This grant will be submitted as DA Lawlor's main MRC programme grant for 2008 as part of the MRC Centre for Causal Analyses in Translational Research. It is concerned with determining the causal effect of vitamin D on perinatal outcomes (gestational diabetes, pre-eclampsia, variations in blood pressure during the antenatal period, intrauterine growth retardation, preterm delivery), vascular outcomes (variations in blood pressure, endothelial function, carotid intima media thickness), metabolic outcomes (variations in fasting glucose, insulin, pro-insulin, lipids) and skeletal health (variations inpeak bone mass and fracture risk in later lifeassessed by DXA scan andcortical bone geometry, and hence bone strength assessed bypQCT). Data from ALSPAC offspring and mothers other relevant studies that are linked to the MRC Centre for Causal Analyses in Translational Epidemiology (CAiTE) will contribute to the programme. Our specific objectives are:

1. To use bioinformatics and genome wide association studies to identify genetic variants that are associated with vitamin D levels.

2. To replicate the association of these variants with vitamin D levels in ALSPAC mothers and offspring.

3. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on perinatal outcomes (gestational diabetes, pre-eclampsia, variations in blood pressure during the antenatal period, intrauterine growth retardation, preterm delivery)using data from ALSPAC, Danish National Birth Cohort, the Norwegian Birth Cohort and the Born in Bradford Cohort.

4. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on vascular outcomes (variations in blood pressure, endothelial function, carotid intima media thickness)using data from ALSPAC (offspring and mothers), the Cardiovascular Risk in Young Finns study, the 1958 UK birth cohort and other CAiTE based adult cohort studies with these measurements.

5. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on metabolic outcomes (variations in fasting glucose, insulin, pro-insulin, lipids)using data from ALSPAC (offspring and mothers), the Cardiovascular Risk in Young Finns study, the 1958 UK birth cohort and other CAiTE based adult cohort studies with these measurements.

6. To use the genetic variants, identified in 1 and tested in 2 above, as instrumental variables to determine the causal effect of vitamin D on skeletal outcomes(variations inpeak bone mass and fracture risk in later lifeassessed by DXA scan andcortical bone geometry, and hence bone strength assessed bypQCT). Data from ALSPAC mothers and offspring will be used for this objective.