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

Guo-Wei Rong; Xiao-Min Li; Hui-Min Lu; Ming-Zhu Su; Yi Jin

doi:10.3389/fnut.2024.1415132

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

Front Nutr. 2024 Dec 13:11:1415132. doi: 10.3389/fnut.2024.1415132. eCollection 2024.

Authors

Guo-Wei Rong^{1

2}, Xiao-Min Li^{1

3

4}, Hui-Min Lu⁵, Ming-Zhu Su^{1

6}, Yi Jin^{1

3

4}

Affiliations

¹ The Wujin Clinical College of Xuzhou Medical University, Changzhou, Jiangsu, China.
² Department of Orthopedics, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China.
³ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
⁴ Department of Pharmacy, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China.
⁵ Department of Outpatient and Emergency, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
⁶ Department of Good Clinical Practice, Wujin Hospital Affiliated with Jiangsu University, Changzhou, Jiangsu, China.

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.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Open Funding Project of Jiangsu Provincial Key Laboratory of Anesthesiology, Xuzhou Medical University (Project ID: XZSYSKF2023011) and the Changzhou Sci & Tech Program (Project ID: CJ20242012) to YJ.