Abstract
Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated
electrical activation with considerable associated morbidity and mortality. To expand the limited
understanding of AF biological mechanisms, we performed two screenings, investigating the genetic
and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We
found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan
(GWAS) identified two novel loci (p-value < 5 108) around SNPs rs745582874, next to gene PBX1,
and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk
alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the
phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites,
in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC
a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with
previous evidence, indicate that the two identified GWAS loci may be considered novel genetic
rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by
metabolic screening, our results demonstrate the valuable contribution of the combined genomic and
metabolomic approach in studying AF in large-scale population studies.