Vitamin D insufficiency and schizophrenia risk: Evaluation of hyperprolinemia as a mediator of association

doi:10.1016/j.schres.2014.03.017

Schizophrenia Research

Volume 156, Issue 1, June 2014, Pages 15-22

https://doi.org/10.1016/j.schres.2014.03.017 Get rights and content

Abstract

25-Hydroxyvitamin D (25(OH)D) deficits have been associated with schizophrenia susceptibility and supplementation has been recommended for those at-risk. Although the mechanism by which a deficit confers risk is unknown, vitamin D is a potent transcriptional modulator and can regulate proline dehydrogenase (PRODH) expression. PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of schizophrenia, and encodes proline oxidase, which catalyzes proline catabolism. l-Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ, cognitive impairment, schizoaffective disorder, and schizophrenia.

We investigated the relationship between 25(OH)D and schizophrenia, comparing fasting plasma 25(OH)D in 64 patients and 90 matched controls. We then tested for a mediating effect of hyperprolinemia on the association between 25(OH)D and schizophrenia.

25(OH)D levels were significantly lower in patients, and 25(OH)D insufficiency associated with schizophrenia (OR 2.1, adjusted p = 0.044, 95% CI: 1.02–4.46). Moreover, 25(OH)D insufficient subjects had three times greater odds of hyperprolinemia than those with optimal levels (p = 0.035, 95% CI: 1.08–8.91), and formal testing established that hyperprolinemia is a significantly mediating phenotype that may explain over a third of the effect of 25(OH)D insufficiency on schizophrenia risk.

This study presents a mechanism by which 25(OH)D insufficiency confers risk of schizophrenia; via proline elevation due to reduced PRODH expression, and a concomitant dysregulation of neurotransmission. Although definitive causality cannot be confirmed, these findings strongly support vitamin D supplementation in patients, particularly for those with elevated proline, who may represent a large subgroup of the schizophrenia population.

Introduction

1α,25(OH)₂D₃, the active form of 25-hydroxyvitamin D (25(OH)D), is a pleiotropic steroid hormone, for which synthesis is initiated in the skin via enzymatic conversion of 7-dehydrocholesterol in the presence of ultraviolet B (UVB) light (Rosen, 2011) and can also be derived from some food sources. In addition to its well-established and vital role in the maintenance of calcium homeostasis and bone mineral density (Heaney, 2008, Rosen, 2011), insufficiency or deficiency of 25(OH)D (the sum of 25(OH)D₂ and 25(OH)D₃), has been associated with cognitive impairment (Llewellyn et al., 2011), metabolic, immune, and malignant disease (reviewed in Rosen, 2011) and more recently depression (Milaneschi et al., 2013). Epidemiological studies have also implicated 25(OH)D deficits in the risk for other psychiatric illness (Eyles et al., 2013), in particular susceptibility to schizophrenia (McGrath et al., 2010a).

Direct and compelling evidence for the association of low vitamin D with increased schizophrenia risk comes from two infant cohort studies. From analysis of a large birth cohort, McGrath et al. (2004) reported a significantly reduced risk of schizophrenia in male infants receiving vitamin D supplements (≥ 2000 IU/day) during their first year of life. Retrospective measurement of 25(OH)D₃ in neonatal blood spots from over 800 schizophrenia patients and matched controls, then demonstrated that infants with low 25(OH)D₃ had a significantly increased risk of schizophrenia (McGrath et al., 2010b). Consistent with these findings, higher 25(OH)D₃ has been associated with a lower risk of psychotic experiences in children (Tolppanen et al., 2012). This body of work has led to the recommendation of maternal, neonatal, infant, or early childhood vitamin D supplementation for those at-risk (McGrath, 2010). A recent finding of 25(OH)D deficiency in patients with first-episode psychosis (Crews et al., 2013), further supports a role for low vitamin D as a risk factor for psychotic illness.

