Empirical power at a type I error of 10 for Scenario 1 under partial heterogeneity (ξ = 0.8).

<p>See Fig. 1 and 2 for background and abbreviation.</p

Empirical power at a type I error of 10⁻³ for Scenario 1 under homogeneity (ξ = 1).

<p>The power estimated from 250 simulations. The covariate is assumed to be explaining a fraction (Rsq) equal to 0, 10 or 20% of the variability in binary trait. Power is presented for 10% (black), 50% (turquoise) and 90% (red) percentiles of CDS length. See Fig. 1 for background and abbreviation.</p

Simulation design parameters.

<p>Simulation design parameters.</p

Strategy for SNP selection using genome-wide association and candidate gene studies.

<p>Strategy for SNP selection using genome-wide association and candidate gene studies.</p

Genetic variation in the vitamin D synthesis and metabolic pathway.

<p>Skin exposure to ultraviolet B (UVB) radiation initiates the conversion of 7-dehydrocholesterol to previtamin D3. 7-dehydrocholesterol reductase (<b><i>DHCR7</i></b>) encodes the enzyme 7-dehydrocholesterol reductase, which converts 7-dehydrocholesterol to cholesterol, thereby removing the substrate from the synthetic pathway of vitamin D3. The previtamin D3 in turn gets converted to vitamin D3 in a heat-dependent process. Vitamin D (represents D2 or D3) is transported to the liver, where it is converted by vitamin D-25-hydroxylase (<b><i>CYP2R1</i></b>) to 25-hydroxyvitamin D [25(OH)D]. This is the major circulating form of vitamin D that is used by clinicians to determine vitamin D status. This form of vitamin D is biologically inactive; it is bound to the vitamin D-binding protein (<b><i>GC</i></b>), transported to the kidneys and converted by 25-hydroxyvitamin D-1α- hydroxylase (1-OHase) (<b><i>CYP27B1</i></b>) to the biologically active form 1,25-dihydroxyvitamin D3 (Calcitriol). Calcitriol increases the expression of 25-hydroxyvitamin D-24- hydroxylase (24-OHase) (<b><i>CYP24A1</i></b>) to catabolise 25(OH)D to the water-soluble, biologically inactive calcitroic acid, which is excreted in the bile. <i>DHCR7</i> and <i>CYP2R1</i> function upstream of the production of 25(OH)D and hence, termed as 25(OH)D synthesis indicators, while <i>GC</i>, <i>CYP27B1</i> and <i>CYP24A1</i> function downstream of the 25(OH)D production and hence, termed as 25(OH)D metabolism indicators.</p

Associations of the five SNPs and allele scores with geographical region, social, dietary and lifestyle factors.

<p>The bars are the 99.6% CI. The effects of the allele scores and the individual SNPs for each lifestyle factor can be identified based on the intensity of the coloured boxes.</p

Association between the SNPs, synthesis, metabolism and metabolism^GWA allele scores and ln 25(OH)D with and without adjustment for biomarkers, dietary and lifestyle indicators.

<p>The bars are the 95% CI. <i>Biomarkers</i>: coagulation markers- von Willebrand factor, tPA and D-dimer; Inflammatory markers- fibrinogen and CRP; Lipid marker- Triglycerides, low density lipoproteins, high density lipoproteins and total cholesterol; Lung function marker- FEV; Cardiovascular disease related factors- diastolic and systolic blood pressures, IgE, IGF1 and HbA1c). <i>Dietary and lifestyle markers</i>: time spent outside, sun cover, oily fish consumption, vitamin D supplements, season, smoking, alcohol consumption, PC/TV time, recreational MET hours, social class, body mass index, abdominal obesity and geographical region.</p

Power and sample size to detect the 5% decrease in blood pressure by 10 nmol/l increase in 25(OH)D observed in the 1958 British birth cohort using genetic proxy indicators (significance level α = 0.05).

<p>The curves in (<b>A</b>) from the bottom to the top of the graph are in the order of min effect size with <i>CYP27B1</i> (short dash), <i>CYP24A1</i> (long dash), <i>DHCR7</i> (dash dot), <i>CYP2R1</i> (dash), <i>GC</i> (dot). The curves in (<b>B</b>) from the bottom to the top of the graph are in the order of min effect size with Synthesis score (dash dot), Metabolism^GWA score (long dash) Metabolism score (dash), both scores (dot). The horizontal black line and attached vertical dashed lines indicate the sample size required for a study with 80% power using the genetic proxy.</p

Association of SNP with ln 25-hydroxyvitamin D adjusted for sex.

<p>MAF, minor allele frequency.</p>†<p>Relative bias has not been estimated where the SNP has an F-statistic less than 1.9.</p

The selection of vitamin D SNPs for the use as instruments in Mendelian Randomization (MR) analysis.

<p>The selection of vitamin D SNPs for the use as instruments in Mendelian Randomization (MR) analysis.</p