Objectives: Primary 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. Methods: We 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. Results: We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA-DRA and in STAT4 with 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 of HLA-DRB6, HLA-DRB9, HLA-DPB2, HLA-DQA2 and HLA-DQB2, and is independent of the association between PAPS and HLA-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 Sjogren syndrome, suggesting colocalized causal variations close to STAT4, TNPO3, and BLK. Conclusions: This study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease.

The authors have declared no competing interest.

This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) grant number R01 AI097134 and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the NIH grant number R01AR070148. This work also received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (PRECISESADS, grant number 115565) including in-kind contributions from the EFPIA members involved. C.W. and G.R. are funded by the Wellcome Trust (WT220788). C.W. is funded by the Medical Research Council (MRC; MC UU 00002/4) and supported by the NIHR Cambridge BRC (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

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The study was approved by the Institutional Review Board of the University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

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