IDENTIFICATION OF A GENETIC-LOCUS FOR FAMILIAL ATRIAL-FIBRILLATION

Background Atrial fibrillation, the most common sustained cardiac-rhyt hm disturbance, affects over 2 million Americans and accounts for one third of all strokes in patients over 65 years of age. The molecular b asis for atrial fibrillation is unknown, and palliative therapy is use d to control the ventricular rate and prevent systemic emboli. We iden tified a family of 26 members of whom 10 had atrial fibrillation that segregated as an autosomal dominant disease. We subsequently identifie d two additional families in which the disease was linked to the same locus. Methods We screened the human genome with 300 polymorphic dinuc leotide-repeat markers using an unconventional strategy of pooling the DNA samples into two groups (affected and unaffected), which reduced the sample size by approximately 90 percent, before performing linkage analysis to map the locus. This made it possible to identify potentia l loci within a few weeks. Results The lod scores for markers D10S569 and D10S607, located at 10q22-q24, were 3.60 in Family 1. The disease locus in Families 2 and 3 was also linked to the same markers, with lo d scores of 6.02 and 5.35 for markers D10S569 and D10S607, respectivel y, when data on all three families were combined. Haplotype analysis o f the three families showed that the locus was between D10S1694 and D1 0S1786, an interval of 11.3 centimorgans. Conclusions Identification o f the gene for familial atrial fibrillation will help to elucidate the molecular basis of the disease and provide insights into acquired for ms. The strategy of pooling DNA samples for analysis is more time and cost effective than conventional screening and should accelerate the p rocess of gene mapping in the future. (C) 1997, Massachusetts Medical Society.