic heterogeneity in this arrhythmia.