Is AFib Genetic? A Look at Family Inheritance Patterns

Atrial fibrillation (AFib) is the most common type of irregular heart rhythm, affecting millions worldwide. While lifestyle and medical conditions contribute to its development, genetics also play a role. Understanding family patterns can help identify individuals at higher risk and inform prevention strategies.

Research has uncovered genetic factors influencing AFib susceptibility, though inheritance patterns are complex. Some cases follow clear familial trends, while others involve multiple genes interacting with environmental influences.

Genes That Influence Atrial Activity

The electrical impulses regulating heart rhythm depend on ion channels, structural proteins, and signaling molecules encoded by specific genes. Variants in these genes can alter atrial conduction, increasing AFib susceptibility. One of the most well-documented genetic contributors is the PITX2 gene, which influences left-right asymmetry during embryonic development. Mutations or polymorphisms in PITX2 can lead to structural and electrical remodeling of the left atrium. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) in the 4q25 locus near PITX2 to AFib risk, with certain variants doubling susceptibility.

Beyond PITX2, ion channel genes such as KCNN3, which encodes a potassium channel involved in atrial repolarization, have been linked to AFib. Variants in KCNN3 can prolong or disrupt atrial action potentials, affecting rhythm stability. Similarly, mutations in SCN5A, which encodes the cardiac sodium channel Nav1.5, have been associated with both inherited and sporadic AFib. Dysfunction in SCN5A can slow conduction and promote reentrant circuits, mechanisms known to trigger AFib.

Structural components of the atrial myocardium also influence AFib susceptibility. Variants in TTN, which encodes the giant sarcomeric protein titin, have been associated with atrial enlargement and fibrosis, both risk factors for AFib. Loss-of-function mutations in TTN frequently appear in patients with dilated cardiomyopathy, but even in those without overt heart failure, certain variants contribute to atrial remodeling. Similarly, mutations in GJA5, which encodes connexin 40, a gap junction protein essential for electrical coupling between atrial myocytes, have been linked to conduction abnormalities predisposing to AFib.

Polygenic Factors

AFib is often influenced by multiple genetic variants, each contributing to overall susceptibility. GWAS have identified over 100 loci linked to AFib, underscoring its polygenic nature. Unlike monogenic disorders, where a single mutation directly causes disease, polygenic influences involve numerous small-effect variants that collectively impact atrial electrophysiology, myocardial structure, and autonomic regulation. These genetic factors interact with environmental influences such as hypertension, obesity, and alcohol consumption, creating a complex risk landscape.

Many identified loci relate to genes involved in cardiac development, ion channel function, and extracellular matrix remodeling. Variants in ZFHX3, a transcription factor involved in cardiac muscle differentiation, are associated with AFib risk. Studies suggest ZFHX3 polymorphisms influence atrial conduction velocity and susceptibility to fibrosis, both factors in arrhythmogenesis. Similarly, common variants in PRRX1, another transcription factor affecting heart morphogenesis, impact atrial size and conduction properties.

Beyond structural and developmental genes, polygenic risk includes variants affecting autonomic regulation and inflammatory pathways. Polymorphisms in SYNE2, which encodes nesprin-2, a protein involved in nuclear-cytoskeletal interactions, have been linked to altered atrial mechanics and conduction. Additionally, variants in MYH6, which encodes the alpha-myosin heavy chain, are associated with atrial contractile function, highlighting how minor alterations in sarcomeric protein composition can influence AFib susceptibility.

Family Aggregation Patterns

AFib often clusters within families, indicating a hereditary component. Large-scale epidemiological studies show individuals with a first-degree relative affected by AFib have a significantly higher risk of developing the condition. Data from the Framingham Heart Study indicate that having a parent with AFib nearly doubles the likelihood of experiencing the arrhythmia. This familial clustering persists even after accounting for shared environmental influences.

Inheritance patterns vary, with some families exhibiting clear autosomal dominant transmission, where AFib appears across multiple generations, while others show more sporadic occurrences influenced by a mix of genetic and environmental factors. Familial forms of AFib tend to manifest earlier and often occur without traditional risk factors such as hypertension or heart disease. Studies of multigenerational families with a high prevalence of AFib have found affected members frequently carry rare or high-impact genetic variants.

Beyond immediate relatives, extended family history also plays a role in risk assessment. Research analyzing large population datasets, such as Scandinavian national health registries, has found that even having an affected second-degree relative, such as a grandparent or uncle, correlates with an elevated likelihood of developing AFib. This broader familial association suggests both rare mutations and common genetic variants contribute to AFib clustering. The interplay between genetic predispositions and external factors further complicates individual risk predictions.

Genetic Testing Approaches

Advancements in genetic testing have improved the ability to assess AFib predisposition. While clinical diagnosis relies on electrocardiographic monitoring and symptom evaluation, genetic screening provides additional insight, particularly for individuals with a strong family history. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) can identify rare variants in genes associated with AFib, such as SCN5A and TTN, aiding in the distinction between inherited and sporadic cases. These approaches are particularly useful when AFib develops in younger individuals without traditional risk factors.

Polygenic risk scores (PRS) offer another tool for predicting AFib susceptibility by aggregating the effects of multiple genetic variants. Unlike single-gene testing, PRS evaluates thousands of variants across the genome, each exerting a minor influence on risk. Large-scale analyses, such as UK Biobank data, indicate individuals in the highest PRS percentile have up to a threefold greater likelihood of developing AFib. This information can be integrated into cardiovascular risk assessments, guiding early interventions such as lifestyle modifications or closer cardiac monitoring in high-risk individuals.