ObjectivesPrimary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS.MethodsWe performed a genome-wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta-analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune-mediated diseases.ResultsWe revealed genetic associations with PAPS in a regulatory locus within the HLA class II region nearHLA-DRAand inSTAT4with a genome-wide level of significance. 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele in the HLA class II locus is associated with overexpression ofHLA-DRB6,HLA-DRB9,HLA-DPB2,HLA-DQA2andHLA-DQB2, and is independent of the association between PAPS andHLA-DRB1*1302. Functional analyses highlighted immune and nervous system related pathways in PAPS-associated loci. The comparison with other immune-mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren’s syndrome, suggesting colocalized causal variations close toSTAT4,TNPO3, andBLK.ConclusionsThis study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease.