Association Between 25(OH) Vitamin D and Schizophrenia: Shared Genetic Correlation, Pleiotropy, and Causality

Overview

Journal Front Nutr

Specialty Nutritional Sciences

Date 2024 Dec 30

PMID 39734669

Authors

Guo-Wei Rong

Xiao-Min Li

Hui-Min Lu

Ming-Zhu Su

Yi Jin

Affiliations

Soon will be listed here.

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.

References

Ahmad S, Arora S, Khan S, Mohsin M, Mohan A, Manda K . Vitamin D and its therapeutic relevance in pulmonary diseases. J Nutr Biochem. 2021; 90:108571. DOI: 10.1016/j.jnutbio.2020.108571. View

Ray D, Chatterjee N . A powerful method for pleiotropic analysis under composite null hypothesis identifies novel shared loci between Type 2 Diabetes and Prostate Cancer. PLoS Genet. 2020; 16(12):e1009218. PMC: 7748289. DOI: 10.1371/journal.pgen.1009218. View

Manousaki D, Mitchell R, Dudding T, Haworth S, Harroud A, Forgetta V . Genome-wide Association Study for Vitamin D Levels Reveals 69 Independent Loci. Am J Hum Genet. 2020; 106(3):327-337. PMC: 7058824. DOI: 10.1016/j.ajhg.2020.01.017. View

Takata A, Matsumoto N, Kato T . Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci. Nat Commun. 2017; 8:14519. PMC: 5333373. DOI: 10.1038/ncomms14519. View

Zhu J, Luo W, Cheng X, Li Y, Zhang Q, Peng W . Vitamin D deficiency and Schizophrenia in Adults: A Systematic Review and Meta-analysis of Observational Studies. Psychiatry Res. 2020; 288:112959. DOI: 10.1016/j.psychres.2020.112959. View

Hart P, Norval M, Byrne S, Rhodes L . Exposure to Ultraviolet Radiation in the Modulation of Human Diseases. Annu Rev Pathol. 2018; 14:55-81. DOI: 10.1146/annurev-pathmechdis-012418-012809. View

de Leeuw C, Mooij J, Heskes T, Posthuma D . MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015; 11(4):e1004219. PMC: 4401657. DOI: 10.1371/journal.pcbi.1004219. View

Yu G, Xu M, Chen Y, Ke H . 25(OH)Vitamin D and autism spectrum disorder: genetic overlap and causality. Genes Nutr. 2023; 18(1):8. PMC: 10134540. DOI: 10.1186/s12263-023-00727-0. View

Nazik Yuksel R, Altunsoy N, Tikir B, Cingi Kuluk M, Unal K, Goka S . Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation. Ther Adv Psychopharmacol. 2014; 4(6):268-75. PMC: 4257987. DOI: 10.1177/2045125314553612. View

10.

McGrath J, Scott J . Urban birth and risk of schizophrenia: a worrying example of epidemiology where the data are stronger than the hypotheses. Epidemiol Psichiatr Soc. 2007; 15(4):243-6. View

11.

Shenker J, Sengupta S, Joober R, Malla A, Chakravarty M, Lepage M . Bipolar disorder risk gene modulates negative symptoms in schizophrenia: a neuroimaging genetics study. J Psychiatry Neurosci. 2017; 42(3):172-180. PMC: 5403662. DOI: 10.1503/jpn.150332. View

12.

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

13.

Valipour G, Saneei P, Esmaillzadeh A . Serum vitamin D levels in relation to schizophrenia: a systematic review and meta-analysis of observational studies. J Clin Endocrinol Metab. 2014; 99(10):3863-72. DOI: 10.1210/jc.2014-1887. View

14.

Kotlicka-Antczak M, Pawelczyk A, Rabe-Jablonska J, Smigielski J, Pawelczyk T . Obstetrical complications and Apgar score in subjects at risk of psychosis. J Psychiatr Res. 2013; 48(1):79-85. DOI: 10.1016/j.jpsychires.2013.10.004. View

15.

Jauhar S, Johnstone M, McKenna P . Schizophrenia. Lancet. 2022; 399(10323):473-486. DOI: 10.1016/S0140-6736(21)01730-X. View

16.

McGrath J, Eyles D, Pedersen C, Anderson C, Ko P, Burne T . Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry. 2010; 67(9):889-94. DOI: 10.1001/archgenpsychiatry.2010.110. View

17.

Kimlin M . Geographic location and vitamin D synthesis. Mol Aspects Med. 2008; 29(6):453-61. DOI: 10.1016/j.mam.2008.08.005. View

18.

Steiner J, Frodl T, Schiltz K, Dobrowolny H, Jacobs R, Fernandes B . Innate Immune Cells and C-Reactive Protein in Acute First-Episode Psychosis and Schizophrenia: Relationship to Psychopathology and Treatment. Schizophr Bull. 2019; 46(2):363-373. PMC: 7442383. DOI: 10.1093/schbul/sbz068. View

19.

Ismailova A, White J . Vitamin D, infections and immunity. Rev Endocr Metab Disord. 2021; 23(2):265-277. PMC: 8318777. DOI: 10.1007/s11154-021-09679-5. View

20.

Gaebler A, Finner-Prevel M, Lammertz S, Schaffrath S, Eisner P, Stohr F . The negative impact of vitamin D on antipsychotic drug exposure may counteract its potential benefits in schizophrenia. Br J Clin Pharmacol. 2022; 88(7):3193-3200. DOI: 10.1111/bcp.15223. View