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Background: Psoriasis is a common chronic, recurrent, immune-mediated disease involved in the skin or joints or both. However, deeper insight into the genetic susceptibility of psoriasis is still unclear., Methods: Here we performed the largest multi-ancestry meta-analysis of genome-wide association study including 28,869 psoriasis cases and 443,950 healthy controls., Results: We identified 74 genome-wide significant loci for psoriasis. Of 74 loci, 32 were novel psoriasis risk loci. Across 74 loci, 801 likely causal genes are indicated and 164 causal genes are prioritized. SNP-based heritability analyses demonstrated that common variants explain 15% of genetic risk for psoriasis. Gene-set analyses and the genetic correlation revealed that psoriasis-related genes have the positive correlations with autoimmune diseases such as ulcerative colitis, inflammatory bowel diseases, and Crohn's disease. Gene-drug interaction analysis suggested that psoriasis-associated genes overlapped with targets of current medications for psoriasis. Finally, we used the multi-ancestry meta-analysis to explore drug repurposing and the potential targets for psoriasis., Conclusions: We identified 74 genome-wide significant loci for psoriasis. Based on 74 loci, we provided new biological insights to the etiology of psoriasis. Of clinical interest, we gave some hints for 76 potential targets and drug repurposing for psoriasis., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Beijing Institute of Brain Disorders in Capital Medical University and the ethical code number is AEEI-2021-077. Competing interests: The authors declare that there are no conflicts of interest., (© 2025. The Author(s).)