July 01, 2010
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Genome-wide association studies identify two common genetic risk variants predisposing to AF

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The first gene predisposing to atrial fibrillation has been identified by genome-wide association studies and the second mapped by two independent groups, both publishing work appearing in the same issue of Nature Genetics.

AF is the most common arrhythmia. It is extremely age-dependent with the claim that 5% of the population has AF older than the age of 65. The lifetime risk for AF is 25% in men and women older than the age of 40 years. In addition to its potential morbidity, it also increases mortality. It is a major risk factor for cardioembolic stroke, accounting for one-third of embolic strokes and about 10% of all ischemic strokes. AF increases the risk of stroke four- to fivefold across all age groups. AF most commonly occurs in association with structural heart disease such as valvular or CAD. However, the so-called “lone AF” occurring earlier in life in individuals without structural heart disease is thought to be primarily genetic in origin. In keeping with this hypothesis, several pedigrees with AF have been genotyped and several mutations identified involving primarily the potassium channels. These single gene disorders are rare and inherited in a mendelian fashion primarily as autosomal dominant.

Robert Roberts, MD
Robert Roberts

Although most of AF (particularly in the older than 60 years group) is associated with structural heart disease, it remains to be determined why only a small percentage of people with the same structural heart defect develop AF. The hypothesis has been proposed that some if not most of these individuals have a genetic predisposition and the injury is the triggering event. Genes that predispose to common disease are felt to have only minimal to moderate effect and act in concert with several other genes to induce the phenotype. This is quite different from the rare single gene disorders (lone AF) that are in themselves capable of inducing the phenotype. Single gene disorders exhibit a phenotypic mendelian pattern and their chromosomal location (locus) can be mapped by a few hundred DNA markers in pedigrees with the disease. This is not the case for genes that predispose to common diseases associated with multiple genes each contributing minimal effect to the phenotype. The technology to perform genome-wide association studies (GWAS) in search of such genes only became available in 2005. Utilizing this technology, the first risk variant for CAD (9p21) was mapped and the deCODE group of Iceland performed the first GWAS and identified the first locus for AF on the long arm of chromosome 4 (4q25). In an issue of Nature Genetics published earlier this year, a second locus was identified and reported by two separate groups, the deCODE group and the CHARGE group.

The deCODE group pursued a GWAS on a population of 2,385 individuals with AF vs. 33,752 controls. In this study, the cases and controls were genotyped using more than 300,000 single nucleotide polymorphisms. They confirmed the association for the previous risk variant of 4q25 and identified a second risk variant on chromosome 16 (16q22) which is in a gene referred to as ZFHX3. The P-value for the difference in the frequency of this risk variant in cases vs. controls was 9.2 × 10-9. This association was analyzed for replication in an independent population consisting of a cohort from Iceland (989 cases, 2027 controls), Norway (725 cases, 725 controls) and the United States (735 cases, 729 controls). A marker in the locus 16q22 which showed genome-wide significance in the Icelandic discovery population was replicated (P=.005). A meta-analysis of the combined populations of more than 40,000 provided an association with a P-value of 1.4 × 10-10. The risk variant (16q22) was also associated with increased risk for ischemic and embolic stroke in a combined analysis of five stroke cohorts. The risk variant is an allele of the zinc finger homeobox 3 (ZFHX3) gene on chromosome 16q22. In the past, this gene has also been referred to as the AT motif-binding factor 1 (ATBF1). The ZFHX3 gene is expressed in multiple tissues, including heart, liver, lung, kidney, pituitary gland and brain. It is associated with the regulation of growth and differentiation of several tissues, including neuronal and skeletal muscle. The risk variant at 16q22 for AF increased the mean relative risk of AF by 21% occurring at a frequency in the European population that varied from 18% to 23%.

In the same issue of Nature Genetics, Benjamin, and colleagues in the CHARGE Study performed a GWAS and showed an association between ZFHX3 gene and AF. This association was also replicated in an independent population. The investigators genotyped more than 3,000 cases of AF and more than 37,000 controls. The CHARGE population consisted of several different cohorts from the United States, Iceland and Holland. The ZFHX3 gene was far more common in cases than controls, with the difference giving a P-value of 2.3 × 10-7. This association with AF was then replicated in an independent cohort, the German AF network (AFNET) consisting of 2,140 cases and 4,073 controls. In a meta-analysis of both the CHARGE and the AFNET populations, the difference between the frequency of this allele (ZFHX3) in cases and controls provided a P-value of 1.8 × 10-15. The imparted relative risk of ZFHX3 in CHARGE was greater than in the Icelandic study, varying from 19% to 44%. The frequency of the risk variant in the general population was similar, about 20%. The confirmation in such large sample sizes indicate ZFHX3 is robustly associated with increased risk for AF. Thus, within 2 years, two genes have been identified and replicated in independent populations predisposing to AF. The exact function of the ZFHX3 gene and the gene at the 4q25 locus in the heart remains to be determined. Both of these genes could ultimately serve as targets for the development of new drugs specifically designed to prevent AF.

Robert Roberts, MD, is the president and CEO of the University of Ottawa Heart Institute and director of the Ruddy Canadian Cardiovascular Genetics Centre at the University of Ottawa Heart Institute. Brandon Roberts, MSc, is a resident at the University of Ottawa Heart Center.

For more information:

  • Benjamin E. Nature Genetics. 2009;41:879-881.
  • Gudbjartsson D. Nature. 2007;448:353-357.
  • Gudbjartsson D. Nature Genetics. 2009;41:876.
  • McPherson R. Science. 2007;316:1488-1491.
  • Vassiliou G. J Lipid Res. 2004;45:1683-1693.