• amyotrophic lateral sclerosis;
  • autism;
  • multiple sclerosis;
  • Parkinson's disease;
  • schizophrenia;
  • vitamin D


  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

It is well established that the vitamin D endocrine system plays a critical role in calcium homeostasis and bone health; however, in recent decades, the broad range of physiological actions of vitamin D has been increasingly recognized. In addition to its role in proliferation, differentiation and immunomodulation, there is mounting evidence to support an intricate role of vitamin D in brain development and function in health and disease. The current review will summarize key concepts in vitamin D metabolism in the brain, and explore the relationship of vitamin D and brain development. A survey of the role of vitamin D in several psychiatric and neurological disorders including schizophrenia, autism, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis (MS) will be presented.

Vitamin D metabolism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Vitamin D is a seco-steroid hormone that comes in two major forms depending on the source, vitamin D2 (ergocalceiferol) of plant origin, and vitamin D3 (cholecalciferol) of animal origin. Vitamin D3 can be either ingested or produced photochemically in the epidermis by action of ultraviolet light (UVB) on 7-dehydrocholesterol. In both instances, vitamin D2 and D3 are biologically inert and require two separate hydroxylations by 25-hydroxylase (liver) and 1-α-hydroxylase (primarily in the kidney) to give rise to the active form (1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 or calcitriol, respectively) [1] (Figure 1).


Figure 1. Vitamin D metabolism. Vitamin D2 and D3 are biologically inert and require two separate hydroxylations by 25-hydroxylase (liver) and 1-α-hydroxylase (primarily in the kidney) to give rise to the active form (1,25-dihydroxyvitamin D3; calcitriol).

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The potential role of 1,25-dihydroxyvitamin D3 in the brain was first suggested by the discovery of high affinity calcitriol receptors in the pituitary [2], and later in the forebrain, hindbrain, and spinal cord [3] of rats. The presence of vitamin D metabolites in the cerebrospinal fluid of healthy patients further implied a role for vitamin D in the brain [4]. The initial assumption that 1,25-dihydroxyvitamin D3 could access the central nervous system (CNS) via passive and/or active transport across the blood brain barrier [5, 6] was challenged by the detection of 25-hydroxylase and 1-α-hydroxylase activity in extra-renal sites, including the brain [7-9]. These findings highlighted the possibility of paracrine production of 1,25-dihydroxyvitamin D3 production in the CNS. The glial cell expression of the 25(OH)D3 24-hydroxylase gene, CYP24A1, producing the enzyme needed to inactivate calcitriol, suggested further control of 1,25-dihydroxyvitamin D3 levels in the CNS [10]. In a rodent model, Spach and Hayes varied the plasma 25-OHD level by varying dietary vitamin D3 and reported that CNS calcitriol correlated with plasma 25-OHD but not with plasma calcitriol [11]. These data provided evidence for calcitriol synthesis in situ in the CNS. Therefore, the presence of 25-hydroxylase and 1-α-hydroxylase required to synthesize 1,25-dihydroxyvitamin D3 and 24-hydroxylase needed to degrade 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in the brain, along with evidence of in situ CNS calcitriol synthesis, consolidated the idea that the CNS is poised to locally metabolize (and regulate) the active form of vitamin D implicating the importance of this active hormone in brain health and disease.

Vitamin D effector proteins

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

(a) Vitamin D receptor (VDR)

Calcitriol exerts its nuclear effect via the vitamin D receptor (VDR). The discovery of the VDR (mRNA and protein) throughout the brain and spinal cord consolidated the importance of this hormone in modulating nervous system function. Studies from adult rats and hamsters provided a detailed topography of the distribution of VDR in the CNS [2, 3], later shown to be similar in humans [8, 12] (see Figure 2). VDR expression was noted in both neurones and glial cells (microglia, astrocytes, oligodendrocytes) in different CNS regions, including: (i) cortex [temporal (that is, auditory, olfactory, entorhinal), frontal (that is, prefrontal, orbitofrontal, primary motor), parietal, cingulated]; (ii) deep grey matter (thalamus, basal ganglia, hypothalamus, hippocampus, amygdala); (iii) cerebellum (granular and Purkinje cell layers); (iv) brainstem nuclei; (v) spinal cord (anterior horn cells); and (vi) ventricular system (that is, choroid plexus ependymal cells) [13, 14]. VDRs have also been reported in the nuclei of Schwann cells and in peripheral neurones [15, 16].


Figure 2. Nuclear targets of vitamin D in the brain. Sites in the brain that have been identified as nuclear targets for the steroid hormone of sunlight soltriol (vitamsin D) derived from data from autoradiograms from rat and mouse brains following injections of [3H]1,25(OH)2-cholecalciferol. There is a wide distribution of nuclear binding of calcitriol throughout the rodent brain involving major interconnected systems including (i) sensory (red dashed line) with target neurones in spinal ganglia, substantia gelatinose, parabrachial nuclei and reticular thalamic nucleus; (ii) autonomic-neuroendocrine (red solid line) with target neurones in interomediolateral column, nucleus reticularis lateralis magnocellularis (lm), nucleus ambiguus (n. Amb), parabrachial nuclei (n. Parabr.), dorsal raphe nucleus, hypothalamic periventricular and paraventricular parvocellular nuclei, bed nucleus of the stria terminalis, central nucleus of the amygdala and piriform cortex; (iii) motor with target neurones in cranial motor nerve nuclei, motor horn nuclei in the spinal cord, nucleus pontis, and Golgi II cells in the cerebellum; and (iv) ‘mental system’ with input from all of the other systems and to involve soltriol target neurones in allocortex and neocortex, amygdala, striatum and brainstem (figure and text adapted with permission from [12]).

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The VDR is a member of the steroid/thyroid hormone superfamily of transcription regulation factors. On binding of calicitriol, VDR heterodimerizes with the retinoid X receptor (RXR), and subsequently binds specific genomic sequences known as vitamin D response elements (VDREs) to influence gene transcription [17]. Recent construction of a genome-wide map of VDR binding provided evidence of enrichment of VDR-binding sites near autoimmune and cancer-associated genes identified from genome-wide association studies [17] (Figure 3). It is likely, however, that the consequences of VDR binding across the genome will be tissue-specific, thereby influencing disease pathogenesis via unique mechanisms. The ubiquitous distribution of the VDR in the CNS compartment poses the challenge of deciphering the role of VDR binding and gene expression in the brain and how it may relate to health and disease (see Figure 2).


Figure 3. Common traits showing enrichment of VDR (vitamin D receptor) binding within intervals identified by genome-wide association studies (GWAS). Forty-seven traits studied by GWAS ( were analysed and those showing significant enrichment of VDR binding defined by ChIP-seq in two lymphoblast cell lines after calcitriol stimulation with a 1% false discovery rate (FDR) are shown (figure and text used with permission from [17]).

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(b) ‘Non-genomic’ effector pathways; MARRS

In addition to the genomic actions of 1,25-dihydroxyvitamin D3 via the VDR, there is some evidence to suggest that vitamin D may act via the Membrane Associated, Rapid Response Steroid binding receptor (MARRS) [18]. The MARRS receptor is thought to play a role in a variety of cellular processes, including immune function through the assembly of MHC class I molecules, DNA binding and gene expression, and molecular chaperoning [19]. The distribution of 1,25-dihydroxyvitamin D3-MARRS binding in the human brain and the consequences of vitamin D deficiency on the functions mediated by this receptor pathway have not been elucidated and warrant further study.

The effects of vitamin D in the nervous system

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Vitamin D has been shown to exert a multitude of effects on the nervous system including neurotrophism, neurotransmission, neuroprotection and neuroplasticity. These will be reviewed here.

(a) Neurotrophic support

Vitamin D has been shown to have broad trophic functions related to neuronal differentiation, maturation and growth. The first evidence implicating a neurotrophic role for vitamin D was gleaned from in vitro studies which demonstrated that synthesis of nerve growth factor (NGF) was stimulated by 1,25-dihydroxyvitamin D3 [20, 21]; the biological relevance of this phenomenom was later confirmed in in vivo models of the adult rat [22]. 1,25-dihydroxyvitamin D3 has subsequently been shown to upregulate the synthesis of glial cell line-derived neurotrophic factor (GDNF) [23], and neurotrophin 3 (NT-3) [21, 24], and downregulate levels of neurotrophin 4 (NT-4) [24]. 1,25-dihydroxyvitamin D3 has also been shown to regulate the gene expression of the low-affinity NGF neurotrophic receptor, p75NTR [25]. An elegant experiment using cultured embryonic hippocampal cells demonstrated enhanced neurite outgrowth and NGF production with the addition of 1,25-dihydroxyvitamin D3 [26] whereas vitamin D3 deprivation in pregnant rats decreased NGF expression in both neonates [27] and adult offspring [28, 29]. Given that vitamin D regulates NGF, known to act on cholinergic neurones in the basal forebrain, and GDNF, known to act on basal ganglia dopaminergic neurones, it is intriguing to speculate how 1,25-dihydroxyvitamin D3 may play an important neuroprotective role in patients who may have vulnerability to selective degeneration of these neuronal subtypes as may be seen in cognitive impairment and PD, respectively [27, 30, 31].

(b) Neurotransmission

In addition to vitamin D's role in neuronal growth and survival, vitamin D and its metabolites have been shown to mediate the synthesis of a variety of neurotransmitters, including acetylcholine, catecholamines, serotonin and dopamine [32-37]. While the majority of studies demonstrate a close temporal relationship between vitamin D exposure and changes in neurotransmitter levels, data suggest that the biological effects of vitamin D may be long-lasting and transgenerational. In a study where rats were treated with vitamin D in the neonatal period, it was found that dopamine levels remained elevated well beyond the period of exposure, with the effect being transmitted to the offspring of treated female rats [38, 39]. These data require replication, but are consistent with the concept of metabolic imprinting [40, 41]. Important features of metabolic imprinting include the presence of a critical period during foetal development or early life during which the foetus is sensitive to environmental exposures, and that such exposures lead to changes that persist through adulthood. Recent evidence suggests that epigenetic regulation may be operative in vitamin D converting enzymes raising the intriguing possibility that early vitamin D exposure (or lack thereof) may induce epigenetic alterations that affect gene expression, and perhaps susceptibility to neurodegenerative diseases later in life [42].

(c) Neuroprotection

There are several lines of evidence that suggest vitamin D may have a neuroprotective role. The administration of vitamin D or its metabolites has been shown to reduce neurological injury and/or neurotoxicity in a variety of animal systems, including: (i) the attentuation of the size of cerebral infarction in rats through presumed GDNF upregulation [43]; (ii) the preservation of mechanical hyperalgesia in a streptozotocin-diabetic rat model through the prevention of NGF depletion [44]; (iii) the decrease in neuronal death in rat foetal hippocampal cultures elicited by calcium mediated neurotoxicity through downregulation of L-type voltage-sensitive Ca2+ channels [45]; (iv) the attenuation of hypokinesia and dopamine neuronal toxicity in a rat model of 6-hydroxydopamine-induced neurotoxicity through the sequestration of free radical and reactive oxygen species (ROS) [46, 47]; (v) the protection of rat cultured mesencephalic dopaminergic neurones from glutamate and dopaminergic toxins by facilitating cellular functions that reduce oxidative stress [48, 49]; and (vi) the reduction of glutamate-induced cell death in cultured rat cortical neurones [50]. These latter studies highlight vitamin D's role in antioxidative metabolism, which is further supported by its ability to downregulate the expression of inducible nitric oxide synthase (iNOS) (and subsequently nitric oxide) in monocyte-derived cells [51], and to potentiate the production of γ-Glutamyl transpeptidase (γ-GT), an enzyme important in the glutathione pathway, in astrocytes exposed to a pro-inflammatory milieu [52].

While these experimental data demonstrate that vitamin D appears to exert its neuroprotective influence through diverse (and potentially overlapping) mechanisms, the extent of neuro-axis regional specificity of these effects is not clear. For example, a rodent model of hypervitaminosis D revealed changes in the synthesis of calcium-binding proteins, such as parvalbumin, restricted to the caudate/putamen but not in the cerebral cortex or hippocampus [53]. Similarly, differences in regional specificity have also been observed in vitamin D's influence on iNOS downregulation [52]. These important nuances should caution against the extension of these experimental data unreservedly to the human brain in health and disease. However, it is certainly tempting to speculate that vitamin D may have a protective effect (or a detrimental one in deficiency states) in human disease, especially as similar pathogenic mechanisms (that is, reactive oxygen and nitrogen species, glutamate excitotoxicity, and calcium dysregulation), have been implicated in the pathogenesis of several neuroinflammatory and neurodegenerative disorders, such as multiple sclerosis, Parkinson's disease, and motor neurone disease [51, 54, 55].

