Genome-wide cross-trait analyses reveal shared genetic architecture and causal links between...

Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk of cardiovascular diseases (CVDs), but the underlying mechanisms remain poorly understood. This study aimed to investigate the shared genetic architecture and potential causal links between ADHD and five major CVDs.

We analyzed genome-wide association study (GWAS) summary statistics of European ancestry for ADHD and five CVDs including coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF), and stroke. Genetic correlation was estimated using LD score regression (LDSC), and shared genetic architecture was explored through genomic structural equation modeling (GenomicSEM) and multivariate GWAS. MAGMA gene-based analysis and functional characterization, including tissue enrichment (GTEx v8) and KEGG pathway analysis, were conducted. Causal effects were assessed using two-sample Mendelian randomization (MR), with multivariable MR and mediation analyses evaluating lifestyle factors as potential mediators.

Significant positive genetic correlations were observed between ADHD and all five CVDs (rg: 0.14 to 0.40). Multivariate GWAS identified 15 independent shared genomic loci (e.g. IL6R), with two being novel (HDGFL1 and SMG6). Gene-based analysis highlighted 73 significant genes enriched in vascular and brain tissues, and in pathways related to neurodevelopment and vascular signaling. MR analyses revealed significant causal effects of ADHD liability on all five CVDs (OR: 1.09 to 1.17), partially mediated by BMI and smoking.

ADHD and CVDs share a substantial genetic architecture. Genetic liability to ADHD increases CVD risk, partly through modifiable lifestyle factors. These findings highlight the importance of early cardiovascular risk monitoring and lifestyle interventions in individuals with ADHD.