Genetic epidemiological studies in European and Asian populations support findings from genome wide association studies showing vitamin D related gene variants associated with serum vitamin D levels.

Previously, I reviewed if the variants identified in the genome-wide association studies (GWAS) of serum vitamin D levels in people of European descent are replicated in African Americans (here).  In this post, I will review replication and candidate gene studies conducted in other populations.

Two GWAS among people of European descent have found vitamin D metabolic pathway gene variants associated with serum 25(OH)D levels (Ahn et al. 2010; Wang et al. 2010; see here).  In the GWAS, the strongest signal of association was observed in vitamin D binding protein (GC), and Single Nucleotide Polymorphism (SNP) rs2282679 had lowest P value.  Smaller scale replication and candidate gene studies in European, Asian, and Hispanic populations also demonstrated the association of GC variants with serum 25(OH)D levels.  Although rs2282679 consistently show strong association in many studies, in these smaller studies, other SNPs in the GC show stronger association than rs2282679 (Bu et al. 2010; Lu et al. 2011; Zhang et al. 2012).

The region around DHCR7 and NADSYN1 showed the second strongest association the GWAS.  Again these GWAS identified SNPs are replicated well, but other SNPs also show strong signal of association (Zhang et al. 2012).  CYP2R1 variants also showed strong signal of association in GWAS.  Of all CYP2R1 SNPs, rs170741657 had lowest P value in one of the GWAS (Wang et al. 2010) and association of this SNP with serum vitamin D level is replicated in European and Chinese population with the lowest P value in the gene (Cooper et al. 2011; Zhang et al. 2012).  In one study in European Americans, another SNP, rs12794714, had lower P value than rs170741657 (Bu et al. 2010).  Another GWAS showed that two other SNPs, rs2060793 and rs1993116, were associated with plasma vitamin D levels (Ahn et al. 2010), but an attempt to replicate in Chinese population was not successful (Lu et al. 2011).

The results of replication and candidate gene studies suggest that 1) these GWAS identified SNPs are highly linked and high LD patterns in European and Asian population make it difficult to pinpoint the causal SNPs.  the causal variants that affect serum vitamin D levels have not been found.  2) In addition to genetic variants, biological (age, BMI, skin color, etc.), socio-cultural (smoking, dietary intake, supplement use, occupation, outdoor activities, sunscreen use, etc.) and environmental (latitude, climate, etc.) factors affect serum vitamin D.  We need to properly adjust these factors in the analysis and examine the interaction of these factors with genetic variants.3) Additional studies are necessary to examine which mutations alter the function of these genes and affect serum vitamin D level.


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

Bu, F.-X., L. Armas, et al. (2010). “Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects.” Human Genetics 128(5): 549-556.

Cooper, J. D., D. J. Smyth, et al. (2011). “Inherited Variation in Vitamin D Genes Is Associated With Predisposition to Autoimmune Disease Type 1 Diabetes.” Diabetes 60(5): 1624-1631.

Lu, L., H. Sheng, et al. (2012). “Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans.” Human Genetics 131(3): 505-512.

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.

Zhang, Y., X. Wang, et al. (2012). “The GC, CYP2R1 and DHCR7 genes are associated with vitamin D levels in northern Han Chinese children” Swiss Med Wkly 142: w13636.

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