(d) Neuroplasticity

Vitamin D may have a crucial role in neuroplasticity. Gene array and proteomic studies on brains of adult rats deprived of vitamin D during gestation have demonstrated many genes involved in nervous system development that are differentially regulated. In particular, vitamin D deficiency has been shown to affect the transcript profiling of a multitude of genes, including those involved in (i) cytoskeletal maintenance (e.g. RhoA, microtubule associated protein-2, growth associated protein-43, neurofilament-light chain, glial fibrillary acidic protein); (ii) mitochondrial function (e.g. ATPase H+ transporting V1B2, Mn-containing superoxide dismutase, cytochrome c, catalase); (iii) synaptic plasticity (e.g. aquaporin-4, apolipoprotein B, myristoylated alanin-rich C kinase substrate); and (iv) cellular proliferation and growth (e.g. growth arrest and DNA-damage-inducible 45 alpha, growth arrest specific 5, insulin-like growth factor 1) [28, 50, 56-59].

Gene pathway analysis of vitamin D and the VDR system in neuronally expressed genes accentuates its role in functions critical to neural development, including growth cone spreading and collapse, neurite and axonal outgrowth and retraction, axonal guidance, dendritic spine morphogenesis, actin-filament and microtubule reorganization, and integrin mediate adhesion (see Figure 4A and B). Given the broad impact of vitamin D deficiency on neural developmental regulatory genes, it is not surprising that gestational vitamin D deficiency during a critical developmental period may result in long-standing aberrant molecular regulation of brain function, and hence influence the phenotypic expression of neurodegenerative disease [60]. It remains plausible, therefore, that vitamin D supplementation when taken later in life may not be effective in preventing neurodegenerative diseases where vitamin D is thought to play a role. Clinical trials targeting vitamin D supplementation during pregnancy with long-term follow-up will be needed to address this issue.


Figure 4. Ingenuity Pathway Analysis (IPA) of neuronally expressed genes regulated by vitamin D. (A and B) Vitamin D affects neuronal gene expression through its influence on various neurotrophic factors (including NT3, NT4, and NGF) and downstream pathways. These vitamin D regulated genes impact diverse functions critical to neural development, including growth cone spreading and collapse, neurite and axonal outgrowth and retraction, axonal guidance, dendritic spine morphogenesis, actin-filament and microtubule reorganization, and integrin mediate adhesion.

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Vitamin D and brain development

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

Given the diverse roles of vitamin D in the nervous system, it is not surprising that vitamin D influences brain development. In the embryonic rat brain, VDR expression is first detected on the 12th day of gestation and appears to be widely distributed with predominance in the neuroepithelium and subventricular zones [13, 61]. During rat embryonic brain development, VDR expression is dynamic as evidenced by its emergence in differentiating fields [27, 61]. Rodent models have been important at capturing the developmental consequences of vitamin D deficiency on embryogenesis and the neonatal period, and have provided a platform from which the long-term consequences of vitamin D deficiency have been examined. Such experimental models include the developmental vitamin-D-deficient model, and the VDR and 1-α-hydroxylase knockout models.

(a) Developmental vitamin D deficient model

In a developmental vitamin D deficient model, Eyles and colleagues induced maternal dietary deprivation of vitamin D in rats prior to mating and maintained this vitamin D deprived state for the duration of the pregnancy. They overcame the relative infertility associated with vitamin D deficiency and found that pups born of the vitamin D deprived dams exhibited conspicuous morphological changes in the brain. Increased overall brain size and cerebral hemispheric length, cortical layer thinning, and larger lateral ventricles were found compared with vitamin-D-sufficient controls [27]. Microscopically, the vitamin-D-depleted pups had evidence of increased cellular proliferation with higher rates of mitosis and decreased apoptosis than usually observed in neuronal differentiation [56]. Evaluation of the cell cultures derived from the neonatal subventricular zone in these vitamin-D-depleted rats revealed increased neurosphere number suggestive of increased cellular division, which decreased with addition of vitamin D [62]. In keeping with this experimental data, developmental vitamin D deficiency also appears to reduce levels of p75NTR, a key neurotrophic receptor involved in developmental apoptosis, and to deregulate cell cycle related genes [27]. The developmental brain abnormalities secondary to gestational vitamin D deficiency may not be fixed and in fact can normalize, to an extent, on reintroduction of vitamin D during a critical time window in the neonatal period [28, 62].

The behavioural consequences of the developmental vitamin D deficiency model have been extensively studied. In adult life, these rats tend to demonstrate subtle alterations in learning and memory, impaired attentional processing, altered spontaneous locomotion, sensitivity to NMDA antagonists, and altered sensitivity to anti-dopaminergic agents [63-67]. Maternal–pup interactions are also altered which likely further impacts early brain development and behaviour [68]. Given that some aspects of the clinical phenotype (disrupted latent inhibition, NMDA antagonist hypersensitivity) and brain morphological changes (that is, increased lateral ventricular size) resemble those found in schizophrenia, the developmental vitamin-D-deficient rat has gained support as a model for this psychiatric disease [31].

(b) VDR knockout model

The phenotype of the VDR knockout mouse model differs significantly from that of the developmental vitamin D model. Mice who have undergone targeted ablation of the VDR are normal at birth, but typically develop growth retardation, hypocalcaemia, hyperparathyroidism, rickets, osteomalacia, and alopecia [69, 70]. These mice exhibit several abnormalities including symmetrical thalamic calcification [71], a shorter gait and motor dysfunction even in the setting of normocalcaemia [72, 73], food neophobia [74], progressive hearing loss secondary to cochlear neural degeneration [75], vestibular dysfunction [76], increased severity of chemically induced seizures [77], and premature ageing [78]. The consequences of the mouse model on behavioural and cognitive performance measures have been conflicting, with increased grooming and anxiety, and aberrant nest-building being observed by some groups but not others [72, 79-81]. Unlike the developmental vitamin-D-deficient model, VDR knockout mice appear cognitively intact on measures of exploration and working memory [73]. The lifetime absence of 1,25-dihydroxyvitamin D3-VDR signalling, the inability to simulate chronic vitamin D deficiency, and the adverse effect of exercise-induced fatigue on behaviour with motoric components have hindered the popularity of this model in studying nervous system disease [31, 73].

(c) 1-α-hydroxylase knockout model

Similar to the VDR knockout mouse model, 1-α-hydroxylase knockout mice demonstrate growth retardation, hypocalcaemia, hypophosphataemia, hyperparathyroidism, and a clinical phenotype of severe rickets and osteomalacia resembling that seen in humans [82, 83]. From a functional point of view, 1-α-hydroxylase knockout mice do not appear to differ significantly from their wild-type counterparts on measures of motor, vestibular, and behavioural function [76]. It is postulated that the resultant elevation of 25-hydroxyvitamin D in this model is capable of binding to VDR thereby activating downstream signalling of this pathway [76]. Given the predominant rickets phenotype and lack of accompanying behavioural abnormalities, the 1-α-hydroxylase knockout mouse model has not been popular for studying the influence of vitamin D on nervous system disease.

The contrasting phenotypic fates of these vitamin D deficiency models highlights the complexity of vitamin D signalling in nervous system development. It is likely that vitamin D has effects on nervous system function which may be mediated, at least in part, independently of its binding to VDR and/or via non-genomic mechanisms.

Vitamin D in psychiatric and neurological disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

The role of vitamin D in brain development and the consequences of early life vitamin D deficiency on subsequent aberrant behaviours and disease risk in animals likely have implications for human disease. An estimated one billion people worldwide have vitamin D deficiency (usually defined as serum 25(OH)D levels less than 25–50 nmol/l) or insufficiency (serum 25(OH)D levels < 75 nmol/l) with pregnant women being at increased risk because of increased foetal requirements and reduction in outdoor activity, most notably during the third trimester [1]. Vitamin D production is dependent entirely on UVB exposure which, in turn, is influenced by season and more significantly by latitude [84, 85]. The importance of vitamin D on human health is illustrated by indications that lighter skin colour evolved to optimize vitamin D production under conditions of low UVB radiation [84]. From an evolutionary perspective, although depigmentation seen in populations at higher latitudes confers a higher risk of skin cancer, most individuals develop cancer beyond their reproductive age thereby making skin cancer a relatively weak selective force compared with serum vitamin D availability [86].

In addition to rickets and osteomalacia, the convergence of in vitro, animal, and epidemiological research points to vitamin D deficiency as a candidate modifiable risk factor for a host of diseases, including those of the human nervous system. On a population level, evidence linking reduced UVB exposure and subsequent hypovitaminosis D to nervous system disease has been derived from studies associating disease incidence/prevalence with [87]:

  • (i) 
    season of birth – the amount of UVB radiation fluctuates across the seasons, with lower levels of exposure (and serum vitamin D levels) in winter and early spring in regions north/south of the equator – this would implicate hypovitaminosis D during gestation or early life to influence risk of disease later in life;
  • (ii) 
    latitude – the amount of UVB radiation correlates strongly with latitude and vitamin D levels – this would suggest individuals living further from the equator have a higher risk of disease;
  • (iii) 
    migrant studies – people who move from a region of high to low UVB exposure (with resultant high to low vitamin D levels) – this would support an increase in disease risk on moving from areas of high to low UVB exposure before a critical age (and vice versa);
  • (iv) 
    vitamin D supplementation – vitamin D levels are influenced by dietary intake and supplementation independent of UVB exposure – this would suggest individuals at risk of hypovitaminosis D may blunt their risk of disease by increasing their oral vitamin D intake [88].

The traditional caveats certainly apply to the application of these lines of epidemiological data to implicate vitamin D deficiency in the pathogenesis of disease. One must consider that (i) seasonal variations may influence levels of UVB itself (independent of vitamin D), exposure to viruses, and availability of other nutrients; (ii) latitudinal differences may be associated with differences in population genetic structure and socio-economic status; (iii) migration within, into, or out of a study population group may relate to the factor of interest, such as vitamin D status (migration bias); and that (iv) vitamin D supplementation may be associated with other health-protective behaviours that may influence disease risk.

The molecular basis by which vitamin D exerts these effects on human disease is not completely known; however, the aforementioned experimental and animal model data have provided a biological framework that will undoubtedly guide mechanism discovery. Further, emerging evidence suggests an intimate and complex relationship between disease susceptibility genes and vitamin D, mediated through putative vitamin-D-binding sites. A recent study demonstrated that, after calcitriol stimulation, 2776 genomic positions are occupied by a VDR and that 229 genes show significant changes in expression in response to vitamin D [17].

Here we highlight nervous system diseases that have been linked with hypovitaminosis D on an epidemiological level, with a particular focus on those diseases wherein susceptibility genes identified by genome-wide association studies have associated VDR-binding sites. The latter was accomplished by (i) identifying susceptibility genes for these nervous system diseases by consulting the catalogue of published genome-wide association studies (GWAS) (; and then (ii) cross-referencing the identified susceptibilty genes with a database of genes known to have VDR-binding sites within or in close proximity to them [17]. The psychiatric and neurological diseases that fulfilled these criteria and were selected for inclusion are schizophrenia, autism, PD, ALS, MS, and AD. These diseases and the evidence implicating their relationship to vitamin D will be discussed briefly here.

A. Psychiatric disease

(i) Schizophrenia

Schizophrenia is a heterogenous psychotic syndrome which affects approximately 1% of the population. The aetiology of schizophrenia is multifactorial with both environmental and genetic factors thought to play important roles [89]. The neuropathology of schizophrenia remains obscure; however, a number of structural abnormalities have been idenitified and confirmed by meta-analysis including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume in the absence of gliosis [90]. The latter feature fuels support for a neurodevelopmental contribution. Intriguingly, these morphological changes are similar to those observed in the developmental vitamin D deficient rat model, as previously described [27]. Further, NGF, neurotrophin, and p75NTR, known to be regulated by vitamin D, are important in mitigating synaptogenesis, neurite and axonal outgrowth all of which have been shown to be aberrant in schizophrenia. These data form important features of the experimental basis on which vitamin D has been implicated in the susceptibility to this disease.

