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Our study aimed to identify novel genetic susceptibility loci associated with PAPS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a genome\u2010wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta\u2010analysis 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\u2010mediated diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near\n                      <jats:italic>HLA\u2010DRA<\/jats:italic>\n                      and in\n                      <jats:italic>STAT1\u2010STAT4<\/jats:italic>\n                      with a genome\u2010wide level of significance; 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele near\n                      <jats:italic>HLA\u2010DRA<\/jats:italic>\n                      is associated with overexpression of\n                      <jats:italic>HLA\u2010DRB6<\/jats:italic>\n                      ,\n                      <jats:italic>HLA\u2010DRB9<\/jats:italic>\n                      ,\n                      <jats:italic>HLA\u2010DQA2<\/jats:italic>\n                      , and\n                      <jats:italic>HLA\u2010DQB2<\/jats:italic>\n                      in immune cells, vascular tissue, and nervous tissue. This association is independent of the association between PAPS and\n                      <jats:italic>HLA\u2010DRB1*1302<\/jats:italic>\n                      . Functional analyses highlighted immune\u2010related pathways in PAPS\u2010associated loci. The comparison with other immune\u2010mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sj\u00f6gren syndrome, suggesting co\u2010localized causal variations close to\n                      <jats:italic>STAT1\u2010STAT4<\/jats:italic>\n                      ,\n                      <jats:italic>TNPO3<\/jats:italic>\n                      , and\n                      <jats:italic>BLK<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study represents a comprehensive large\u2010scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic 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