A number of small studies have also suggested that 25(OH)D deficits also extend into adulthood schizophrenia: Significantly lower circulating 25(OH)D levels have been reported in adult patients with chronic schizophrenia compared to other psychiatric patients (Humble et al., 2010, Itzhaky et al., 2012, Menkes et al., 2012) as well as healthy controls (Rey-Sánchez et al., 2009, Partti et al., 2010, Doknic et al., 2011, Itzhaky et al., 2012). The importance of 25(OH)D level maintenance in the adult population has also been highlighted by a large cohort study, from which it was reported that women with high dietary vitamin D consumption had a 37% lower risk of psychosis-like symptoms as compared to women with low consumption (Hedelin et al. 2010). To date no mechanism has been found to underpin the increased schizophrenia risk associated with vitamin D insufficiency.

The highest known genetic risk of schizophrenia, aside from that shared by monozygotic twins, is conferred by hemizygous microdeletion of chromosome 22q11 (Karayiorgou and Gogos, 2004). The proline dehydrogenase gene (PRODH), located within the common deleted region, encodes the PRODH/proline oxidase (POX) enzyme that catalyzes the first step in proline catabolism (see Supplementary data, Fig. S1). Proline is a neuromodulator at glutamatergic synapses (reviewed in Phang et al., 2001) and in humans the peripheral hyperprolinemia that can arise from mutations in PRODH, and which likely reflects CNS hyperprolinemia (Dingman and Sporn, 1959, Efrom, 1965, Baxter et al., 1985, Gogos et al., 1999, Jacquet et al., 2003, Shanti et al., 2004, Paterlini et al., 2005), has been significantly associated with cognitive impairment and decreased IQ (Raux et al., 2007), schizoaffective disorder (Jacquet et al., 2005) and schizophrenia (Clelland et al., 2011, Orešič et al., 2011).

25(OH)D is a potent modulator of gene expression, and has been shown to significantly upregulate PRODH gene expression in the presence of a p53 activator (Thompson et al., 2010). Screening the Gene Expression Omnibus (GEO) database to identify reproducible, biological regulators of PRODH, we also identified two GEO studies showing direct upregulation of PRODH in response to 25(OH)D₃ treatment (GEO accession numbers GDS2628 and GDS1847GDS2628GDS1847). We hypothesized that schizophrenia risk may be mediated by proline elevation arising due to 25(OH)D deficits and the resultant decrease of PRODH expression. We therefore measured levels of 25(OH)D in the same plasma samples from 64 schizophrenia patients and 90 matched controls that were also assayed for fasting proline (Clelland et al., 2011), to investigate a causal relationship between 25(OH)D, hyperprolinemia, and schizophrenia.

Section snippets

Database screening

Using a nonbiased approach, the GEO database (accessible at http://www.ncbi.nlm.nih.gov/geo/) was screened for molecules that regulate PRODH, using the Gene Profiles query term “PRODH”. PRODH expression data was extracted from two retrieved studies, GEO accession numbers GDS2628 and GDS1847GDS2628GDS1847. The materials and methods employed to generate this microarray expression data were published in Wood et al. (2004) and Bossé et al. (2007) respectively.

Study participants

Male and female, African American,

Vitamin D positively regulates PRODH gene expression in vitro

Searching for regulators of PRODH expression, we identified two microarray gene expression studies in which treatment with vitamin D upregulated PRODH expression in vitro (Supplementary data, results one).

25(OH)D insufficiency is significantly associated with schizophrenia

Patients and control subjects were well matched on demographic characteristics, including variables with a likely role in determining vitamin D levels, such as ethnicity (within each diagnostic group, 33–35% were African-American, 33–34% Caucasian, and 33% Hispanic), Body Mass Index (BMI), and

Discussion

A series of large cohort studies has implicated insufficiency of vitamin D in the susceptibility to both psychosis and schizophrenia (McGrath et al., 2004, Hedelin et al., 2010, McGrath et al., 2010b, Tolppanen et al., 2012), However, the mechanism by which this deficit confers risk remains unknown. Based upon data showing regulation of PRODH by vitamin D, this current study in which we performed a formal test of causal mediation, suggests that over one third of the association between 25(OH)D

Role of funding source

This work was supported by grants from the National Institute of Mental Health at the National Institutes of Health (MH070601-02 to J.C.), and the National Center for Advancing Translational Sciences at the National Institutes of Health (KL2 TR000081, formerly the National Center for Research Resources, Grant Number KL2 RR024157. to C.C.). The New York University Clinical and Translational Science Institute is supported in part by grant UL1 TR000038 from the National Center for Advancing

Contributors

Concept and design: JDC and CLC. Acquisition of human subject samples and data: JDC, VD, AK, AK, KED, RN, and AR. Statistical analysis and interpretation of results: JDC, LLR, and CLC. Writing of the manuscript: JDC and CLC. All authors contributed to and have approved the manuscript.