The environmental influence on susceptibility to schizophrenia has long been discussed, with hypovitaminosis D being a leading suspect. Epidemiological studies have repeatedly pointed to a season-of-birth effect in schizophrenia [91-96]. In northern latitudes, an excess number of births occur in the winter and early spring with a mirror effect occurring in the southern hemisphere – the magnitude of the effect on disease risk increasing with distance from the equator. With regards to latitude, several studies have demonstrated increased incidence and prevalence of schizophrenia at higher latitudes in both hemispheres [97]. Interestingly, children of Afro-Caribbean, Black African, and Asian migrants to northern climates (such as the United Kingdom) have an increased risk of the disease compared with natives, adding further support of a possible contribution of vitamin D in the pathogenesis of the disease [98, 99]. The use of vitamin D supplementation in the gestational and/or perinatal period appears to reduce the risk of developing schizophrenia later in life [100, 101]. A recent study of serum neonatal 25(OH)D levels in a Danish population-based cohort implicated a role of neonatal 25(OH)D with later risk of developing schizophrenia. However, both low and high concentrations were associated with increased disease risk, findings that demand further interrogation [102].

There is a known heritable component in schizophrenia, with clustering being observed within families, especially in monozygotic twin pairs [103]. Monozygotic twins may be discordant for the disease suggesting gene-environment interactions. A recent study suggested a latitude-driven adaptation for both schizophrenia and vitamin D related genes and proposed a model in which schizophrenia is, at least in part, a maladaptive by-product of latitude dependent adaptive changes in vitamin D metabolism [104]. Interestingly, GWAS have highlighted several genes associated with susceptibility to schizophrenia, many of which have a VDR-binding site within or close to them. The genes that are potentially regulated by vitamin D subserve a diverse range of biological functions including membrane transport, maintenance of nucleosome structure, and signal transduction to name a few (see Table 1). Some of these vitamin D mediated genes have an intimate relationship with brain morphology and function as evidenced by their demonstrated role in neuronal migration and gyration, dendritic spine morphology, and neuronal connectivity (see Table 1) [105-108]. The full scope of the functional impact of vitamin D on the expression of these schizophrenia-associated genes in the brain warrants further study.

Table 1. Schizophrenia and autism associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene nameGene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (; Ensembl (; Human Protein Reference Database (

SchizophreniaVRK2vaccinia related kinase 22p16.1Member of vaccinia-related kinase (VRK) family of serine/threonine protein kinasesNeuronal migration and gyration; Dendritic spine morphology [105]
ZNF804Azinc finger protein 804A2q32.1Member of zinc-finger protein family of unknown functionDorsolateral prefrontal, orbitofrontal, hippocampus, and amygdala connectivity [106]
SLC17A3solute carrier family 17 (sodium phosphate), member 36p21.3Membrane protein involved in phosphate transportNone known
BTN3A2butyrophilin, subfamily 3, member A26p22.1Part of butyrophilin (BTN) and immunoglobulin superfamilies, residing in the juxta-telomeric region of the MHC class 1 locusNone known
BTN2A2butyrophilin, subfamily 2, member A26p22.1
BTN3A1butyrophilin, subfamily 3, member A16p22.1
HIST1H2BJhistone cluster 1, H2bj6p22.1Core histones responsible for the nucleosome structure of the chromosomal fibre in eukaryotesDendritic spine morphology [107]
HIST1H2AGhistone cluster 1, H2ag6p22.1None known
PRSS16protease, serine, 16 (thymus)6p21Serine protease expressed exclusively in the thymus with role in the alternative antigen presenting pathway during positive T-cell selectionNone known
NOTCH4notch 46p21.3Member of Type 1 transmembrane protein family – cell surface receptor linked to signal transduction important for developmental processes by controlling cell fate decisionsFrontal lobe (executive) function [108]
HLA-DQA1major histocompatibility complex, class II, DQ alpha 16p21.3Part of MHC class II molecule – heterodimer with beta chain (DQB); plays central role in immune system by presenting peptides derived from extracellular proteinsNone known
AutismPPP2R5Cprotein phosphatase 2, regulatory subunit B′, gamma14q32.31Serine/threonine phosphatase implicated in the negative control of cell growth and divisionRetinogenesis and photoreceptor development [126]
(ii) Autism

Autism is part of a spectrum of developmental disorders characterized by deficits in social cognition, language, communication, and stereotypical patterns of behaviour [109]. Neuropathological features lack clear definition; however, the disorder shows changes consistent with pre- and post-natal developmental abnormalities that involve multiple brain regions, including the cerebral cortex, subcortical white matter, amygdala, brainstem, and cerebellum [110]. It has been proposed that autism demonstrates developmentally specific neural changes, with early brain overgrowth at the beginning of life (thought to be secondary to excessive neurone number), slowing or arrest of growth during early childhood, and neurodegeneration in adult life, at least in a subset of patients [111]. As vitamin D has been shown to inhibit excessive cellular proliferation in early rat brain development [27, 62], it has been argued that gestational hypovitaminosis D contributes to excessive neuronal proliferation in the developing brain and, therefore, could serve as a useful model for autism [112].

Epidemiological evidence for a contribution of vitamin D to the pathogenesis of autism exists but is less striking than for schizophrenia. This, in part, relates to issues of ascertainment, sensitivity/specificity of diagnosis, and differences in study methodology. Seasonality of birth has been reported to be associated with autism in the early spring in Scandinavia, Japan, United Kingdom, and the USA [113-115]. Some studies report an increased peak of births during summer months [116], and others show this effect restricted to men [114] or not existent at all [117]. A latitude effect has been illustrated on both the magnitude of the month of birth effect and in overall disease prevalence [118]; however, the effect has only been discernible in a cohort prior to the surge in autism prevalence in the 1990s. Migration appears to affect prevalence rates of autism. Gillberg and colleagues, while reporting on prevalence rates of autism in immigrant families in Sweden, observed an increased prevalence of autism in first born children of mothers who had recently immigrated [119]. A more recent study found that autism was 3–4 times more prevalent in children of Somali immigrant families to Sweden compared with the non-Somali population [120, 121]. The evidence that vitamin D supplementation affects rates of autism has been circumstantial at best. There is some data suggesting that vitamin D intake may positively influence measures of cognition, and that deficiency states result in increased risk of lower verbal IQs, suboptimal outcomes in communication and social development, features observed in autism [122, 123].

Genetic contribution to autism risk is strong, based on family and twin studies, and there is some overlap of autism spectrum disorders with known genetic disorders [124, 125]. The list of candidate autism risk genes identified by GWAS is proliferating exponentially. Given the complex genetic architecture of the disease, it has been suggested that gene-environment interactions must play a substantial role. On review of the GWAS identified genes, the PPP2R5C gene, a serine/threonine phosphatase implicated in the control of cell growth and division, appears to have a VDR-binding site. PPP2R5C has been implicated in retinogenesis and photoreceptor development [126], an interesting finding considering abnormal retinal function determined by electroretinography has been described in the disease (see Table 1) [127]. The role this susceptibility gene may play (if any) with the more broad and complex neurological phenotype is not known; however, it is clear that its regulation by vitamin D accentuates possible gene-environment interactions in a genetically susceptible individual.

B. Neurological disease

(i) Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by the cardinal features of tremor, rigidity, akinesia, and postural instability. Pathologically, PD affects the central dopaminergic pathways with neuronal loss and α-synuclein aggregates in multiple brain regions [128, 129]. As previously discussed, a biological basis for a potential role of vitamin D in PD has been illustrated in various experimental rodent models wherein vitamin D exerts a neuroprotective effect on mesencephalic dopaminergic neurones exposed to a variety of toxic conditions [46-49].

The relationship between hypovitaminosis D and risk of Parkinson's disease has long been suggested from epidemiological studies. A season-of-birth effect has been observed in various PD cohorts, with an excess of births being reported in winter and early spring in England and Scotland [130]. A latitude effect may be operative in PD risk with a north-to-south latitude gradient (higher prevalence in the north) being observed in several studies [131-134]. Vitamin D status has been implicated in PD; low serum 25(OH)D levels have been shown in PD patients compared with age-matched controls and patients with Alzheimer's dementia (controlled for duration of disease), and observational studies have demonstrated an increased risk of osteoporosis and hip fractures in PD patients [135-137]. Clearly, as low vitamin D status and its clinical consequences may be secondary to a host of factors, including advanced age, reduced mobility from disease, reverse causation cannot be excluded. Studies investigating the effect of migration and vitamin D supplementation on PD risk are lacking.

There is a clear heritable component in PD. Genetic studies have pointed to a possible role of vitamin D in susceptibility to the disease. Polymorphisms in the VDR gene have been shown to associate with PD risk in American and Korean cohorts, with the former cohort also showing an age of onset effect [138, 139]. The relatively small sample sizes and the inconsistent replication of SNPs in the VDR gene in discovery and validation sets dampen the impact of these findings. GWAS have identified an increasing number of candidate risk genes in PD, several of which have VDR-binding sites closely associated with them raising the possibility that vitamin D may influence their expression. The biological relevance of a subset of these susceptibility genes with associated VDR binding on brain function has been well delineated with evidence for roles in nigrostriatal dopaminergic neurotransmission, neurogenesis and neurite outgrowth, and neural ectodermal expression (especially within the marginal and subventricular zones) (see Table 2) [140-144].

Table 2. PD (Parkinson's disease) and ALS (amyotrophic lateral sclerosis) associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene nameGene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (; Ensembl (; Human Protein Reference Database (

PDBST1bone marrow stromal cell antigen 14p15Stromal cell line-derived glycosylphosphatidylinositol-anchored molecule that facilitates pre-B-cell growth and calcium homeostasisDopaminergic neuronal vulnerability via aberrant calcium homeostasis [140]
GAKcyclin G associated kinase4p16Serine/threonine kinase involved in regulating cell cycle controlNeuronal development [141]
STBD1starch binding domain 14q21.1Integral membrane protein of unknown functionNone known
HLA-DRAmajor histocompatibility complex, class II, DR alpha6p21.3Member of HLA class II expressed on antigen presenting cells involved in presenting peptides derived from extracellular proteinsNone known
SFXN2sideroflexin 210q24.32Transport/cargo protein in mitochondrial membrane involved in iron transportNeural ectodermal expression (esp. marginal/subventricular zones) [142]
LRRK2leucine-rich repeat kinase 212q12Leucine-rich repeat kinase family that encodes a primarily cytoplasmic protein; associates with mitochondrial outer membrane – interacts with parkin, phosphoproteins, miRNAsNeurogenesis and neurite outgrowth [143, 144]
ALSCSNK1G3casein kinase 1, gamma 35q23Member of serine/threonine kinase family that preferentially phosphorylates acidic substrates using ATP as a phosphate donorSynapse plasticity; TDP-43 hyperphosphorylation [155]
ATXN1ataxin 16p23RNA binding protein involved in regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolismNeuronal survival; spinocerebellar function [156]
MOBKL2BMOB1, Mps One Binder kinase activator-like 2B9p21.2Protein known to bind Mps1p, a kinase essential for spindle pole body duplication and mitotic checkpoint regulationNeuronal brain/spinal cord apoptosis (overexpression) [157]
SUSD1sushi domain containing 19q31.3-q33.1Calcium binding protein with unknown functionNone known
IFNKinterferon, kappa9Member of type I interferon family – glycoprotein involved in host defences against viral infectionsNone known
C9orf72chromosome 9 open reading frame 729p21.2An unclassified protein of unknown functionNone known
ITPR2inositol 1,4,5-triphosphate receptor, type 212p11Transport protein involved in chemoattractant signal transduction and spatiotemporal organization of calcium microdomains facilitating cellular processes such as cell migrationMotor neurone intracellular calcium regulation; glutamate mediated neurotransmission [158]
LIPClipase, hepatic15q21-q23Hepatic triglyceride lipase with dual function of a triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptakeNone known
UNC13Aunc-13 homolog A19p13.11Diacylglycerol and phorbol ester receptor thought to play a role in synaptic vesicle primingPresynaptic vesicle priming (esp. glutamate) [159]
SOD1superoxide dismutase 121q22.11Isozyme that binds copper/zinc ions to convert free superoxide radicals to molecular oxygen and hydrogen peroxideNeuritogeneiss, axonal growth, guidance, and synaptogenesis [161, 162]
(ii) Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both the central and peripheral nervous systems [145]. ALS pathology reveals degeneration of motor neurones and corticospinal tracts, brainstem nuclei, and spinal cord anterior horn cells, with a subset of patients having intracytoplasmic transactive responsive DNA-binding protein inclusions (TDP-43) [146]. Multiple effector pathways are thought to contribute to ALS pathology including neurotrophic factor deficiency, glutamate toxicity, and damage from ROS [54]. Given that many of these effector pathways are influenced by vitamin D in rodent models, there has been growing interest in the concept that this secosteroid may influence susceptibility to and disease progression in ALS.

