Two genome-wide association studies in European descent populations identifies SNPs associated with serum vitamin D level in three vitamin D metabolic pathway genes (GC, DHCR7, and CYP2R1)

Ahn, J., K. Yu, et al. (2010). “Genome-wide association study of circulating vitamin D levels.” Human Molecular Genetics 19(13): 2739-2745.

Wang, T. J., F. Zhang, et al. (2010). “Common genetic determinants of vitamin D insufficiency: a genome-wide association study.” The Lancet 376(9736): 180-188.

The vitamin D hypothesis of evolution of skin color suggests that lighter color skin among Europeans evolved as a response to lower UV exposure in northern latitude, because low vitamin D level can cause bone disorders as well as many other common disease (See here).  However, Jablonski and Chaplin did not explain evolutionary mechanisms very well and they did not mention variation of vitamin D metabolic and signaling pathway genes, which may contribute to evolution of pigmentation traits.  I think that one step to understand the mechanisms of evolution of pigmentation characteristics is identifying genetic variants associated with vitamin D level and vitamin D deficiency in European populations

There are two genome-wide association studies done among people of European descent (Ahn et al., 2010 and Wang et al., 2010), and these studies identified single nucleotide polymorphisms (SNPs) in vitamin D pathway genes associated with serum vitamin D, 25-hydroxy-vitamine D [25(OH)D].  25(OH)D is the primary form of vitamin D in the serum, which is converted to biologically active form, 1,25-dihydroxy-vitamine D [1,25(OH)2D in the kidney.  In both studies, associations with transformed (log or square-root) serum 25(OH)D level were tested using linear regression model adjusting for age, sex, BMI, and season.  In addition, Ahn et al adjusted for supplement intake, dietary vitamin D intake, region/latitude, vitamin D assay batch.

In both studies, they found SNPs in or near major vitamin D metabolic pathway genes, including vitamin D binding protein (GC), DHCR7, and CYP2R1.  Also, in both study, the SNP that showed the strongest association was rs2282679 located in the GC gene.

When the skin is exposed to the UVR, 7-dehydrocholesterol is converted to Pre-vitamin D3.  Also, in the skin,DHCR7 (7-dehydrocholesterol reductase) catalyzes the conversion of 7-dehydrocholesterol to cholesterol, so increased activity of DHCR7 potentially lower the 7-dehydrocholesterol available for vitamin D synthesis.  The vitamin D binding protein (GC) binds to vitamin D and its plasma metabolites and transports them to target tissues.  CYP2R1 is one of the enzymes that converts vitamin D to 25-hydroxy-vitamine D, 25(OH)D, in the liver.

It is far from understanding how vitamin D affected the course of evolution of skin color.  We do not know variation of these genes in the world and we do not know if these genes show evidence of selection.   These SNPs may not be the ones that change the function of genes or affect serum vitamin D level, but are linked to causal variants.  However, the findings are very important.  Now, we can examine variation of these genes in other populations and examine if these variants are associated with vitamin D level in other populations.  Fine mapping of these genes will help identify causal SNPs that affect function of genes and vitamin D level.


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