Genetic variation in macrophage-restricted FOLR2 is associated with neurodevelopmental and reproductive immune phenotypes.

INTRODUCTION: Folate receptor beta (FRβ), encoded by FOLR2, 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. METHODS: 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 FOLR2 variation-rare functional and regulatory, rare functional coding, and protein-altering variants-across 170,889 individuals from two large, independent electronic health record-linked biobanks (BioVU and eMERGE). RESULTS: In ancestry-specific and cross-ancestry meta-analyses, we identified significant associations between FOLR2 variation and phenotypes including pervasive developmental disorders such as attention-deficit hyperactivity disorder, genitourinary infections in pregnancy, and tension headache (P < 3.95 × 10-5). Additional suggestive associations included dyspareunia and ocular inflammation. DISCUSSION: These findings uncover previously unrecognized links between FOLR2 variation and human phenotypes, providing genetic evidence that folate receptor beta may influence neurodevelopmental and immune-mediated traits. Our study highlights FOLR2 as a candidate gene of interest in the biology of macrophage-related disease and reproductive immunology.