{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:08:21Z","timestamp":1789016901669,"version":"build-2803163510"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Folate receptor beta (FR\u03b2), encoded by\n                      <jats:italic>FOLR2<\/jats:italic>\n                      , is a cell surface receptor with restricted expression in monocytes and macrophages and is highly expressed at the maternal-fetal interface, yet its genetic contributions to human disease remain unexplored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Given the importance of placental macrophages to host defense, including against viral infections, we performed a gene-based phenome-wide association study (PheWAS) using three classes of\n                      <jats:italic>FOLR2<\/jats:italic>\n                      variation\u2014rare functional and regulatory, rare functional coding, and protein-altering variants\u2014across 170,889 individuals from two large, independent electronic health record\u2013linked biobanks (BioVU and eMERGE).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In ancestry-specific and cross-ancestry meta-analyses, we identified significant associations between\n                      <jats:italic>FOLR2<\/jats:italic>\n                      variation and phenotypes including pervasive developmental disorders such as attention-deficit hyperactivity disorder, genitourinary infections in pregnancy, and tension headache (P\u2009&amp;lt;\u20093.95\u2009\u00d7\u200910\n                      <jats:sup>-5<\/jats:sup>\n                      ). Additional suggestive associations included dyspareunia and ocular inflammation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings uncover previously unrecognized links between\n                      <jats:italic>FOLR2<\/jats:italic>\n                      variation and human phenotypes, providing genetic evidence that folate receptor beta may influence neurodevelopmental and immune-mediated traits. Our study highlights\n                      <jats:italic>FOLR2<\/jats:italic>\n                      as a candidate gene of interest in the biology of macrophage-related disease and reproductive immunology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1804188","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:29:14Z","timestamp":1789014554000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic variation in macrophage-restricted FOLR2 is associated with neurodevelopmental and reproductive immune phenotypes"],"prefix":"10.3389","volume":"17","author":[{"given":"Elizabeth A.","family":"Jasper","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Quantitative and Clinical Sciences, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]},{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Jaworski","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center","place":["Nashville, TN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahram Namjou","family":"Khales","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atlas","family":"Khan","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Columbia University","place":["New York City, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Digna R. 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