The association between neonatal vitamin D status and risk of schizophrenia

Darryl W Eyles,Anders D Børglum,Xiaoying Cui,Pankaj Sah,Preben Bo Mortensen ,Carsten Bøcker Pedersen ,Thomas H J Burne,Esben Agerbo,Ole Mors,David Kvaskoff,Men Chee Tan,Arieh Cohen,Maciej Trzaskowski,Manuel Mattheisen,David M Hougaard,Victor Anggono,Naomi R Wray,Bent Nørgaard‐Pedersen ,Sandra Meier,Helen Gooch,Se-Eun Jang ,Anna A E Vinkhuyzen,John J Mcgrath

doi:10.1038/s41598-018-35418-z

Abstract

Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12–1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia.

Highlights

Hypotheses linking developmental vitamin D deficiency and altered brain development are biologically plausible, since the vitamin D receptor (VDR) is expressed in the brain, in areas of interest to schizophrenia research such as dopaminergic-rich brain regions[9]
We have confirmed that neonatal vitamin D deficiency was associated with a significantly increased risk of schizophrenia
As the developing fetus is totally reliant on maternal vitamin D stores, and neonatal 25OHD concentrations are strongly correlated with maternal sera concentrations at birth (r ~ 0.80)[18], our findings support the hypothesis that maternal vitamin D deficiency is a risk factor for schizophrenia in the offspring

Summary

Introduction

Hypotheses linking developmental vitamin D deficiency and altered brain development are biologically plausible, since the vitamin D receptor (VDR) is expressed in the brain, in areas of interest to schizophrenia research such as dopaminergic-rich brain regions[9]. A schizophrenia case-control study (n = 848) demonstrated that neonates with vitamin D deficiency had an increased risk of being diagnosed with schizophrenia in later life (i.e. lowest versus reference [fourth] quintile Incidence Rate Ratio (IRR) = 2.1; 95% CIs 1.3–3.5)[11]. While gene by environment interaction studies require large sample sizes (compared to the samples required to detect the main effects of the genetic and environmental risk factors)[12], we had the opportunity to explore these research questions based on Danish neonatal samples that had been both assayed for 25OHD concentration and genotyped. Psychiatric research based on large case-control samples with both genetic and environmental risk factors has been scant[13]

Methods

Results

Conclusion