Nation-wide inititative on atrial fibrillation: epidemiologic, genetic and molecular properties in the Norwegian population.

Atrial fibrillation is a cardiac rhythm disorder that increases risk for stroke, heart failure, dementia and death. It affects more than 30 million individuals worldwide. A substantial proportion of the patients are diagnosed at an early age. Individuals with early-onset are more likely to have a heritable predisposition for their atrial fibrillation. The GENAF Norway study is a national and international collaboration, involving renowned researchers in the field of atrial fibrillation in Norway and worldwide. In the GENAF Norway project, we will for the first time describe the young population with atrial fibrillation in Norway - an underdiagnosed and undertreated group of patients. We have identified ~10.000 individuals with early-onset atrial fibrillation in the national reimbursement registry for primary healthcare services (KUHR). We have shown that 3-4 per 1000 individuals develop atrial fibrillation before age 50 years in Norway, and that the frequency of primary healthcare consultations for atrial fibrillation in young men is higher than in young women. There may be several explanations for the difference in utilization og primary healthcare services, e.g. increased burden of atrial fibrillation in young men or misdiagnosis in young women with atrial fibrillation due to atypical symptoms. We aim to explore this using questionnaire data at a later stage of the project. We have invited the 10.000 individuals with early-onset atrial fibrillation to participate in our study, through their general practitioners, and have enrolled more than 1000 individuals with early-onset AF so far. In preliminary analyses from whole-genome sequencing in 90 individuals with early-onset atrial fibrillation, we have identified a high frequency of mutations in the titin gene, which is important in the heart muscle. We have shown that the mutations alter the structural properties in mouse hearts. We will perform whole-genome sequencing in all enrolled participants. We expect to publish the results shortly. Identification of clinical and genetic factors that are associated with atrial fibrillation will aid the development of better tools for prediction of risk and treatment effect, in addition to new treatment options. Ultimately, we aim to deliver more individualized and tailored treatment for atrial fibrillation in the future.

Our goal is to establish a sustainable atrial fibrillation (AF) genetics initiative in Norway and to elucidate the molecular mechanisms underlying this common cardiac arrhythmia. AF affects more than 30 million individuals worldwide and increases the risk of stroke, heart failure, dementia and death. Current treatment options for AF are limited, may have serious potential side effects and are only partially successful. This clearly shows that we have insufficient knowledge about the underlying mechanisms of the disease. While genetic research in AF has expanded rapidly internationally, Norwegian contributions have been limited. In this proposal, we will perform the first national meta-analysis of genome-wide association studies (GWAS) on AF in Norway with ~10 000 AF cases, aiming to discover new common variants associated with AF. Early-onset of AF indicates genetic predisposition, and often leads to a more severe prognosis. We will I) describe the burden of disease and co-morbidity in the total population with early-onset AF in Norway, and II) invite all identified individuals for whole-genome sequencing to identify common and rare variants associated with early-onset AF. Our preliminary analyses have identified a high frequency of mutations in the titin gene, which is important in the heart muscle. We will evaluate the effects of the mutations on structural, molecular and electrical properties of the atrium in a mouse model. Genetic variants identified in the GWAS meta-analysis will be functionally characterized in zebrafish experiments, to identify the mechanistic links between the genetic variants and atrial fibrillation pathophysiology. We integrate data from all parts of this project to build prediction models for identifying groups of individuals with increased risk for AF, AF-related stroke, recurrence of AF after antiarrhythmic treatment, and thus to aid the development of tailored monitoring, treatment, and prevention of this common and deadly arrhythmia.