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Investigating causality in the association between 25(OH)D and schizophrenia.

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Taylor, Amy E 
Ware, Jennifer J 
Gage, Suzanne H 
Richards, J Brent 


Vitamin D deficiency is associated with increased risk of schizophrenia. However, it is not known whether this association is causal or what the direction of causality is. We performed two sample bidirectional Mendelian randomization analysis using single nucleotide polymorphisms (SNPs) robustly associated with serum 25(OH)D to investigate the causal effect of 25(OH)D on risk of schizophrenia, and SNPs robustly associated with schizophrenia to investigate the causal effect of schizophrenia on 25(OH)D. We used summary data from genome-wide association studies and meta-analyses of schizophrenia and 25(OH)D to obtain betas and standard errors for the SNP-exposure and SNP-outcome associations. These were combined using inverse variance weighted fixed effects meta-analyses. In 34,241 schizophrenia cases and 45,604 controls, there was no clear evidence for a causal effect of 25(OH)D on schizophrenia risk. The odds ratio for schizophrenia per 10% increase in 25(OH)D conferred by the four 25(OH)D increasing SNPs was 0.992 (95% CI: 0.969 to 1.015). In up to 16,125 individuals with measured serum 25(OH)D, there was no clear evidence that genetic risk for schizophrenia causally lowers serum 25(OH)D. These findings suggest that associations between schizophrenia and serum 25(OH)D may not be causal. Therefore, vitamin D supplementation may not prevent schizophrenia.



Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Meta-Analysis as Topic, Odds Ratio, Polymorphism, Single Nucleotide, Schizophrenia, Vitamin D

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Springer Science and Business Media LLC
Medical Research Council (MR/L003120/1)
Medical Research Council (G0800270)
Wellcome Trust (100114/Z/12/Z)
British Heart Foundation (None)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
Medical Research Council (G0800270/1)
AET, JJW, SHG and MRM are members of the UK Centre for Tobacco and Alcohol Studies, a UK Clinical Research Council Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. Support from the Medical Research Council (MC_UU_12013/1, MC_UU_12013/6) is also gratefully acknowledged. SB is supported by the Wellcome Trust (grant number 100114). JJW is supported by a Post-Doctoral Research Fellowship from the Oak Foundation. The authors declare no conflict of interest.