Abstract
BACKGROUND: Epidemiological studies have established that autoimmune diseases (AD) increase cardiovascular disease (CVD) risk. We aimed to elucidate their shared genetic architecture and clinical implications. METHODS: We conducted a cross-trait multivariate genome-wide association study (GWAS) for three autoimmune diseases (type 1 diabetes, systemic lupus erythematosus, and rheumatoid arthritis) and four cardiovascular diseases (coronary artery disease, heart failure, stroke, and peripheral artery disease). We performed both genome-wide and locus-based analysis including fine-mapping, functional annotation, enrichment analyses, transcriptome-wide association studies (TWAS), and proteome-wide and drug-repurposing Mendelian randomization (MR). We constructed a polygenic risk score (PRS) and explored its pleiotropic effects beyond AD and CVD in the UK Biobank population. RESULTS: In the multivariate GWAS, we identified 259 genome-wide significant association signals that were enriched primarily in arterial tissues and lipid metabolism pathways. Through convergent evidence from TWAS and MR analyses, we prioritized 15 therapeutic targets including TGFB1 and IL6R, and identified histone deacetylase inhibitors as candidate drugs. The polygenic risk score showed discriminative ability in cardiovascular risk stratification among autoimmune patients, with individuals in the highest PRS decile exhibiting significantly elevated CVD risk compared to those in the 2nd-9th deciles (hazard ratios: 1.60 [95% CI: 1.19-2.15] for type 1 diabetes, 2.28 [95% CI: 1.14-4.56] for systemic lupus erythematosus, and 2.33 [95% CI: 1.94-2.80] for rheumatoid arthritis). Additionally, the PRS revealed pleiotropic associations with risk of various health conditions, including polyneuropathy, chronic renal failure, and depressive episodes. CONCLUSION: Our study unveils the shared genetic architecture between autoimmune and cardiovascular diseases, providing insights for therapeutic development and risk stratification.