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Blood Vitamin D Levels Tied to Dozens of Genetic Variants in UK Biobank GWAS

NEW YORK – Blood serum levels of vitamin D appear to be influenced by genetic variants at dozens of sites in the genome, according to a new genome-wide association study by a team from Canada and the UK.

As they reported in the American Journal of Human Genetics on Thursday, the researchers analyzed array-based genotyping profiles for nearly 401,500 UK Biobank participants, searching for SNPs linked to their documented serum levels of 25-hydroxyvitamin D (25OHD). After folding in SNP profiles for nearly 42,3000 more European individuals from a prior GWAS focuses on 1,25-dihydroxyvitamin D levels, they focused in on vitamin D-associated SNPs at 69 loci.

"Taken together, these results identify new biological pathways that influence 25OHD levels and demonstrate that this metabolite is moderately polygenic," senior author J. Brent Richards, a human genetics and epidemiology researcher affiliated with McGill University, the Jewish General Hospital in Montreal, and King's College London, and his co-authors wrote.

The steroid pro-hormone 25OHD has been implicated in immune system activity and in a wide range of cellular processes, the team explained. But although 25OHD can be produced in response to ultraviolet light exposure or ingested in certain foods, past studies suggested that blood levels of the fat-soluble metabolite vary depending on an individual's age, skin pigmentation, weight, and heritable factors.

"An improved understanding of the genetic determinants of 25OHD has helped re-assess the role of vitamin D in the etiology of complex diseases, such as musculoskeletal disorders, autoimmune disease such as multiple sclerosis, and cancer, through methods for causal inference, such as Mendelian randomization," the authors explained, though genetic contributors found so far seem to explain only a fraction of the estimated heritability for serum 25OHD levels.

For their study, the investigators analyzed almost 20.4 million directly genotyped or imputed SNPs in 401,460 UK Biobank participants who had their serum 25OHD levels assayed, taking factors such as age, sex, season, and supplement use into account. Their subsequent meta-analysis, which included another 42,274 European individuals, highlighted variants at 63 new vitamin D-linked loci and half a dozen variants already known to be associated with vitamin D levels.

In a series of follow-up analyses, the team estimated that the variants identified so far explain roughly 16 percent of the heritability in serum 25OHD levels and noted that the vitamin D-associated variants often fell in pathways involved in processes such as lipid metabolism or skin keratinization.

Bringing in available expression data from GTEx and other efforts, meanwhile, they saw potential ties between the loci linked to 25OHD levels in the blood and genes with pronounced expression in tissues such as the skin, liver, or gastrointestinal tract.

"Further research is warranted to better characterize the identified genetic variants, validate these findings, and identify ancestry-specific variants in other ethnic groups, and to better understand the biological pathways influencing 25OHD levels," the authors wrote. "The genetic instruments for 25OHD identified here should be used with caution in future [Mendelian randomization] analyses assessing the association between vitamin D and other complex traits and diseases."