The epidemiological evidence incriminating vitamin D as a possible risk factor in ALS is sparse. The relatively low population prevalence probably contributes but there may be no association. Season of birth observations have been conflicting with a few studies reporting excess births between April and July [147], and others reporting birth excess in between October and December (with a trough between April and July) [148]. A latitude gradient has been suggested, but the results are divergent. An American cohort outlining the geographic distribution of ALS using mortality data demonstrated a north-west to south-east gradient [149], a finding mirrored in a more recent study which found a higher ALS-associated death rate in more northern states [150]. On the contrary, a reverse latitude gradient (that is, south-to-north) was captured in separate Italian cohorts. However, the results from these studies are difficult to interpret given ascertainment bias [151, 152]. Similarly, a study evaluating the role of environmental factors in ALS in the UK found clustering of ALS cases in South-East England within certain postcode districts, especially in high population density areas [153, 154].

Similar to PD, studies have highlighted that vitamin D deficiency is prevalent in patients with ALS. However, it is probable that this is secondary to the consequences of the disease, such as decreased UVB exposure from reduced mobility and advance aged. The impact of vitamin D supplementation on subsequent disease susceptibility and progression in ALS is not known.

There is a genetic component to susceptibility to ALS. In addition to familial ALS wherein several risk genes have been established, there is increasing evidence of a complex genetic architecture even in patients with the ‘sporadic’ form of the disease. GWAS have identified a number of biologically relevant candidate genes, some of which have VDR-binding sites within or in close proximity to them fuelling support to a link between vitamin D and the pathogenesis of ALS (see Table 2). Epidemiological evidence linking vitamin D status and ALS is weak at best but molecular evidence may support a role for vitamin D in the pathogenesis of the disease. Several of the ALS susceptibility genes with associated VDR-binding sites have been implicated in salient brain functions such as neuritogenesis, axonal growth, guidance, and synaptogenesis, motor neurone intracellular calcium regulation and glutamate mediated neurotransmission, and hyperphosphorylation of TDP-43 (see Table 2) [155-162].

(iii) Multiple sclerosis

Multiple sclerosis (MS) is a CNS disorder primarily affecting young adults which demonstrates substantial clinical heterogeneity [163]. MS pathology demonstrates foci of demyelination characterized by the nature and extent of inflammatory infiltration, with acute MS lesions having a preponderence of macrophages, lymphocytes (mostly Th1 and Th17), and ROS (such as nitric oxide) throughout and chronic lesions having inflammation, if present, concentrated along the outer rim [164]. The recognition of diffuse changes in normal appearing white matter and axonal loss both within and outside of plaques has broadened this plaque-centred view [165-167]. The mechanistic link of vitamin D in influencing susceptibility to and disease activity in MS has concentrated on vitamin D's neuroimmunomodulatory role first appreciated in the animal model, experimental allergic encephalomyelitis (EAE). In EAE, vitamin D both prevents onset of clinical symptoms and reversibly blocks progression of clinical signs depending on the time of its administration [168, 169], an effect which disappears in VDR knockout EAE mice [170]. It is thought that vitamin D mediates these affects through a plethora of neuroimmunomoedulatory mechanisms which go beyond the scope of this review.

From an epidemiological standpoint, vitamin D deficiency has long been considered a suspect in MS susceptibility. A month-of-birth effect in MS is unequivocal, with MS risk being increased for late spring birth and decreased for those in late autumn [171]. More strikingly, in Scotland, which has the world's highest MS rate, risk differences between April and November birth reach an astonishing 50%, confirmed in three independent studies [171]. The mechanism by which gestational vitamin D deficiency contributes to increased MS risk later in life is not clear; however, animal model data suggest that developmental vitamin D deficiency may alter thymic development, impact T-cell selection, and disrupt T-cell homeostasis to favour a proinflammatory phenotype [172]. The neurodevelopmental impact of gestational vitamin D deficiency in relation to MS risk is not clear and warrants further study. A latitude gradient has been noted in MS with the prevalence of the disease being minimal at the equator and increased in both Northern and Southern latitudes, observations that have been replicated in multiple cohorts [173] (reviewed in [174] and [175]). Further dissection of a latitudinal gradient performed in the ethnically homogenous farmer population from France revealed that a north-east to south-west gradient in MS prevalence mirrored mean annual solar irradiation and mean regional serum vitamin D levels in normal adults [88, 173]. The relationship between latitude and MS disease prevalence is further illustrated by migration studies. Small but influential studies suggest that people younger than 15 years at the time of migration tend to adopt the MS risk of the country to which they migrate, whereas those older than 15 years carry the risk of MS of their country of origin [176]. The precise timing of this effect is unclear; however, the critical age of migration may extend into early adulthood [177].

Additional lines of evidence of hypovitaminosis D in MS risk come from serological data of 25(OH)D levels and effect of vitamin D supplementation on MS disease risk and clinical activity. Hypovitaminosis D has been commonly found in MS patients, but the influence of increasing age, sensitivity to heat, and disability may all negatively influence serum 25(OH)D levels [178, 179]. A prospective longitudinal study of a large number of individuals serving in the US military implemented a nested case-control design comparing serum 25(OH)D levels collected before the date of onset of MS symptoms, and demonstrated an inverse correlation of MS risk with serum 25(OH)D levels, particularly before the age of 20 years [180]. Vitamin D supplementation has been suggested to reduce the risk of MS. A study that prospectively followed two cohorts of nurses within the USA found that vitamin D supplementation was inversely related to MS susceptibility in people who consumed at least 400 IU/day of vitamin D, which is considered a modest intake and only marginally increases serum 25(OH)D levels [181]. Individuals drawn from the same cohort were used to evaluate the impact of dietary vitamin D during adolescence and found that intake ≥400 IU/day of vitamin D from multivitamins was associated with a reduced risk of MS, although the findings were not statistically significant [182] possibly because of the small sample size. In addition to influencing MS risk, there is increasing evidence to suggest that vitamin D may modify clinical and radiographic activity of disease [183, 184].

A genetic component to MS susceptibility is unequivocal. Genetic epidemiological studies have highlighted that first-degree relatives of individuals with MS have a 15–35 fold greater risk of developing the disorder compared with the general population [185]. The greatest influence of genetic risk in MS is nestled in the class II region of the MHC, specifically on haplotypes bearing the HLA-DRB1*15 allele but there is a large influence of epistatic interactions. Several non-MHC loci with much smaller effect size than the MHC region have been identified in GWAS [186]. Variants of one such gene, CYP27B1 (known to encode the 1-α-hydroxylase enzyme and therefore important for vitamin D metabolism) have been associated with MS susceptibility in Australian, Swedish and Canadian cohorts [187-189]. The discovery of VDREs in the classical promotor position of the main risk allele HLA-DRB1*15 [190] and VDR-binding sites associated with several non-MHC MS susceptibility genes identified by GWAS [191], highlight the intricate interplay between MS susceptibility genes and vitamin D (see Table 3).

Table 3. MS (multiple sclerosis) associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene nameGene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (; Ensembl (; Human Protein Reference Database (

MSEVI5ecotropic viral integration site 51p22.1Function not known but thought to be involved in regulation of cell cycle progressionNone known (mRNA detected in foetal/adult brain) [193]
RPL5ribosomal protein L51p22.1Ribosomal protein (60S subunit) – binds 5S rRNA to transport nonribosome-associated cytoplasmic 5S rRNA to the nucleolus for assembly into ribosomesNone known
CXCR4chemokine (C-X-C motif) receptor 42q21A CXC chemokine receptor (G-protein coupled) specific for stromal cell-derived factor-1 which demonstrates chemotactic activity for lymphocytesNeuronal/oligodendrocyte precursor survivor and migration; interneurone migration; neuronal cell cycle regulation [194-197]
HLA-Bmajor histocompatibility complex, class I, B6p21.3Member of HLA class I expressed in nearly all cells involved in antigen presentationNone known
HLA-DRAmajor histocompatibility complex, class II, DR alpha6p21.3Member of HLA class II expressed on antigen presenting cells involved in presenting peptides derived from extracellular proteinsNone known
HLA-DRB1major histocompatibility complex, class II, DR beta 16p21.3
HLA-DQB1major histocompatibility complex, class II, DQ beta 16p21.3
ASAP1ArfGAP with SH3 domain, ankyrin repeat and PH domain 18q24.1-q24.2GTPase activating protein involved in membrane traffickingNone known
SH3GL2SH3-domain GRB2-like 29p22SH3 domain involved in signalling for cell polarization, motility, enzymatic activation, and transcriptional regulation.CNS development; found in abundance in presynaptic neuroganglia [198]
ZMIZ1zinc finger, MIZ-type containing 110q22.3Member of PIAS (protein inhibitor of activated STAT) family – regulate activity of various transcription factorsNone known
TNFRSF1ATumour necrosis factor receptor superfamily, member 1A12p13.2Member of TNF-receptor superfamily – activates NF-kappaB, mediates apoptosis, and regulates inflammationNeurodevelopment and neuroprotection [199, 200]
METTL1methyltransferase like 112q13RNA methyltransferase involved in regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolismNone known
CYP27B1cytochrome P450, family 27, subfamily B, polypeptide 112q13.1-q13.3Member of cytochrome P450 superfamily – hydroxylation of 25-hydroxyvitamin D3 to form 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D31-alpha-hydroxylase diffusely expressed throughout brain (neurones and glial cells) [8]
MPHOSPH9M-phase phosphoprotein 912q24.31Cell cycle control protein – induction of transition from G2 to M phaseNeuronal survival and synaptic plasticity [201]
CLEC16AC-type lectin domain family 16, member A16p13.13Function not knownNone known
IRF8interferon regulatory factor 816q24.1Member of IRF family – regulates expression of genes stimulated by IFN-alpha and IFN-beta; controls expression of IFN-alpha and IFN-beta-regulated genes induced by viral infectionNone known
ZNF433zinc finger protein 43319p13.2DNA binding protein of unknown functionNone known
CD40CD40 molecule, TNF receptor superfamily member 520q12-q13.2Member of TNF-receptor superfamily – mediates several immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal centre formationNeuronal development, maintenance, and protection (expressed in neurones, astrocytes, glial cells, and cerebral vasculature) [202-204]

The premise that MS is an inflammatory-mediated demyelinating disease has sculpted the view that the discovered susceptibility genes primarily play a role in immunological processes. There is evidence, however, that inflammatory demyelination does not completely account for the extent of neurodegeneration observed in the disease [167]. Genes, such as those found in the MHC, are also expressed in neurones and glial cells in the CNS and may, therefore, subserve broader biological functions [192]. On review of the MS susceptibility genes with evidence of VDR binding, their role is far more complex than has been appreciated and likely extends beyond the traditional immunological point-of-view. In a subset of these genes, there are varying degrees of experimental evidence to suggest an influence of these genes on the brain (beyond inflammation) in processes including (but not limited to) neuronal/oligodendrocyte precursor survival, proliferation and migration, neuronal cell cycle regulation, synaptic plasticity, and motor axon trajectory delineation (see Table 3 for cited examples) [8, 193-204]. It is clear that further study aimed at unravelling the effect of vitamin D on the expression of these genes, the impact of these genes on both immunological and brain function and how they influence MS susceptibility needs to take centre stage.

(iv) Alzheimer's disease

Alzheimer's disease is a neurodegenerative disease characterized by memory dysfunction and impairment in other cognitive domains. Epidemiological studies have established several risk factors for the development of AD, the most striking of which is increasing age. Other important risk factors include hypertension, hyperlipidaemia, hyperhomocysteinaemia, diabetes/insulin resistance, obesity, physical inactivity, smoking, low education, and inflammatory factors [205]. Neuropathologically, the AD brain features neuronal, neurite and synaptic loss, most pronounced in specific brain regions (that is, entorhinal cortex, subiculum/CA1 regions of the hippocampus, and association cortex) and a stage-dependent distribution of amyloid and, in particular, tau pathology [205]. Given the role of vitamin D in maintaining neurite outgrowth, promoting synaptic plasticity, facilitating neurotransmitter synthesis (e.g. acetylcholine), protecting against oxidative stress and mitochondrial dysfunction, reducing pro-inflammatory responses, and regulating the rate of ageing, there is a plausible biological basis to support a role for vitamin D in the pathogenesis of cognitive impairment and AD.

