| Summary: | Introduction and aims: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and its complex pathophysiology is incompletely understood. At the time of beginning of this work, genome-wide association studies (GWAS) on AF had yielded about 30 associations, mostly with common variants in the non-coding genome that affect AF risk through unknown mechanisms. Recently, rare coding variants in the sarcomere genes MYH6 and MYL4 associated with increased risk of AF, representing a novel implication of the sarcomere in arrhythmogenesis in the absence of cardiomyopathy. The aim of this doctoral research was to perform GWASs on AF and search for novel associations. Furthermore, to gain insights into the mechanisms by which novel and published variants affect AF risk by assessing their effects on other cardiovascular diseases and on normal cardiac conduction, using electrocardiogram (ECG) measurements. Through association analysis we observed that one of the strongest AF variants, in MYH6, accounts for 20% of Icelandic cases of coarctation of the aorta (CoA), thus we decided to explore this variant and its effects on structural heart disease in detail resulting in a separate paper. The overall purpose of identifying novel associations of sequence variants with AF is to further the understanding of underlying pathogenesis and facilitate advances in treatment. Methods: We conducted four GWASs. In all cases, genotype information of Icelandic participants was based on whole-genome sequencing of 15,220 and chip-typing of 151,677 individuals performed at deCODE genetics. We tested AF variants for association with measurements in 289,297 sinus rhythm ECGs from 62,974 individuals. Three GWASs on AF and one on CoA were performed: i) A GWAS among 13,471 AF cases and 374,939 controls from Iceland with additional follow up in samples from the US. ii) A meta-analysis of GWAS on AF among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on ...
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