Integrated Genomic and Transcriptomic Analysis Reveals the Genetic Basis and Causal Association Between Obesity and...

Area of Science:

• Genetics and Cardiovascular Disease
• Metabolic Disorders Research

Background:

• Observational studies link obesity to increased atrial fibrillation (AF) risk.
• Underlying genetic mechanisms and causality between obesity and AF remain unclear.

Purpose of the Study:

• Systematically investigate genetic associations between obesity and AF.
• Determine the causal relationship direction.
• Identify key pleiotropic genes involved.

Main Methods:

• Utilized pooled genome-wide association study (GWAS) data for obesity and AF.
• Employed linkage disequilibrium score regression (LDSC), high-definition likelihood inference (HDL), and bidirectional Mendelian randomization (MR).
• Applied multi-trait analysis of GWAS (MTAG), functional mapping and annotation (FUMA), GCTA conditional and joint analysis (GCTA-COJO), and gene-based association analyses.

Main Results:

• Confirmed significant genetic correlation between obesity and AF (LDSC: p < 10^-19; HDL: p < 10^-12).
• Established a causal effect of obesity on AF (MR IVW: p < 10^-13), with no evidence of reverse causality.
• Identified 62 shared pleiotropic genes, enriched in transcriptional regulation and cardiac pathways; NFATC2IP, NUCKS1, and PCCB highlighted as key genes.

Conclusions:

• Provides genetic evidence for a shared basis and unidirectional causality from obesity to AF.
• Identifies NFATC2IP, NUCKS1, and PCCB as key pleiotropic genes.
• Offers potential genetic insights and therapeutic targets for obesity-related AF.