Conflict of interest

Dr. C. Clelland and Dr. J. Clelland are the inventors on a US patent application that is based in part upon this study data. If awarded, the patent will be owned by their respective institutions, and Drs. Clelland may benefit financially in the future if the patent is licensed. Dr. C. Clelland and Dr. J. Clelland declare no other conflict of interest. Dr. Read, Dr. Drouet, Ms. Kaon, Ms. Kelly, Dr. Duff, Dr. Nadrich and Dr. Rajparia declare no conflict of interest.

Acknowledgments

The authors would like to thank Ellie DeCandia RN and the nursing staff of the New York University Clinical and Translational Science Institute, for their invaluable assistance during this study.

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No matter measured 25(OH)D or 25(OH)D3 and their measurements. Quality assessment of studies showed that 6 of case-control studies (Bergemann et al., 2008; Bogers et al., 2016; Cha et al., 2011; Higuchi et al., 1987; Kulaksizoglu and Kulaksizoglu, 2017; Schneider et al., 2000) were considered as low-quality and the rest (Akinlade et al., 2017; Bulut et al., 2016; Clelland et al., 2014; Graham et al., 2015; Itzhaky et al., 2012; Malik et al., 2019; Norelli et al., 2010; Rey-Sánchez et al., 2009; Yazici et al., 2019a; Yazici et al., 2019b; Yuksel et al., 2014; Zhu et al., 2015)were high-quality studies. The quality score of cross-section studies showed that 7 of 18 were high-quality(Abdullah et al., 2012; Doknic et al., 2011; Humble et al., 2010; Jamilian et al., 2013; Partti et al., 2010; Patel and Minajagi, 2018; Zoghbi et al., 2019), and the rest of the studies (Agarwal, 2013a; Bazzano et al., 2016; Boerman et al., 2016; Bruins et al., 2018; Cieslak et al., 2014 ; Grados et al., 2015; Lally et al., 2016; Menkes et al., 2012; Murie et al., 2012; Salavert et al., 2017; Yoo et al., 2018) were moderate-quality.
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To investigate the acute and long-term effects of vitamin D supplementation on the recovery of patients with traumatic brain injury (TBI).
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The mean vitamin D serum level in patients with TBI at admission was 13.62 ± 9.01 ng/mL. The level significantly increased from 14.03 ± 8.68 ng/mL at admission to 37.42 ± 12.57 ng/mL at 3 months post TBI in the supplement group (P < 0.001). The cognitive outcomes (Mini-Mental Status Examination/Clinical Dementia Rating, P = 0.042/P = 0.044) and GOS-E score (total TBI, P = 0.003; mild-to-moderate TBI, P = 0.002) significantly improved from the first week to 3 months post TBI in the patients with vitamin D supplementation.
Administration of vitamin D supplements in mild-to-moderate TBI patients with significant vitamin D deficiency during the acute phase of the injury may improve long-term performance and cognitive outcomes. Therefore, the treatment strategies should be individually planned for the patients with TBI based on their baseline vitamin D level.
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The association between low plasma vitamin D levels and the increased risk of schizophrenia has also been reported. Vitamin D is suggested as a potential therapeutic agent to improve symptoms of schizophrenia [12-14]. The etiology of schizophrenia is not clearly understood, but one of the leading hypotheses is the dysregulation in the levels and actions of dopamine in the brain [15,16].
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Hypovitaminosis D might enhance the IL-6 mediated damage to the hippocampus (Samuelsson et al., 2006), thereby resulting in volume loss. Very recently, proline elevation due to reduced proline dehydrogenase gene (PRODH) expression with resultant dysregulation of neurotransmission has been reported as the mechanistic basis for the link between vitamin D insufficiency and schizophrenia risk (Clelland et al., 2014), since vitamin D has been shown to significantly up-regulate PRODH gene expression. PRODH facilitates conversion of proline to glutamate (Phang et al., 2010).
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VD and specifically VD3 insufficiency is associated with osteomalacia and rickets (Ebeling, 2014; Rani, Maheshwari, Prasad, Karthik Reddy, & Reddy, 2013) with reduced mobility and bone fragility (Lippi, Sanchis-Gomar, & Montagnana, 2014), although there is no precise consensus on how long a person must be exposed to inadequately low vitamin D to result in this disease (McCarty, Chesson Jr., Jain, & Marino, 2014), probably due to the high subjectivity of physiological processes underlying this aspect. Furthermore, some evidence has associated VD insufficiency with a wide variety of medical conditions, such as autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus (SLE)) (Gentile et al., 2013), sleep disorders (McCarty et al., 2014), diabetes-type I, inflammatory bowel disease, multiple sclerosis (Al-Daghri et al., 2014; Brance et al., 2014; Delvin, Souberbielle, Viard, & Salle, 2014; Martinesi et al., 2014), cancers (Teleni et al., 2013), cardiovascular disease and thrombosis (Targher, Pichiri, & Lippi, 2012), diabetes (Mitri, Muraru, & Pittas, 2011), infections (Cannell et al., 2008; Macaluso et al., 2013), neurological and psychiatric conditions such as dementia, schizophrenia and depression (Anastasiou, Yannakoulia, & Scarmeas, 2014; Annweiler, Annweiler, Montero-Odasso, Bartha, & Beauchet, 2014; Clelland et al., 2014; Spedding, 2014), as well as some neurodevelopmental disorders, such as Rett syndrome (Motil et al., 2011; Sarajlija, Djuric, Kisic Tepavcevic, Grkovic, & Djordjevic, 2013). VD, and in particular VD3, can be taken in from food products (such as fish, egg yolk and liver), but a sufficient amount is also synthesized in the body, mainly from sun-exposed skin keratinocytes.
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Vitamin D insufficiency and schizophrenia risk: Evaluation of hyperprolinemia as a mediator of association

