Variants conferring risk of atrial fibrillation on chromosome 4q25

Abstract

A genome-wide association scan in populations from Sweden, North America and China has identified two single-letter sequence variants on chromosome 4q25 as risk factors for atrial fibrillation, the most common form of cardiac arrhythmia. Both are adjacent to the PITX2 gene, known to be involved in early heart development. This work identifies PITX2 as a target for diagnostic tests and possibly for therapeutic intervention. As the most common cardiac arrythmia, atrial fibrillation is of interest to physicians, and has recently been shown to have genetic components. Gudjbartsson et al. have conducted a genome-wide association scan in populations from around the globe, and find a strong link to a gene involved in early heart development. This gene, PITX2, could be a candidate for therapeutic intervention. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria1. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality2. Recent studies have provided evidence of a genetic contribution to AF3,4,5. Mutations in potassium-channel genes have been associated with familial AF6,7,8,9,10 but account for only a small fraction of all cases of AF11,12. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left–right asymmetry of the heart13,14,15.