The evidence linking vitamin D deficiency to AD is limited. Data evaluating the influence of season-of-birth, latitude, and migration data on AD risk are scarce and, when present, are conflicting [206]. Similarly, a role for vitamin D insufficiency in AD disease pathogenesis and/or phenotypic expression has been a source of debate [207, 208]. Discrepant results on the role of vitamin D in AD risk likely stem from several factors, including underpowered sample sizes, cross-sectional study design, retrospective analysis of vitamin D levels and cognitive function, and lack of adjustment for confounding clinical variables. Further, where associations between low serum vitamin D levels and dementia have been reported, the issue of reverse causation (that is, vitamin D deficiency is a consequence rather than a cause of dementia) hinders definitive interpretation. However, recent prospective, longitudinal cohort studies do provide some support to the idea that hypovitaminosis D may influence subsequent risk of AD. Annweiler et al. prospectively followed a cohort of women aged 75 years and older and found that those who developed AD had lower baseline vitamin D intake than non-demented women or those who developed other dementias. In addition, they reported that women in the highest quintile of dietary vitamin D intake substantially decreased the risk of an AD diagnosis 7 years later compared with individuals in the lowest four quintiles combined (adjusted OR = 0.23, P = 0.007) [209]. Similarly, in a population-based, prospective cohort study of 858 Italian adults 65 years and older, Llewellyn et al. showed that patients with vitamin D deficiency at baseline had an increased risk of cognitive decline over a median follow-up period of 6 years, an effect which remained after adjusting for relevant comorbidities and excluding subjects with known dementia at baseline [210]. Interestingly, a trend toward a dose–response relationship between vitamin D status and cognitive measures was also observed with subjects in the lowest quartiles of serum vitamin D performing lower on the Mini-Mental Status Examination than those in the upper quartiles, a finding that has been replicated in other studies [211]. These studies do not demonstrate causality between serum vitamin D levels and cognitive status especially given that vitamin D status may be a surrogate for other lifestyle factors that are difficult to control. That being said, with the increasing number of people affected by AD and the relative safety and cost-effectiveness of vitamin D supplementation, it may be reasonable to consider exploring a possible link between vitamin D and AD more closely in well-controlled, prospective, longitudinal studies and/or clinical trials.

Alzheimer's disease susceptibility demonstrates a heritable component with recent GWAS pointing to an increasing number of genes of modest effect associated with late onset AD [212]. Genetic studies have supported a role for vitamin D in AD risk as evidenced by association of the disease with genetic variation in the vitamin D receptor gene (Vdr) [213-215]. The observation that VDR-binding sites are closely associated with several candidate AD susceptibility genes adds further support to this claim; however, detailed study exploring the role of vitamin D on gene expression and disease susceptibility is needed. The brain function of a selection of the AD susceptibility genes with associated VDR binding sites is outlined in Tables 4 [216-225].

Table 4. AD associated gene regions with VDR (vitamin D receptor) binding
DiseaseGene symbolGene namegene locationProtein function*Role in brain function
  1. *Data derived from NCBI Gene (; Ensembl (; Human Protein Reference Database (

Alzheimer's diseaseABCA7ATP-binding casette, subfamily A, member 719p13.3Member of family of transporter proteins that exhibits a regulatory response to cholesterol influx and effluxHighly expressed in brain including hippocampal CA1 neurones and microglia; regulates amyloid precursor protein processing [216, 217]
DIP2Cdisco-interacting protein 2, homolog C10p15.3Protein with zinc-finger domains that interacts with the transcription factor discoNeuroblast/neuronal expression throughout embryologic development; highly expressed in neocortex, striatum, and thalamus [218]
FRMD4AFERM domain containing-4A10p13Member of FERM superfamily involved in cell structure, transport, and signalling functionsInteracts with Arf6 which has been shown to regulate dendritic branching in hippocampal neurones and neurite outgrowth; possible role in amyloid precursor protein processing [219-221]
PICALMPhosphatidylinositol-binding clathrin assembly protein11q14.2Clathrin assembly protein that recruits clathrin and adaptor protein complex 2 (AP2) to cell membranes at sites of coated-pit formation and clathrin-vesicle assemblyExpressed in hippocampal and cortical neurones (pre- and post-synaptically), brain vascular endothelial cells; possible role in amyloid precursor protein processing [222-224]
ZNF224Zinc finger protein 2419q13.2Contains a Kruppel-associated box (KRAB) domain and functions as a transcriptional repressorNone known; associated with intermediate phenotypes in AD (neurofibillary tangle burden) [225]


  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

This review has highlighted the extensively diverse role of vitamin D and its metabolites in both nervous system health and disease. The convergence of in vitro, ex vivo, and animal model data provides compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Animal models have also contributed to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The role of vitamin D likely goes beyond its direct function on cellular processes in that this secosteroid may influence the expression of genes via vitamin D response elements. The culmination of epidemiological, neuropathological, experimental, and molecular genetic findings certainly implicate vitamin D in influencing susceptibility to a number of psychiatric and neurological diseases, such as schizophrenia, autism, Parkinson's disease, ALS, MS, and AD. Much more needs to be done to unravel how vitamin D deficiency may alter disease risk. The timing of vitamin D deficiency (and supplementation) and its influence on disease risk, the tissue-specific consequences of vitamin D deficiency on gene expression, and the regional influence of vitamin D status on the CNS structure and function, are a few key issues to be addressed. Given the enormous morbidity and mortality associated with these devastating diseases, the potential impact of vitamin D supplementation at a population level is staggering and is certainly worthy of further investigation in well-designed clinical trials.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References

