We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide association study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrichment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared heritability with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 3 10 À9 ) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architecture of 25OHD.

PurposeTime outdoors during childhood is negatively associated with incident myopia. Consequently, additional time outdoors has been suggested as a public health intervention to reduce the prevalence of myopia. We investigated whether there were specific ages during early childhood when the time outdoors versus incident myopia association was strongest.MethodsChildren participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied from age 2 to 15 years. Parentally reported time outdoors and time spent reading were assessed longitudinally in early childhood (ages 2, 3, 4, 5, 7, and 9 years). Noncycloplegic autorefraction was carried out longitudinally in later childhood (ages 10, 11, 12, and 15 years). Information was available for 2833 participants. Cox proportional hazards regression was used to test for association between time outdoors and incident myopia.ResultsFrom 3 years of age onward, greater time outdoors was associated with a reduced risk of incident myopia. The hazard ratio for myopia changed progressively from 0.90 (95% CI 0.83–0.98, P = 0.012) at age 3 years, to 0.86 (95% CI 0.78–0.93, P = 0.001) at age 9 years, for each additional SD of time spent outdoors per day. These associations were independent of two major risk factors for myopia: time reading and number of myopic parents.ConclusionsAdditional time spent outdoors across the 3 to 9 years age range was associated with a reduced incidence of myopia between ages 10 and 15 years. There was a trend for the association to increase toward the older end of the 3 to 9 years range.

EPIC Study data cannot be deposited publicly as these collaborative data originate from multiple research institutions across European countries with different legal frameworks. The authors confirm that researchers seeking the analysis dataset for this work can submit a data request to the EPIC-InterAct study