A PheWAS approach to identify associations of GBA1 variants with comprehensive phenotypes beyond neurological diseases

Given the established association between numerous GBA1 variants and specific neurological diseases, we extended the exploration by a phenome-wide association study to assess the impact of GBA1 variants on a wider spectrum of health-related traits. We identified 41 phenotypes associated with GBA1 variants, 39 of which were unreported, including 21 non-neurological and 20 neurological phenotypes. Based on variant-level association tests, we found beyond the neurological phenotypes particularly decreased gray-white matter contrast measures across 13 distinct brain regions, the non-coding variant rs9628662 was associated with six non-neurological traits such as hypermetropia. Another non-coding variant rs3115534 showed associations with eight biomarkers of multiple categories, and an increased risk of benign digestive neoplasms. Notably, compared to protein-coding variant p.T408M, the rs3115534 had opposing effects on three hematological biomarkers. Additionally, gene-level association analyses revealed significant associations with three neurological diseases including Parkinson’s disease. The findings demonstrated that GBA1 variants significantly impact various health-related traits.