Endocrinol Metab.  2021 Dec;36(6):1189-1200. 10.3803/EnM.2021.1241.

Unveiling Genetic Variants Underlying Vitamin D Deficiency in Multiple Korean Cohorts by a Genome-Wide Association Study

Affiliations
  • 1Division of Endocrinology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Korea
  • 2Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea
  • 3Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Korea
  • 4Department of Public Health Science, Seoul National University, Seoul, Korea
  • 5Institute of Health and Environment, Seoul National University, Seoul, Korea
  • 6RexSoft, Inc, Seoul, Korea
  • 7Department of Internal Medicine, Seoul National University, Seoul, Korea

Abstract

Background
Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS).
Methods
We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed.
Results
rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles.
Conclusion
The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations.

Keyword

Vitamin D deficiency; Genome-wide association study; Asians; Genetic predisposition to disease; Polymorphism, single nucleotide

Figure

  • Fig. 1 Schematic plot of the study design: mega- and meta-analysis of genome-wide association study data. IBS, identity-by-state; PC, principal component; IQR, interquartile range.

  • Fig. 2 Genome-wide association of circulating 25-hydroxylvitamin D concentrations by chromosome positions and log10 P value (Manhattan plot) and quantile-quantile plots (QQ-plot) for meta-analysis. (A) Manhattan plot for meta-analysis. (B) QQ-plot: They-axis shows the observed −log10 P values, and the x-axis shows the expected −log10 P values for meta-analysis. GC, group-specific component; PDE3B, phosphodiesterase 3B; ACTE1P, actin epsilon 1, pseudogene; NADSYN1, glutamine-dependent NAD(+) synthetase.

  • Fig. 3 Network analysis and postulated mechanisms for the effect of actin epsilon 1, pseudogene (ACTE1P) rs12803256 single nucleotide polymorphism (SNP) on serum 25-hydroxyvitamin D concentrations. (A) Interaction network for proteins related to vitamin D deficiency, which was adapted from the genome-wide association study (GWAS) catalog data and our data. ACTE1P gene is a long non-coding RNA, and rs12803256 was related with the expression of glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7) on Genotype-Tissue Expression database (GTEx) data. Phosphodiesterase 3B (PDE3B) was shown to be associated with cytochrome P450 2R1 (CYP2R1) and SEC23 homolog A (SEC23A), and the results were replicated in our study. (B) A mechanism for the effect of the rs12803256 SNP of DHCR7/NADSYN1 on vitamin D deficiency is postulated. Moreover, the PDE3B gene was related to the CYP2R1 gene. COPB1, coat complex subunit beta 1; RRAS2, RAS-related protein; GC, group-specific component.


