Association between 25(OH) vitamin D and schizophrenia: shared genetic correlation, pleiotropy, and causality

Abstract

Background: This study delves into the complex interplay between genetics, 25-hydroxyvitamin D (25OHD), and schizophrenia (SCZ). It leverages extensive sample data derived from Genome-Wide Association Studies (GWAS) to uncover genetic correlations.

Methods: Employing Linkage Disequilibrium Score Regression (LDSC) and S-LDSC, this study investigates genetic connections between 25OHD and SCZ. It examines Single Nucleotide Polymorphism (SNP) heritability in specific tissues and incorporates diverse immune cell datasets for genetic enrichment analysis. Local genetic correlations were analyzed using HESS software, and pleiotropy analysis identified shared genetic loci in brain tissues. Hyprcoloc analysis was used to explore shared genetic factors between 25OHD, immune cells, and SCZ, complemented by a bidirectional Mendelian Randomization (MR) to probe potential causal links.

Results: We identified a significant negative genetic correlation between 25OHD levels and SCZ. PLACO analysis revealed 35 pleiotropic loci with strong enrichment in brain regions, particularly the cerebellum, frontal cortex, and hippocampus. Eight loci (1p34.2, 2p23.3, 3p21.1, 5q31.2, 12q23.2, 14q32.33, 16p13.3, and 16q24.3) exhibited strong colocalization, highlighting potential drug targets. Gene and tissue enrichment analyses emphasized neurological and immune-related mechanisms, including hyaluronan metabolism. Bidirectional MR analysis supported a causal effect of SCZ on 25OHD levels.

Conclusion: Our study identifies NEK4 as a potential therapeutic target and highlights the involvement of hyaluronan metabolism in the genetic association between 25OHD and SCZ. These findings provide valuable insights into shared genetic pathways, immune-related connections, and causal interactions in the context of SCZ.

Keywords: Mendelian randomization; genetic overlap; genome-wide association study; schizophrenia; vitamin D.

Figure 1

Overview of statistical analyses performed in the study. SNP, Single Nucleotide Polymorphism; LDSC, Linkage Disequilibrium Score Regression; HDL, high-definition likelihood; HESS, Heritability Estimation from Summary Statistics; PLACO, Protein–Ligand Affinity by Comparable Co-Evolution; MAGMA, Multi-marker Analysis of GenoMic Annotation; GWAS, Genome-Wide Association Study; eQTL, Expression Quantitative Trait Locus; S-LDS, Stratified Linkage Disequilibrium Score.

Figure 2

Analysis of local genetic correlation and heritability distribution across different genomic regions. (A) Average local genetic correlations (rg) for Vitamin D-specific, SCZ-specific, and interaction regions, highlighting the significant negative correlation in the interaction regions. (B) Frequency distribution of local genetic correlations, showing a concentration of negative correlations in interaction regions, suggesting a complex negative genetic relationship between Vitamin D and SCZ in these areas.

Figure 3

Manhattan plots illustrating pleiotropic associations between 25OHD and SCZ. (A) Manhattan plot showing pleiotropic SNP signals between 25OHD and SCZ, with significant associations observed on chromosomes 3, 7, 8, 14, and 19. (B) Manhattan plot highlighting pleiotropic genes identified by the MAGMA method, such as STAB1 and NT5DC2, which are significantly associated with both 25OHD and SCZ.

Figure 4

Tissue-specific analysis and gene enrichment of pleiotropic signals between 25OHD and SCZ. (A) Tissue-specific analysis reveals significant enrichment of pleiotropic signals in brain regions such as the cortex, frontal cortex, and cerebellum. (B) The enrichment of pleiotropic MAGMA genes is particularly pronounced in brain tissues, with both upregulated and downregulated genes showing significant associations, highlighting the central role of these regions in the genetic relationship between 25OHD and SCZ.

Figure 5

S-LDSC estimates of heritability enrichment across different immune cells and brain tissues. The figure highlights significant heritability enrichment in specific immune cells, such as Tgd.vg2-.Sp and T.4SP24-.Th, as well as in key brain regions including the entorhinal cortex, limbic system, and cerebral cortex. These findings suggest critical roles for both immune cells and these specific brain regions in the genetic relationship between 25OHD and SCZ.