G. D and G. E. conceived the idea of the review. G. D., S. K., J. K., S. R., and G. E. drafted the manuscript and critically reviewed the content. G. D. is supported by the AANF/CMSC John F. Kurtzke Clinician-Scientist Award, a Goodger Scholarship (University of Oxford), and the NIHR Biomedical Research Centre, Oxford.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Vitamin D metabolism
  5. Vitamin D effector proteins
  6. The effects of vitamin D in the nervous system
  7. Vitamin D and brain development
  8. Vitamin D in psychiatric and neurological disease
  9. Conclusions
  10. Acknowledgements
  11. Conflicts of interest
  12. References
  • 1
    Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266281
  • 2
    Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 1979; 206: 11881190
  • 3
    Stumpf WE, Sar M, Clark SA, DeLuca HF. Brain target sites for 1,25-dihydroxyvitamin D3. Science 1982; 215: 14031405
  • 4
    Balabanova S, Richter HP, Antoniadis G, Homoki J, Kremmer N, Hanle J, Teller WM. 25-Hydroxyvitamin D, 24, 25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D in human cerebrospinal fluid. Klin Wochenschr 1984; 62: 10861090
  • 5
    Gascon-Barre M, Huet PM. Apparent [3H]1,25-dihydroxyvitamin D3 uptake by canine and rodent brain. Am J Physiol 1983; 244: E266271
  • 6
    Pardridge WM, Sakiyama R, Coty WA. Restricted transport of vitamin D and A derivatives through the rat blood-brain barrier. J Neurochem 1985; 44: 11381141
  • 7
    Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 2001; 86: 888894
  • 8
    Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005; 29: 2130
  • 9
    Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL, Portale AA. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin d-dependent rickets type 1. Mol Endocrinol 1997; 11: 19611970
  • 10
    Naveilhan P, Neveu I, Baudet C, Ohyama KY, Brachet P, Wion D. Expression of 25(OH) vitamin D3 24-hydroxylase gene in glial cells. Neuroreport 1993; 5: 255257
  • 11
    Spach KM, Hayes CE. Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J Immunol 2005; 175: 41194126
  • 12
    Stumpf WE, Privette TH. The steroid hormone of sunlight soltriol (vitamin D) as a seasonal regulator of biological activities and photoperiodic rhythms. J Steroid Biochem Mol Biol 1991; 39: 283289
  • 13
    Prufer K, Veenstra TD, Jirikowski GF, Kumar R. Distribution of 1,25-dihydroxyvitamin D3 receptor immunoreactivity in the rat brain and spinal cord. J Chem Neuroanat 1999; 16: 135145
  • 14
    Baas D, Prufer K, Ittel ME, Kuchler-Bopp S, Labourdette G, Sarlieve LL, Brachet P. Rat oligodendrocytes express the vitamin D(3) receptor and respond to 1,25-dihydroxyvitamin D(3). Glia 2000; 31: 5968
  • 15
    Cornet A, Baudet C, Neveu I, Baron-Van Evercooren A, Brachet P, Naveilhan P. 1,25-Dihydroxyvitamin D3 regulates the expression of VDR and NGF gene in Schwann cells in vitro. J Neurosci Res 1998; 53: 742746
  • 16
    Tague SE, Smith PG. Vitamin D receptor and enzyme expression in dorsal root ganglia of adult female rats: modulation by ovarian hormones. J Chem Neuroanat 2011; 41: 112
  • 17
    Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton SM, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res 2010; 20: 13521360
  • 18
    Nemere I, Safford SE, Rohe B, DeSouza MM, Farach-Carson MC. Identification and characterization of 1,25D3-membrane-associated rapid response, steroid (1,25D3-MARRS) binding protein. J Steroid Biochem Mol Biol 2004; 89–90: 281285
  • 19
    Khanal RC, Nemere I. The ERp57/GRp58/1,25D3-MARRS receptor: multiple functional roles in diverse cell systems. Curr Med Chem 2007; 14: 10871093
  • 20
    Wion D, MacGrogan D, Neveu I, Jehan F, Houlgatte R, Brachet P. 1,25-Dihydroxyvitamin D3 is a potent inducer of nerve growth factor synthesis. J Neurosci Res 1991; 28: 110114
  • 21
    Neveu I, Naveilhan P, Jehan F, Baudet C, Wion D, De Luca HF, Brachet P. 1,25-dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells. Brain Res Mol Brain Res 1994; 24: 7076
  • 22
    Saporito MS, Brown ER, Hartpence KC, Wilcox HM, Vaught JL, Carswell S. Chronic 1,25-dihydroxyvitamin D3-mediated induction of nerve growth factor mRNA and protein in L929 fibroblasts and in adult rat brain. Brain Res 1994; 633: 189196
  • 23
    Naveilhan P, Neveu I, Wion D, Brachet P. 1,25-Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport 1996; 7: 21712175
  • 24
    Neveu I, Naveilhan P, Baudet C, Brachet P, Metsis M. 1,25-dihydroxyvitamin D3 regulates NT-3, NT-4 but not BDNF mRNA in astrocytes. Neuroreport 1994; 6: 124126
  • 25
    Naveilhan P, Neveu I, Baudet C, Funakoshi H, Wion D, Brachet P, Metsis M. 1,25-Dihydroxyvitamin D3 regulates the expression of the low-affinity neurotrophin receptor. Brain Res Mol Brain Res 1996; 41: 259268
  • 26
    Brown J, Bianco JI, McGrath JJ, Eyles DW. 1,25-dihydroxyvitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons. Neurosci Lett 2003; 343: 139143
  • 27
    Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F. Vitamin D3 and brain development. Neuroscience 2003; 118: 641653
  • 28
    Feron F, Burne TH, Brown J, Smith E, McGrath JJ, Mackay-Sim A, Eyles DW. Developmental Vitamin D3 deficiency alters the adult rat brain. Brain Res Bull 2005; 65: 141148
  • 29
    Fernandes de Abreu DA, Eyles D, Feron F. Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology 2009; 34 Suppl. 1: S265277
  • 30
    Kalueff AV, Tuohimaa P. Neurosteroid hormone vitamin D and its utility in clinical nutrition. Curr Opin Clin Nutr Metab Care 2007; 10: 1219
  • 31
    Eyles DW, Feron F, Cui X, Kesby JP, Harms LH, Ko P, McGrath JJ, Burne TH. Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology 2009; 34 Suppl. 1: S247257
  • 32
    Baksi SN, Hughes MJ. Chronic vitamin D deficiency in the weanling rat alters catecholamine metabolism in the cortex. Brain Res 1982; 242: 387390
  • 33
    Sonnenberg J, Luine VN, Krey LC, Christakos S. 1,25-Dihydroxyvitamin D3 treatment results in increased choline acetyltransferase activity in specific brain nuclei. Endocrinology 1986; 118: 14331439
  • 34
    Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK. Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. Brain Res Mol Brain Res 1996; 36: 193196
  • 35
    Cass WA, Smith MP, Peters LE. Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine. Ann N Y Acad Sci 2006; 1074: 261271
  • 36
    Kesby JP, Cui X, Ko P, McGrath JJ, Burne TH, Eyles DW. Developmental vitamin D deficiency alters dopamine turnover in neonatal rat forebrain. Neurosci Lett 2009; 461: 155158
  • 37
    Cass WA, Peters LE, Fletcher AM, Yurek DM. Evoked dopamine overflow is augmented in the striatum of calcitriol treated rats. Neurochem Int 2012; 60: 186191
  • 38
    Tekes K, Gyenge M, Folyovich A, Csaba G. Influence of neonatal vitamin A or vitamin D treatment on the concentration of biogenic amines and their metabolites in the adult rat brain. Horm Metab Res 2009; 41: 277280
  • 39
    Tekes K, Gyenge M, Hantos M, Csaba G. Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats. Alterations in the biogenic amine contents of the adult brain. Brain Dev 2009; 31: 666670
  • 40
    Barker DJ. The fetal origins of diseases of old age. Eur J Clin Nutr 1992; 46 Suppl. 3: S39
  • 41
    Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr 1999; 69: 179197
  • 42
    Wjst M, Heimbeck I, Kutschke D, Pukelsheim K. Epigenetic regulation of vitamin D converting enzymes. J Steroid Biochem Mol Biol 2010; 121: 8083
  • 43
    Wang Y, Chiang YH, Su TP, Hayashi T, Morales M, Hoffer BJ, Lin SZ. Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats. Neuropharmacology 2000; 39: 873880
  • 44
    Riaz S, Malcangio M, Miller M, Tomlinson DR. A vitamin D(3) derivative (CB1093) induces nerve growth factor and prevents neurotrophic deficits in streptozotocin-diabetic rats. Diabetologia 1999; 42: 13081313
  • 45
    Brewer LD, Thibault V, Chen KC, Langub MC, Landfield PW, Porter NM. Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci 2001; 21: 98108
  • 46
    Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y. Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res 2001; 904: 6775
  • 47
    Smith MP, Fletcher-Turner A, Yurek DM, Cass WA. Calcitriol protection against dopamine loss induced by intracerebroventricular administration of 6-hydroxydopamine. Neurochem Res 2006; 31: 533539
  • 48
    Shinpo K, Kikuchi S, Sasaki H, Moriwaka F, Tashiro K. Effect of 1,25-dihydroxyvitamin D(3) on cultured mesencephalic dopaminergic neurons to the combined toxicity caused by L-buthionine sulfoximine and 1-methyl-4-phenylpyridine. J Neurosci Res 2000; 62: 374382
  • 49
    Ibi M, Sawada H, Nakanishi M, Kume T, Katsuki H, Kaneko S, Shimohama S, Akaike A. Protective effects of 1 alpha,25-(OH)(2)D(3) against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology 2001; 40: 761771
  • 50
    Taniura H, Ito M, Sanada N, Kuramoto N, Ohno Y, Nakamichi N, Yoneda Y. Chronic vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons. J Neurosci Res 2006; 83: 11791189
  • 51
    Garcion E, Sindji L, Montero-Menei C, Andre C, Brachet P, Darcy F. Expression of inducible nitric oxide synthase during rat brain inflammation: regulation by 1,25-dihydroxyvitamin D3. Glia 1998; 22: 282294
  • 52
    Garcion E, Sindji L, Leblondel G, Brachet P, Darcy F. 1,25-dihydroxyvitamin D3 regulates the synthesis of gamma-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J Neurochem 1999; 73: 859866
  • 53
    de Viragh PA, Haglid KG, Celio MR. Parvalbumin increases in the caudate putamen of rats with vitamin D hypervitaminosis. Proc Natl Acad Sci U S A 1989; 86: 38873890
  • 54
    Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010; 140: 918934
  • 55
    Garcion E, Nataf S, Berod A, Darcy F, Brachet P. 1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis. Brain Res Mol Brain Res 1997; 45: 255267
  • 56
    Ko P, Burkert R, McGrath J, Eyles D. Maternal vitamin D3 deprivation and the regulation of apoptosis and cell cycle during rat brain development. Brain Res Dev Brain Res 2004; 153: 6168
  • 57
    Almeras L, Eyles D, Benech P, Laffite D, Villard C, Patatian A, Boucraut J, Mackay-Sim A, McGrath J, Feron F. Developmental vitamin D deficiency alters brain protein expression in the adult rat: implications for neuropsychiatric disorders. Proteomics 2007; 7: 769780
  • 58
    Eyles D, Almeras L, Benech P, Patatian A, Mackay-Sim A, McGrath J, Feron F. Developmental vitamin D deficiency alters the expression of genes encoding mitochondrial, cytoskeletal and synaptic proteins in the adult rat brain. J Steroid Biochem Mol Biol 2007; 103: 538545
  • 59
    Grecksch G, Ruthrich H, Hollt V, Becker A. Transient prenatal vitamin D deficiency is associated with changes of synaptic plasticity in the dentate gyrus in adult rats. Psychoneuroendocrinology 2009; 34 Suppl. 1: S258264
  • 60
    Levenson CW, Figueiroa SM. Gestational vitamin D deficiency: long-term effects on the brain. Nutr Rev 2008; 66: 726729
  • 61
    Veenstra TD, Prufer K, Koenigsberger C, Brimijoin SW, Grande JP, Kumar R. 1,25-Dihydroxyvitamin D3 receptors in the central nervous system of the rat embryo. Brain Res 1998; 804: 193205
  • 62
    Cui X, McGrath JJ, Burne TH, Mackay-Sim A, Eyles DW. Maternal vitamin D depletion alters neurogenesis in the developing rat brain. Int J Dev Neurosci 2007; 25: 227232
  • 63
    Burne TH, Becker A, Brown J, Eyles DW, Mackay-Sim A, McGrath JJ. Transient prenatal Vitamin D deficiency is associated with hyperlocomotion in adult rats. Behav Brain Res 2004; 154: 549555
  • 64
    Becker A, Eyles DW, McGrath JJ, Grecksch G. Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats. Behav Brain Res 2005; 161: 306312
  • 65
    Becker A, Grecksch G. Pharmacological treatment to augment hole board habituation in prenatal Vitamin d-deficient rats. Behav Brain Res 2006; 166: 177183
  • 66
    Harms LR, Eyles DW, McGrath JJ, Mackay-Sim A, Burne TH. Developmental vitamin D deficiency alters adult behaviour in 129/SvJ and C57BL/6J mice. Behav Brain Res 2008; 187: 343350
  • 67
    Kesby JP, O'Loan JC, Alexander S, Deng C, Huang XF, McGrath JJ, Eyles DW, Burne TH. Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring. Psychopharmacology (Berl) 2012; 220: 455463
  • 68
    Burne TH, O'Loan J, Splatt K, Alexander S, McGrath JJ, Eyles DW. Developmental vitamin D (DVD) deficiency alters pup-retrieval but not isolation-induced pup ultrasonic vocalizations in the rat. Physiol Behav 2011; 102: 201204
  • 69
    Li YC, Pirro AE, Amling M, Delling G, Baron R, Bronson R, Demay MB. Targeted ablation of the vitamin D receptor: an animal model of vitamin d-dependent rickets type II with alopecia. Proc Natl Acad Sci U S A 1997; 94: 98319835
  • 70
    Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, Kawakami T, Arioka K, Sato H, Uchiyama Y, Masushige S, Fukamizu A, Matsumoto T, Kato S. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet 1997; 16: 391396
  • 71
    Kalueff A, Loseva E, Haapasalo H, Rantala I, Keranen J, Lou YR, Minasyan A, Keisala T, Miettinen S, Kuuslahti M, Tuchimaa P. Thalamic calcification in vitamin D receptor knockout mice. Neuroreport 2006; 17: 717721
  • 72
    Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. Impaired motor performance in mice lacking neurosteroid vitamin D receptors. Brain Res Bull 2004; 64: 2529
  • 73
    Burne TH, McGrath JJ, Eyles DW, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. Behav Brain Res 2005; 157: 299308
  • 74
