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

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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.

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