Background: The role of vitamin D in calcium metabolism and bone health is well documented. Vitamin D enables normal bone mineralization and prevents hypocalcemic tetany. It is also necessary for bone growth and bone remodeling by osteoblasts and osteoclasts. Vitamin D deficiency is common and typically arises from inadequate intake, inadequate sunlight exposure, and limited absorption or conversion into active metabolites (often due to liver or kidney disorders). Recent studies suggest that vitamin D influences various health conditions (such as diabetes, heart disease and hypertension) and mortality. Accumulating evidence also suggests previously unsuspected roles for vitamin D in brain development and neuroprotection. Recent population-based studies link vitamin D deficiency in old age with cognitive function cross-sectionally (Buell, et al., 2009; Lee, et al., 2009; Llewellyn, et al., 2009) and prospectively (Llewellyn, et al., in review). Further research is needed to establish whether vitamin D deficiency influences cognitive development in children.

The mechanisms underlying these associations are unclear, and residual confounding is possible, particularly in cross-sectional studies. Vitamin D receptors are present in a wide variety of cells, including neurons and glial cells, and genes encoding the enzymes involved in the metabolism of vitamin D are also expressed in the brain (McCann & Ames, 2008). In a recent review, Buell and Dawson-Hughes (2008) emphasize that Vitamin D may be neuroprotective through antioxidative mechanisms, immunomodulation, neuronal calcium regulation, detoxification mechanisms and enhanced nerve conduction. Vitamin D may play a role in brain detoxification pathways by reducing cellular calcium, inhibiting the synthesis of inducible nitric oxide synthase and increasing levels of the antioxidant glutathione (Garcion, 2002). Vitamin D stimulates neurogenesis and regulates the synthesis of neurotrophic factors which are important for cell differentiation and survival (Brown, et al., 2003). Vitamin D is also an immunosuppressor and may inhibit autoimmune damage to the nervous system (Garcion, 2002). Calcitriol stimulates amyloid-beta phagocytosis and clearance while protecting against apoptosis (Masoumi, et al., 2009). Low levels of vitamin D may also be associated with an increased risk of neurological diseases such as multiple sclerosis (Munger, et al., 2006), and Parkinson's (Newmark & Newmark, 2007).

The majority of brain development occurs in utero and during childhood. Optimal cognitive development in early-life may confer resistance to late-life cognitive decline and dementia in late life through 'cognitive reserve' and higher levels of midlife functioning. To our knowledge no prospective study has examined the association between in utero or early childhood vitamin D levels and childhood cognition or educational attainment. We also intend to examine whether genetic variants associated with vitamin D levels are also associated with cognitive function in childhood using an instrumental variables approach.

We would envisage the following series of papers to result from this work:

1) Association of childhood vitamin D with childhood intelligence.

2) Association of childhood vitamin D with educational attainment (key stage and GCSE) and the possible mediation by intelligence.

3) Association of maternal vitamin D during pregnancy with childhood intelligence and educational attainment (taking into account childhood vitamin D levels).

4) Possible neuroimaging studies (in collaboration with Tomas Paus and others) to further explore the above.

This work fits very well with Debbie Lawlor's MRC funded vitamin D grant which had as a main focus vascular and metabolic outcomes but noted that we would also examine relevant associations with a wide range of other health outcomes for which causal claims for vitamin D have been made. In this respect bone and respiratory/atopy phenotypes were specifically mentioned (in the grant and original proposal to exec.) but IQ and educational outcomes were not and therefore we are submitting this request here.

Methods

Existing data and planned (funded) vitamin D assays will be used. Analyses will be completed by Anna Tolpeinan with supervison by Debbie Lawlor and input (including development of analysis plan) from other applicants. Our preliminary analysis plan is to use multivariable regression models with adjustment for potential confounders. Potential mediators will be added as additional terms to fully adjusted models. Debbie Lawlor has access to all necessary data except educational attainment. We are aware that these data have been funded by the ESRC large grant and would be very keen to collaborate with the key person involved in the funding and collection of those data.