    Minasyan A, Keisala T, Lou YR, Kalueff AV, Tuohimaa P. Neophobia, sensory and cognitive functions, and hedonic responses in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 2007; 104: 274280
  • 75
    Zou J, Minasyan A, Keisala T, Zhang Y, Wang JH, Lou YR, Kalueff A, Pyykko I, Tuohimaa P. Progressive hearing loss in mice with a mutated vitamin D receptor gene. Audiol Neurootol 2008; 13: 219230
  • 76
    Minasyan A, Keisala T, Zou J, Zhang Y, Toppila E, Syvala H, Lou YR, Kalueff AV, Pyykko I, Tuohimaa P. Vestibular dysfunction in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 2009; 114: 161166
  • 77
    Kalueff AV, Minasyan A, Keisala T, Kuuslahti M, Miettinen S, Tuohimaa P. Increased severity of chemically induced seizures in mice with partially deleted Vitamin D receptor gene. Neurosci Lett 2006; 394: 6973
  • 78
    Keisala T, Minasyan A, Lou YR, Zou J, Kalueff AV, Pyykko I, Tuohimaa P. Premature aging in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 2009; 115: 9197
  • 79
    Kalueff AV, Lou YR, Laaksi I, Tuohimaa P. Increased anxiety in mice lacking vitamin D receptor gene. Neuroreport 2004; 15: 12711274
  • 80
    Keisala T, Minasyan A, Jarvelin U, Wang J, Hamalainen T, Kalueff AV, Tuohimaa P. Aberrant nest building and prolactin secretion in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 2007; 104: 269273
  • 81
    Burne TH, Johnston AN, McGrath JJ, Mackay-Sim A. Swimming behaviour and post-swimming activity in Vitamin D receptor knockout mice. Brain Res Bull 2006; 69: 7478
  • 82
    Dardenne O, Prud'homme J, Arabian A, Glorieux FHS, Arnaud R. Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin d-deficiency rickets. Endocrinology 2001; 142: 31353141
  • 83
    Panda DK, Miao D, Bolivar I, Li J, Huo R, Hendy GN, Goltzman D. Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem 2004; 279: 1675416766
  • 84
    Jablonski NG, Chaplin G. Colloquium paper: human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci U S A 2010; 107 Suppl. 2: 89628968
  • 85
    Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988; 67: 373378
  • 86
    Parra EJ. Human pigmentation variation: evolution, genetic basis, and implications for public health. Am J Phys Anthropol 2007; Suppl. 45: 85105
  • 87
    McGrath J. Does ‘imprinting’ with low prenatal vitamin D contribute to the risk of various adult disorders? Med Hypotheses 2001; 56: 367371
  • 88
    Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol 2008; 7: 268277
  • 89
    van Os J, Kapur S. Schizophrenia. Lancet 2009; 374: 635645
  • 90
    Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122 (Pt 4): 593624
  • 91
    Hare EH. Season of birth in schizophrenia and neurosis. Am J Psychiatry 1975; 132: 11681171
  • 92
    Torrey EF, Miller J. Season of birth and schizophrenia: southern hemisphere data. Aust N Z J Psychiatry 1997; 31: 308309
  • 93
    Davies G, Welham J, Chant D, Torrey EF, McGrath J. A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull 2003; 29: 587593
  • 94
    Berk M, Terre-Blanche MJ, Maude C, Lucas MD, Mendelsohn M, O'Neill-Kerr AJ. Season of birth and schizophrenia: southern hemisphere data. Aust N Z J Psychiatry 1996; 30: 220222
  • 95
    McGrath JJ, Welham JL. Season of birth and schizophrenia: a systematic review and meta-analysis of data from the Southern Hemisphere. Schizophr Res 1999; 35: 237242
  • 96
    Suvisaari JM, Haukka JK, Lonnqvist JK. Season of birth among patients with schizophrenia and their siblings: evidence for the procreational habits hypothesis. Am J Psychiatry 2001; 158: 754757
  • 97
    Saha S, Chant DC, Welham JL, McGrath JJ. The incidence and prevalence of schizophrenia varies with latitude. Acta Psychiatr Scand 2006; 114: 3639
  • 98
    Bhugra D, Leff J, Mallett R, Der G, Corridan B, Rudge S. Incidence and outcome of schizophrenia in whites, African-Caribbeans and Asians in London. Psychol Med 1997; 27: 791798
  • 99
    Cantor-Graae E, Selten JP. Schizophrenia and migration: a meta-analysis and review. Am J Psychiatry 2005; 162: 1224
  • 100
    McGrath J, Eyles D, Mowry B, Yolken R, Buka S. Low maternal vitamin D as a risk factor for schizophrenia: a pilot study using banked sera. Schizophr Res 2003; 63: 7378
  • 101
    McGrath J, Saari K, Hakko H, Jokelainen J, Jones P, Jarvelin MR, Chant D, Isohanni M. Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophr Res 2004; 67: 237245
  • 102
    McGrath JJ, Eyles DW, Pedersen CB, Anderson C, Ko P, Burne TH, Norgaard-Pedersen B, Hougaard DM, Mortensen PB. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry 2010; 67: 889894
  • 103
    Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 2000; 97: 1217
  • 104
    Amato R, Pinelli M, Monticelli A, Miele G, Cocozza S. Schizophrenia and vitamin D related genes could have been subject to latitude-driven adaptation. BMC Evol Biol 2010; 10: 351
  • 105
    Felix TM, Petrin AL, Sanseverino MT, Murray JC. Further characterization of microdeletion syndrome involving 2p15-p16.1. Am J Med Genet A 2010; 152A: 26042608
  • 106
    Esslinger C, Walter H, Kirsch P, Erk S, Schnell K, Arnold C, Haddad L, Mier D, Opitz von Boberfeld C, Raab K, Witt SH, Rietschel M, Cichon S, Meyer-Lindenberg A. Neural mechanisms of a genome-wide supported psychosis variant. Science 2009; 324: 605
  • 107
    Loe-Mie Y, Lepagnol-Bestel AM, Maussion G, Doron-Faigenboim A, Imbeaud S, Delacroix H, Aggerbeck L, Pupko T, Gorwood P, Simonneau M, Moalic JM. SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution. Hum Mol Genet 2010; 19: 28412857
  • 108
    Wassink TH, Nopoulos P, Pietila J, Crowe RR, Andreasen NC. NOTCH4 and the frontal lobe in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2003; 118B: 17
  • 109
    Levy SE, Mandell DS, Schultz RT. Autism. Lancet 2009; 374: 16271638
  • 110
    Schmitz C, Rezaie P. The neuropathology of autism: where do we stand? Neuropathol Appl Neurobiol 2008; 34: 411
  • 111
    Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, Morgan J. Mapping early brain development in autism. Neuron 2007; 56: 399413
  • 112
    Eyles DW. Vitamin D and autism: does skin colour modify risk? Acta Paediatr 2010; 99: 645647
  • 113
    Tanoue Y, Oda S, Asano F, Kawashima K. Epidemiology of infantile autism in southern Ibaraki, Japan: differences in prevalence in birth cohorts. J Autism Dev Disord 1988; 18: 155166
  • 114
    Mouridsen SE, Nielsen S, Rich B, Isager T. Season of birth in infantile autism and other types of childhood psychoses. Child Psychiatry Hum Dev 1994; 25: 3143
  • 115
    Stevens MC, Fein DH, Waterhouse LH. Season of birth effects in autism. J Clin Exp Neuropsychol 2000; 22: 399407
  • 116
    Barak Y, Ring A, Sulkes J, Gabbay U, Elizur A. Season of birth and autistic disorder in Israel. Am J Psychiatry 1995; 152: 798800
  • 117
    Kolevzon A, Weiser M, Gross R, Lubin G, Knobler HY, Schmeidler J, Silverman JM, Reichenberg A. Effects of season of birth on autism spectrum disorders: fact or fiction? Am J Psychiatry 2006; 163: 12881290
  • 118
    Grant WB, Soles CM. Epidemiologic evidence supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism. Dermatoendocrinol 2009; 1: 223228
  • 119
    Gillberg IC, Gillberg C. Autism in immigrants: a population-based study from Swedish rural and urban areas. J Intellect Disabil Res 1996; 40 (Pt 1): 2431
  • 120
    Barnevik-Olsson M, Gillberg C, Fernell E. Prevalence of autism in children born to Somali parents living in Sweden: a brief report. Dev Med Child Neurol 2008; 50: 598601
  • 121
    Dealberto MJ. Prevalence of autism according to maternal immigrant status and ethnic origin. Acta Psychiatr Scand 2011; 123: 339348
  • 122
    Benton D, Roberts G. Effect of vitamin and mineral supplementation on intelligence of a sample of schoolchildren. Lancet 1988; 1: 140143
  • 123
    Cannell JJ. Autism and vitamin D. Med Hypotheses 2008; 70: 750759
  • 124
    Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 6377
  • 125
    Folstein S, Rutter M. Genetic influences and infantile autism. Nature 1977; 265: 726728
  • 126
    Kim JW, Jang SM, Kim CH, An JH, Kang EJ, Choi KH. Neural retina leucine-zipper regulates the expression of Ppp2r5c, the regulatory subunit of protein phosphatase 2A, in photoreceptor development. FEBS J 2010; 277: 50515060
  • 127
    Ritvo ER, Creel D, Realmuto G, Crandall AS, Freeman BJ, Bateman JB, Barr R, Pingree C, Coleman M, Purple R. Electroretinograms in autism: a pilot study of b-wave amplitudes. Am J Psychiatry 1988; 145: 229232
  • 128
    Forno LS. Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol 1996; 55: 259272
  • 129
    Shults CW. Lewy bodies. Proc Natl Acad Sci U S A 2006; 103: 16611668
  • 130
    Mattock C, Marmot M, Stern G. Could Parkinson's disease follow intra-uterine influenza?: a speculative hypothesis. J Neurol Neurosurg Psychiatry 1988; 51: 753756
  • 131
    Lux WE, Kurtzke JF. Is Parkinson's disease acquired? Evidence from a geographic comparison with multiple sclerosis. Neurology 1987; 37: 467471
  • 132
    Wermuth L, von Weitzel-Mudersbach P, Jeune B. A two-fold difference in the age-adjusted prevalences of Parkinson's disease between the island of Als and the Faroe Islands. Eur J Neurol 2000; 7: 655660
  • 133
    Wermuth L, Pakkenberg H, Jeune B. High age-adjusted prevalence of Parkinson's disease among Inuits in Greenland. Neurology 2002; 58: 14221425
  • 134
    Wermuth L, Bech S, Petersen MS, Joensen P, Weihe P, Grandjean P. Prevalence and incidence of Parkinson's disease in The Faroe Islands. Acta Neurol Scand 2008; 118: 126131
  • 135
    Sato Y, Kikuyama M, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in Parkinson's disease. Neurology 1997; 49: 12731278
  • 136
    Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V. Prevalence of vitamin D insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 2008; 65: 13481352
  • 137
    Evatt ML, Delong MR, Kumari M, Auinger P, McDermott MP, Tangpricha V. High prevalence of hypovitaminosis D status in patients with early Parkinson disease. Arch Neurol 2011; 68: 314319
  • 138
    Kim JS, Kim YI, Song C, Yoon I, Park JW, Choi YB, Kim HT, Lee KS. Association of vitamin D receptor gene polymorphism and Parkinson's disease in Koreans. J Korean Med Sci 2005; 20: 495498
  • 139
    Butler MW, Burt A, Edwards TL, Zuchner S, Scott WK, Martin ER, Vance JM, Wang L. Vitamin D receptor gene as a candidate gene for Parkinson disease. Ann Hum Genet 2011; 75: 201210
  • 140
    Saad M, Lesage S, Saint-Pierre A, Corvol JC, Zelenika D, Lambert JC, Vidailhet M, Mellick GD, Lohmann E, Durif F, Pollak P, Damier P, Tison F, Silburn PA, Tzourio C, Forlani S, Loriot MA, Giroud M, Helmer C, Portet F, Amouyel P, Lathrop M, Elbaz A, Durr A, Martinez M, Brice A. Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population. Hum Mol Genet 2011; 20: 615627
  • 141
    Bai T, Seebald JL, Kim KE, Ding HM, Szeto DP, Chang HC. Disruption of zebrafish cyclin G-associated kinase (GAK) function impairs the expression of Notch-dependent genes during neurogenesis and causes defects in neuronal development. BMC Dev Biol 2010; 10: 7
  • 142
    Li X, Han D, Kin Ting Kam R, Guo X, Chen M, Yang Y, Zhao H, Chen Y. Developmental expression of sideroflexin family genes in Xenopus embryos. Dev Dyn 2010; 239: 27422747
  • 143
    Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE 2011; 6: e18568
  • 144
    Winner B, Melrose HL, Zhao C, Hinkle KM, Yue M, Kent C, Braithwaite AT, Ogholikhan S, Aigner R, Winkler J, Farrer MJ, Gage FH. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol Dis 2011; 41: 706716
  • 145
    Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet 2007; 369: 20312041
  • 146
    Geser F, Lee VM, Trojanowski JQ. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology 2010; 30: 103112
  • 147
    Ajdacic-Gross V, Wang J, Gutzwiller F. Season of birth in amyotrophic lateral sclerosis. Eur J Epidemiol 1998; 14: 359361
  • 148
    Fang F, Valdimarsdottir U, Bellocco R, Ronnevi LO, Sparen P, Fall K, Ye W. Amyotrophic lateral sclerosis in Sweden, 1991-2005. Arch Neurol 2009; 66: 515519
  • 149
    Betemps EJ, Buncher CR. Birthplace as a risk factor in motor neurone disease and Parkinson's disease. Int J Epidemiol 1993; 22: 898904
  • 150
    Sejvar JJ, Holman RC, Bresee JS, Kochanek KD, Schonberger LB. Amyotrophic lateral sclerosis mortality in the United States, 1979-2001. Neuroepidemiology 2005; 25: 144152
  • 151
    Uccelli R, Binazzi A, Altavista P, Belli S, Comba P, Mastrantonio M, Vanacore N. Geographic distribution of amyotrophic lateral sclerosis through motor neuron disease mortality data. Eur J Epidemiol 2007; 22: 781790
  • 152
    Chio A, Cucatto A, Calvo A, Terreni AA, Magnani C, Schiffer D. Amyotrophic lateral sclerosis among the migrant population to Piemonte, northwestern Italy. J Neurol 1999; 246: 175180
  • 153
    Scott KM, Abhinav K, Stanton BR, Johnston C, Turner MR, Ampong MA, Sakel M, Orrell RW, Howard R, Shaw CE, Leigh PN, Al-Chalabi A. Geographical clustering of amyotrophic lateral sclerosis in South-East England: a population study. Neuroepidemiology 2009; 32: 8188
  • 154
    Scott KM, Abhinav K, Wijesekera L, Ganesalingam J, Goldstein LH, Janssen A, Dougherty A, Willey E, Stanton BR, Turner MR, Ampong MA, Sakel M, Orrell R, Howard R, Shaw CE, Nigel Leigh P, Al-Chalabi A. The association between ALS and population density: a population based study. Amyotroph Lateral Scler 2010; 11: 435438
  • 155
    Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H. Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 2008; 64: 6070
  • 156
