The "missing" link in atrial fibrillation heritability

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, represents a major health burden to individuals and health care system within the Western world. The lifetime risk for the development of AF at age 40 years has been estimated to be approximately 1 in 4. Atrial fibrillation is associated with substantial morbidity and a 2-fold increased risk of mortality. Given its increasing prevalence with age, coupled with the aging population, the number of Americans affected with AF is expected to increase from approximately 2.3 million in the year 2000 to nearly 16 million by 2050. This AF epidemic is further complicated by the lack of highly effective therapies. One reason for the lack of effective therapies for AF stems from incomplete understanding of the complex pathophysiology of the arrhythmia. Atrial fibrillation has often been regarded as a condition that occurs in the context of atrial electrical and structural remodeling that can result from cardiac and systemic disorders. However, up to 30% of patients have no obvious cause and are said to have idiopathic or "lone" AF. Up until recently, AF was considered to be a sporadic, nongenetic disorder, but we and others have shown that lone AF has a substantial genetic basis. Mutations in genes encoding cardiac ion channels (KCNQ1, KCNE1-5, KCNJ2, KCNA5, and SCN5A), gap junctions (GJA5), and signaling molecules (atrial natriuretic peptide, nucleoporins [NUP155]) have been reported in isolated cases and small kindreds. The advent of the human genome and HapMap projects and high-throughput genotyping has fundamentally accelerated our ability to discover the genetic contribution to common variation in human disease. In 2007, a genome-wide association study identified 2 genetic variants that associated with AF. More recently, 2 additional AF loci on chromosomes 16q22 and 1q21 have been identified. It is quite likely, however, that the effects of alleles in many genes contribute to common complex diseases such as AF. The overall AF risk associated with common variants identified by the genome-wide association study approach is small (odds ratios, 1.1-2.5) and explains less than 10% of the heritability in lone AF. This raises the possibility that rare independent variants with large effects strong effects may account for a large fraction of the risk for lone AF.