25(OH)Vitamin D and autism spectrum disorder: genetic overlap and causality.

Objective: To identify whether there exists a genetic correlation and causal relationship between 25(OH)D and autism spectrum disorder (ASD).

Methods: Based on large-scale genome-wide association studies, a series of genetic approaches were adopted to obtain summary statistics. Using linkage disequilibrium score regression, we assessed the shared polygenic structure between traits and performed pleiotropic analysis under composite null hypothesis (PLACO) to identify pleiotropic loci between complex traits. A bidirectional Mendelian randomization (MR) analysis was applied to investigate whether there is a causal relationship between 25(OH)D and ASD.

Results: The linkage disequilibrium score regression (LDSC) showed a negative genetic correlation between 25(OH)D and ASD (r_g = - 0.227, P < 0.05), and PLACO analysis identified 20 independent pleiotropic loci matched to 24 pleiotropic genes, of which the function reveals an underlying mechanism on 25(OH)D and ASD. In Mendelian randomization analysis, the inverse variance-weighted (IVW) method with OR = 0.941 (0.796, 1.112) and p < 0.474 did not show a causal relationship between 25(OH)D and ASD, while, in the reverse Mendelian randomization analysis, IVW method showed OR = 1.042 (0.930, 1.169), indicating no causal relationship either.

Conclusion: This study provides evidence for a shared genetic overlap between 25(OH)D and ASD. Bidirectional MR analysis also did not show a definite causal relationship between 25(OH)D and ASD.