Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

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 × 10−8) 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.

Metabolomic Profiles, Ideal Cardiovascular Health, and Risk of Heart Failure and Atrial Fibrillation: Insights From the Framingham Heart Study

“…To date, a limited number of studies have evaluated the relationship between circulating metabolites and AF. 38 , 39 , 40 , 41 , 42 , 43 , 44 In the community‐based ARIC (Atherosclerosis Risk in Community) Study, glycolithocholate sulfate and glycocholenate sulfate (bile acid metabolites) in Black individuals 38 and pseudouridine and uridine (pyrimidine metabolism), and acisoga (polyamine metabolism) were associated with incident AF. 39 However, a prior FHS study found no association of AF risk with the 217 metabolites in the sample studied with 156 AF events with 10 years of follow‐up.…”

Phenotypic spectrum ofFAM47E-SHROOM3haplotype composition in a general population sample

“…Data processing, read alignment and QC were conducted as detailed previously. 23,24 We retained 3422 samples with a post-QC mean target coverage of 68.4X.…”

“…Data processing, read alignment and QC were conducted as detailed previously. 23,24 We retained 3422 samples with a post-QC mean target coverage of 68.4X. WES data were used as a population-specific reference panel for genotype imputation onto the whole CHRIS sample as reported previously.…”

Pervasive Influence of Hormonal Contraceptives on the Human Plasma Proteome in a Broad Population Study

“…Some recent work has been published evaluating the impact of age, sex and diet, amongst others, on the human metabolome (Verri Hernandes et al, 2022). Moreover, gene-metabolite associations (König et al, 2022), as well as genetic and metabolomic determinants of disease (Emmert et al, 2021), have been investigated. We performed a general exploratory analysis of the data set to identify relevant factors affecting the plasma proteome and found hormonal contraceptives to be the main factor explaining the variation in a human plasma proteome from European individuals.…”

“…In recent work, we have been evaluating the impact of age, sex and diet, amongst others, on the human metabolome (Verri Hernandes et al, 2022). Moreover, gene-metabolite associations (König et al, 2022), as well as genetic and metabolomic determinants of disease (Emmert et al, 2021), have been investigated. Using Scanning SWATH (Messner et al, 2021) acquisition on Triple TOF 6600 Instruments (Sciex) we created a MS-based plasma proteomics data set with low technical variability for n = 3,632 CHRIS participants.…”