Abstract

Introduction

Section snippets

Database screening

Study participants

Vitamin D positively regulates PRODH gene expression in vitro

25(OH)D insufficiency is significantly associated with schizophrenia

Discussion

Role of funding source

Contributors

Conflict of interest

Acknowledgments

Pharmacol. Biochem. Behav.

Schizophr. Res.

Schizophr. Res.

Brain Res.

Schizophr. Res.

Am. J. Clin. Nutr.

Front. Neuroendocrinol.

Am. J. Clin. Nutr.

J. Steroid Biochem. Mol. Biol.

Brain Res. Mol. Brain Res.

Schizophr. Res.

Psychiatry Res.

Clin. Chim. Acta

Does the addition of a second antipsychotic drug improve clozapine treatment?

Schizophr. Bull.

The moderator–mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations

J. Pers. Soc. Psychol.

A cross-sectional study of vitamin D deficiency among immigrants and Norwegians with psychosis compared to the general population

J. Clin. Psychiatry

1alpha,25-dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes

Physiol. Genomics

Population-based norms for the Mini-Mental State Examination by age and educational level

JAMA

The penetration of proline and proline derivatives into brain

J. Neurochem.

Bone remodeling, bone mass and weight gain in patients with stabilized schizophrenia in real-life conditions treated with long-acting injectable risperidone

Neuroendocrinology

Familial hyperprolinemia. Report of a second case, associated with congenital renal malformations, hereditary hematuria and mild mental retardation, with demonstration of an enzyme defect

N. Engl. J. Med.

Evidence that hyperprolinemia alters glutamatergic homeostasis in rat brain: neuroprotector effect of guanosine

Neurochem. Res.

Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention

Anticancer Res.

Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

Mol. Psychiatry

The gene encoding proline dehydrogenase modulates sensorimotor gating in mice

Nat. Genet.

Vitamin D deficiency and psychotic features in mentally ill adolescents: a cross-sectional study

BMC Psychiatry

Vitamin D in health and disease

Clin. J. Am. Soc. Nephrol.

Why the IOM recommendations for vitamin D are deficient

J. Bone Miner. Res.