Skip to main content
Premium Trial:

Request an Annual Quote

Atrial Fibrillation GWAS Provides Clues to Heart Condition

NEW YORK (GenomeWeb) – An international team led by investigators in the US and Norway has implicated seven loci in atrial fibrillation risk, including two sites not associated with the common heart condition in the past.

"[T]his study identified two [atrial fibrillation] loci that both point to a mechanism of cardiac structural remodeling as a substrate of [atrial fibrillation]," co-corresponding authors Cristen Willer, a researcher at the University of Michigan, and Norwegian University of Science and Technology researcher Kristian Hveem, and their colleagues wrote.

As they reported in the American Journal of Human Genetics, Willer, Hveem, and colleagues did a genome-wide association study involving more than 6,300 individuals from Norway with atrial fibrillation and more than 61,600 without. Their search led to new chromosome 1 and 2 loci near genes involved in processes related to muscle elasticity and sarcomere muscle protein structure — results they verified in hundreds of thousands more cases and controls before examining the full suite of risk loci in detail.

Tens of millions of individuals around the world are affected by atrial fibrillation, the team explained, a condition marked by out-of-sync electrical activity in the heart's atrial region that dials up the risk of stroke, heart failure, or even death. Although factors such as age and obesity are implicated in atrial fibrillation risk, the authors noted that the condition also appears to run in families, generating interest in genetic contributors to atrial fibrillation.

"Although rare mutations in genes encoding cardiac ion channels, gap junctions, and signaling molecules have been shown to contribute to [atrial fibrillation] risk in individual families, [atrial fibrillation] is generally considered a complex and polygenic disease," they wrote.

To search for loci to add to those already linked to atrial fibrillation, the researchers used Illumina arrays to genotype 6,337 atrial fibrillation sufferers and 61,607 unaffected controls, all participating in an ongoing population health study in a Norwegian county. By comparing nearly 9 million directly genotyped and imputed SNPs in the cases and controls, they narrowed in on two loci that had not been linked to atrial fibrillation previously.

The team validated the new loci — a locus on chromosome 2 marked by missense variants affecting the titin-coding gene TTN and a chromosome 1 locus involving variants in and around DMRTA2 and other genes — using data for 30,679 atrial fibrillation cases and 278,895 controls, enrolled through projects in the US, UK, Norway, or Denmark. In the process, the group verified associations at five of the 16 loci with reported atrial fibrillation associations in past studies.

Through a series of follow-up analyses, the researchers considered risk variants in the context of age of disease onset and other clinical or lifestyle factors. They also did fine mapping at the newly identified loci, considered atrial fibrillation-related expression quantitative trait locus and regulatory clues, and performed a gene-based search for rarer alterations over-represented in protein-coding sequences from the atrial fibrillation cases.

The team noted that the risky atrial fibrillation alleles identified tended to coincide with early-onset forms of the disease, for example, while a search for lower frequency risk variants within a subset of the atrial fibrillation cases and controls pointed to a slight but non-statistically significant over-representation in alterations affecting genes previously implicated in familial atrial fibrillation studies.

Together with available chromatin accessibility profiles, regulatory information, and expression profiles, the loci identified led the study's authors to suspect that atrial fibrillation risk may stem in part from changes to epigenetic features and pathways that are normally active during fetal heart development.

Willer, Hveem, and co-authors cautioned that "[t]his hypothesis needs confirmation," but noted that it "might provide a foundation for directing future functional experiments to identify the functional genes and genetic mechanisms at [atrial fibrillation] risk loci."