    Duvick L, Barnes J, Ebner B, Agrawal S, Andresen M, Lim J, Giesler GJ, Zoghbi HY, Orr HT. SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron 2010; 67: 929935
  • 157
    Bolger TA, Zhao X, Cohen TJ, Tsai CC, Yao TP. The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2. J Biol Chem 2007; 282: 2918629192
  • 158
    Mikoshiba K. Inositol 1,4,5-trisphosphate IP(3) receptors and their role in neuronal cell function. J Neurochem 2006; 97: 16271633
  • 159
    Varoqueaux F, Sons MS, Plomp JJ, Brose N. Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol Cell Biol 2005; 25: 59735984
  • 160
    van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, Lemmens R, Schelhaas HJ, Groen EJ, Huisman MH, van der Kooi AJ, de Visser M, Dahlberg C, Estrada K, Rivadeneira F, Hofman A, Zwarts MJ, van Doormaal PT, Rujescu D, Strengman E, Giegling I, Muglia P, Tomik B, Slowik A, Uitterlinden AG, Hendrich C, Waibel S, Meyer T, Ludolph AC, Glass JD, Purcell S, Cichon S, Nothen MM, Wichmann HE, Schreiber S, Vermeulen SH, Kiemeney LA, Wokke JH, Cronin S, McLaughlin RL, Hardiman O, Fumoto K, Pasterkamp RJ, Meininger V, Melki J, Leigh PN, Shaw CE, Landers JE, Al-Chalabi A, Brown RH Jr, Robberecht W, Andersen PM, Ophoff RA, van den Berg LH. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 2009; 41: 10831087
  • 161
    Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 2007; 10: 615622
  • 162
    Lenzken SC, Romeo V, Zolezzi F, Cordero F, Lamorte G, Bonanno D, Biancolini D, Cozzolino M, Pesaresi MG, Maracchioni A, Sanges R, Achsel T, Carri MT, Calogero RA, Barabino SM. Mutant SOD1 and mitochondrial damage alter expression and splicing of genes controlling neuritogenesis in models of neurodegeneration. Hum Mutat 2011; 32: 168182
  • 163
    Giovannoni G, Ebers G. Multiple sclerosis: the environment and causation. Curr Opin Neurol 2007; 20: 261268
  • 164
    Stadelmann C, Wegner C, Bruck W. Inflammation, demyelination, and degeneration – recent insights from MS pathology. Biochim Biophys Acta 2011; 1812: 275282
  • 165
    Moore GR, Laule C, Mackay A, Leung E, Li DK, Zhao G, Traboulsee AL, Paty DW. Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss. J Neurol 2008; 255: 18021811
  • 166
    DeLuca GC, Ebers GC, Esiri MM. Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts. Brain 2004; 127: 10091018
  • 167
    DeLuca GC, Williams K, Evangelou N, Ebers GC, Esiri MM. The contribution of demyelination to axonal loss in multiple sclerosis. Brain 2006; 129: 15071516
  • 168
    Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest 1991; 87: 11031107
  • 169
    Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci U S A 1996; 93: 78617864
  • 170
    Meehan TF, DeLuca HF. The vitamin D receptor is necessary for 1alpha,25-dihydroxyvitamin D(3) to suppress experimental autoimmune encephalomyelitis in mice. Arch Biochem Biophys 2002; 408: 200204
  • 171
    Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC. Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005; 330: 120
  • 172
    Harvey L, Burne TH, McGrath JJ, Eyles DW. Developmental vitamin D3 deficiency induces alterations in immune organ morphology and function in adult offspring. J Steroid Biochem Mol Biol 2010; 121: 239242
  • 173
    Vukusic S, Van Bockstael V, Gosselin S, Confavreux C. Regional variations in the prevalence of multiple sclerosis in French farmers. J Neurol Neurosurg Psychiatry 2007; 78: 707709
  • 174
    Pierrot-Deseilligny C, Souberbielle JC. Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis? Brain 2010; 133: 18691888
  • 175
    Handel AE, Giovannoni G, Ebers GC, Ramagopalan SV. Environmental factors and their timing in adult-onset multiple sclerosis. Nat Rev Neurol 2010; 6: 156166
  • 176
    Dean G, Elian M. Age at immigration to England of Asian and Caribbean immigrants and the risk of developing multiple sclerosis. J Neurol Neurosurg Psychiatry 1997; 63: 565568
  • 177
    Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain 2000; 123: 968974
  • 178
    Soilu-Hanninen M, Airas L, Mononen I, Heikkila A, Viljanen M, Hanninen A. 25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler 2005; 11: 266271
  • 179
    van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Taylor BV, Kilpatrick T, Butzkueven H, McMichael AJ. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol 2007; 254: 581590
  • 180
    Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296: 28322838
  • 181
    Munger KL, Zhang SM, O'Reilly E, Hernan MA, Olek MJ, Willett WC, Ascherio A. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62: 6065
  • 182
    Munger KL, Chitnis T, Frazier AL, Giovannucci E, Spiegelman D, Ascherio A. Dietary intake of vitamin D during adolescence and risk of multiple sclerosis. J Neurol 2011; 258: 479485
  • 183
    Embry AF, Snowdon LR, Vieth R. Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2000; 48: 271272
  • 184
    Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler 2008; 14: 12201224
  • 185
    Dyment DA, Ebers GC, Sadovnick AD. Genetics of multiple sclerosis. Lancet Neurol 2004; 3: 104110
  • 186
    Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D'Alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D'Hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppa V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Ruckert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sorensen PS, Sondergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvanen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214219
  • 187
    Australia and New Zealand Multiple Sclerosis Genetics Consortium. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 2009; 41: 824828
  • 188
    Sundqvist E, Baarnhielm M, Alfredsson L, Hillert J, Olsson T, Kockum I. Confirmation of association between multiple sclerosis and CYP27B1. Eur J Hum Genet 2010; 18: 13491352
  • 189
    Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol 2011; 70: 881886
  • 190
    Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA, Deluca GC, Herrera BM, Chao MJ, Sadovnick AD, Ebers GC, Knight JC. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. Plos Genet 2009; 5: e1000369
  • 191
    Disanto G, Sandve GK, Berlanga-Taylor AJ, Ragnedda G, Morahan JM, Watson CT, Giovannoni G, Ebers GC, Ramagopalan SV. Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet 2012; 21: 35753586
  • 192
    Belgard TG, Marques AC, Oliver PL, Abaan HO, Sirey TM, Hoerder-Suabedissen A, Garcia-Moreno F, Molnar Z, Margulies EH, Ponting CP. A transcriptomic atlas of mouse neocortical layers. Neuron 2011; 71: 605616
  • 193
    Faitar SL, Dabbeekeh JT, Ranalli TA, Cowell JK. EVI5 is a novel centrosomal protein that binds to alpha- and gamma-tubulin. Genomics 2005; 86: 594605
  • 194
    Li G, Adesnik H, Li J, Long J, Nicoll RA, Rubenstein JL, Pleasure SJ. Regional distribution of cortical interneurons and development of inhibitory tone are regulated by Cxcl12/Cxcr4 signaling. J Neurosci 2008; 28: 10851098
  • 195
    Lieberam I, Agalliu D, Nagasawa T, Ericson J, Jessell TM. A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 2005; 47: 667679
  • 196
    Dziembowska M, Tham TN, Lau P, Vitry S, Lazarini F, Dubois-Dalcq M. A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia 2005; 50: 258269
  • 197
    Wang Y, Li G, Stanco A, Long JE, Crawford D, Potter GB, Pleasure SJ, Behrens T, Rubenstein JL. CXCR4 and CXCR7 have distinct functions in regulating interneuron migration. Neuron 2011; 69: 6176
  • 198
    Giachino C, Lantelme E, Lanzetti L, Saccone S, Bella Valle G, Migone N. A novel SH3-containing human gene family preferentially expressed in the central nervous system. Genomics 1997; 41: 427434
  • 199
    Oldreive CE, Doherty GH. Effects of tumour necrosis factor-alpha on developing cerebellar granule and Purkinje neurons in vitro. J Mol Neurosci 2010; 42: 4452
  • 200
    Taoufik E, Petit E, Divoux D, Tseveleki V, Mengozzi M, Roberts ML, Valable S, Ghezzi P, Quackenbush J, Brines M, Cerami A, Probert L. TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. Proc Natl Acad Sci U S A 2008; 105: 61856190
  • 201
    Ward GR, Franklin SO, Gerald TM, Dempsey KT, Clodfelter DE Jr, Krissinger DJ, Patel KM, Vrana KE, Howlett AC. Glucocorticoids plus opioids up-regulate genes that influence neuronal function. Cell Mol Neurobiol 2007; 27: 651660
  • 202
    Hou H, Obregon D, Lou D, Ehrhart J, Fernandez F, Silver A, Tan J. Modulation of neuronal differentiation by CD40 isoforms. Biochem Biophys Res Commun 2008; 369: 641647
  • 203
    Omari KM, Dorovini-Zis K. CD40 expressed by human brain endothelial cells regulates CD4+ T cell adhesion to endothelium. J Neuroimmunol 2003; 134: 166178
  • 204
    Tan J, Town T, Mori T, Obregon D, Wu Y, DelleDonne A, Rojiani A, Crawford F, Flavell RA, Mullan M. CD40 is expressed and functional on neuronal cells. EMBO J 2002; 21: 643652
  • 205
    Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010; 362: 329344
  • 206
    Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonal birth patterns of neurological disorders. Neuroepidemiology 2000; 19: 177185
  • 207
    Lu'o'ng KV, Nguyen LT. The beneficial role of vitamin D in Alzheimer's disease. Am J Alzheimers Dis Other Demen 2011; 26: 511520
  • 208
    Pogge E. Vitamin D and Alzheimer's disease: is there a link? Consult Pharm 2010; 25: 440450
  • 209
    Annweiler C, Rolland Y, Schott AM, Blain H, Vellas B, Herrmann FR, Beauchet O. Higher vitamin D dietary intake is associated with lower risk of Alzheimer's disease: a 7-year follow-up. J Gerontol A Biol Sci Med Sci 2012; 67: 12051211
  • 210
    Llewellyn DJ, Lang IA, Langa KM, Muniz-Terrera G, Phillips CL, Cherubini A, Ferrucci L, Melzer D. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010; 170: 11351141
  • 211
    Oudshoorn C, Mattace-Raso FU, van der Velde N, Colin EM, van der Cammen TJ. Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's disease. Dement Geriatr Cogn Disord 2008; 25: 539543
  • 212
    Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron 2010; 68: 270281
  • 213
    Lehmann DJ, Refsum H, Warden DR, Medway C, Wilcock GK, Smith AD. The vitamin D receptor gene is associated with Alzheimer's disease. Neurosci Lett 2011; 504: 7982
  • 214
    Gezen-Ak D, Dursun E, Ertan T, Hanagasi H, Gurvit H, Emre M, Eker E, Ozturk M, Engin F, Yilmazer S. Association between vitamin D receptor gene polymorphism and Alzheimer's disease. Tohoku J Exp Med 2007; 212: 275282
  • 215
    Wang L, Hara K, Van Baaren JM, Price JC, Beecham GW, Gallins PJ, Whitehead PL, Wang G, Lu C, Slifer MA, Zuchner S, Martin ER, Mash D, Haines JL, Pericak-Vance MA, Gilbert JR. Vitamin D receptor and Alzheimer's disease: a genetic and functional study. Neurobiol Aging 2012; 33: 1844 e118449
  • 216
    Morgan K. The three new pathways leading to Alzheimer's disease. Neuropathol Appl Neurobiol 2011; 37: 353357
  • 217
    Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Ruther E, Schurmann B, Heun R, Kolsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Gallacher J, Hull M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alperovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Bjornsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossu P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 2011; 43: 429435
  • 218
    Mukhopadhyay M, Pelka P, DeSousa D, Kablar B, Schindler A, Rudnicki MA, Campos AR. Cloning, genomic organization and expression pattern of a novel Drosophila gene, the disco-interacting protein 2 (dip2), and its murine homolog. Gene 2002; 293: 5965
  • 219
    Lambert JC, Grenier-Boley B, Harold D, Zelenika D, Chouraki V, Kamatani Y, Sleegers K, Ikram MA, Hiltunen M, Reitz C, Mateo I, Feulner T, Bullido M, Galimberti D, Concari L, Alvarez V, Sims R, Gerrish A, Chapman J, Deniz-Naranjo C, Solfrizzi V, Sorbi S, Arosio B, Spalletta G, Siciliano G, Epelbaum J, Hannequin D, Dartigues JF, Tzourio C, Berr C, Schrijvers EM, Rogers R, Tosto G, Pasquier F, Bettens K, Van Cauwenberghe C, Fratiglioni L, Graff C, Delepine M, Ferri R, Reynolds CA, Lannfelt L, Ingelsson M, Prince JA, Chillotti C, Pilotto A, Seripa D, Boland A, Mancuso M, Bossu P, Annoni G, Nacmias B, Bosco P, Panza F, Sanchez-Garcia F, Zompo MD, Coto E, Owen M, O'Donovan M, Valdivieso F, Caffara P, Scarpini E, Combarros O, Buee L, Campion D, Soininen H, Breteler M, Riemenschneider M, Van Broeckhoven C, Alperovitch A, Lathrop M, Tregouet DA, Williams J, Amouyel P. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease. Mol Psychiatry 2012. doi: 10.1038/mp.2012.75 [Epub ahead of print]
  • 220
    Hernandez-Deviez DJ, Casanova JE, Wilson JM. Regulation of dendritic development by the ARF exchange factor ARNO. Nat Neurosci 2002; 5: 623624
  • 221
    Albertinazzi C, Za L, Paris S, de Curtis I. ADP-ribosylation factor 6 and a functional PIX/p95-APP1 complex are required for Rac1B-mediated neurite outgrowth. Mol Biol Cell 2003; 14: 12951307
  • 222
    Ferrari R, Moreno JH, Minhajuddin AT, O'Bryant SE, Reisch JS, Barber RC, Momeni P. Implication of common and disease specific variants in CLU, CR1, and PICALM. Neurobiol Aging 2012; 33: 1846 e718
  • 223
    Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O'Donovan M, Owen MJ, Williams J. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 2009; 41: 10881093
  • 224
    Xiao Q, Gil SC, Yan P, Wang Y, Han S, Gonzales E, Perez R, Cirrito JR, Lee JM. Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. J Biol Chem 2012; 287: 2127921289
  • 225
    Shulman JM, Chibnik LB, Aubin C, Schneider JA, Bennett DA, De Jager PL. Intermediate phenotypes identify divergent pathways to Alzheimer's disease. PLoS ONE 2010; 5: e11244