Reference

1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007; 357:266–81.
Article
2. Scaranti M, Junior Gde C, Hoff AO. Vitamin D and cancer: does it really matter? Curr Opin Oncol. 2016; 28:205–9.
3. Altieri B, Muscogiuri G, Barrea L, Mathieu C, Vallone CV, Mascitelli L, et al. Does vitamin D play a role in autoimmune endocrine disorders?: a proof of concept. Rev Endocr Metab Disord. 2017; 18:335–46.
Article
4. Skaaby T, Thuesen BH, Linneberg A. Vitamin D, cardiovascular disease and risk factors. Adv Exp Med Biol. 2017; 996:221–30.
Article
5. Lee CJ, Iyer G, Liu Y, Kalyani RR, Bamba N, Ligon CB, et al. The effect of vitamin D supplementation on glucose metabolism in type 2 diabetes mellitus: a systematic review and meta-analysis of intervention studies. J Diabetes Complications. 2017; 31:1115–26.
Article
6. Gois PH, Ferreira D, Olenski S, Seguro AC. Vitamin D and infectious diseases: simple bystander or contributing factor? Nutrients. 2017; 9:651.
Article
7. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006; 84:18–28.
Article
8. Makariou S, Liberopoulos EN, Elisaf M, Challa A. Novel roles of vitamin D in disease: what is new in 2011? Eur J Intern Med. 2011; 22:355–62.
Article
9. Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D status: United States, 2001–2006. NCHS Data Brief. 2011; 59:1–8.
10. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011; 31:48–54.
Article
11. van Schoor N, Lips P. Global overview of vitamin D status. Endocrinol Metab Clin North Am. 2017; 46:845–70.
Article
12. Choi HS, Oh HJ, Choi H, Choi WH, Kim JG, Kim KM, et al. Vitamin D insufficiency in Korea: a greater threat to younger generation: the Korea National Health and Nutrition Examination Survey (KNHANES) 2008. J Clin Endocrinol Metab. 2011; 96:643–51.
13. Hunter D, De Lange M, Snieder H, MacGregor AJ, Swaminathan R, Thakker RV, et al. Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation. J Bone Miner Res. 2001; 16:371–8.
Article
14. Karohl C, Su S, Kumari M, Tangpricha V, Veledar E, Vaccarino V, et al. Heritability and seasonal variability of vitamin D concentrations in male twins. Am J Clin Nutr. 2010; 92:1393–8.
Article
15. Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet. 2010; 19:2739–45.
Article
16. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010; 376:180–8.
17. Malik S, Fu L, Juras DJ, Karmali M, Wong BY, Gozdzik A, et al. Common variants of the vitamin D binding protein gene and adverse health outcomes. Crit Rev Clin Lab Sci. 2013; 50:1–22.
Article
18. Anderson D, Holt BJ, Pennell CE, Holt PG, Hart PH, Blackwell JM. Genome-wide association study of vitamin D levels in children: replication in the Western Australian Pregnancy Cohort (Raine) study. Genes Immun. 2014; 15:578–83.
Article
19. Moy KA, Mondul AM, Zhang H, Weinstein SJ, Wheeler W, Chung CC, et al. Genome-wide association study of circulating vitamin D-binding protein. Am J Clin Nutr. 2014; 99:1424–31.
Article
20. Sapkota BR, Hopkins R, Bjonnes A, Ralhan S, Wander GS, Mehra NK, et al. Genome-wide association study of 25(OH) vitamin D concentrations in Punjabi Sikhs: results of the Asian Indian diabetic heart study. J Steroid Biochem Mol Biol. 2016; 158:149–56.
Article
21. Wang J, Thingholm LB, Skieceviciene J, Rausch P, Kummen M, Hov JR, et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet. 2016; 48:1396–406.
Article
22. Hong J, Hatchell KE, Bradfield JP, Bjonnes A, Chesi A, Lai CQ, et al. Transethnic evaluation identifies low-frequency loci associated with 25-hydroxyvitamin D concentrations. J Clin Endocrinol Metab. 2018; 103:1380–92.
Article
23. Lu L, Bennett DA, Millwood IY, Parish S, McCarthy MI, Mahajan A, et al. Association of vitamin D with risk of type 2 diabetes: a Mendelian randomisation study in European and Chinese adults. PLoS Med. 2018; 15:e1002566.
Article
24. Lee C, Choe EK, Choi JM, Hwang Y, Lee Y, Park B, et al. Health and Prevention Enhancement (H-PEACE): a retrospective, population-based cohort study conducted at the Seoul National University Hospital Gangnam Center, Korea. BMJ Open. 2018; 8:e019327.
Article
25. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011; 96:53–8.
Article
26. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96:1911–30.
Article
27. Moon S, Kim YJ, Han S, Hwang MY, Shin DM, Park MY, et al. The Korea Biobank Array: design and identification of coding variants associated with blood biochemical traits. Sci Rep. 2019; 9:1382.
Article
28. Seo S, Park K, Lee JJ, Choi KY, Lee KH, Won S. SNP genotype calling and quality control for multi-batch-based studies. Genes Genomics. 2019; 41:927–39.
Article
29. Song YE, Lee S, Park K, Elston RC, Yang HJ, Won S. ONETOOL for the analysis of family-based big data. Bioinformatics. 2018; 34:2851–3.
Article
30. Kowalski MH, Qian H, Hou Z, Rosen JD, Tapia AL, Shan Y, et al. Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations. PLoS Genet. 2019; 15:e1008500.
Article
31. Loh PR, Danecek P, Palamara PF, Fuchsberger C, Reshef YA, Finucane HK, et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat Genet. 2016; 48:1443–8.
Article
32. Revez JA, Lin T, Qiao Z, Xue A, Holtz Y, Zhu Z, et al. Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun. 2020; 11:1647.
Article
33. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26:2190–1.
Article
34. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38:e164.
Article
35. Lee SH, Wray NR, Goddard ME, Visscher PM. Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet. 2011; 88:294–305.
Article
36. Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011; 88:76–82.
Article
37. Choi S, Lee S, Cichon S, Nothen MM, Lange C, Park T, et al. FARVAT: a family-based rare variant association test. Bioinformatics. 2014; 30:3197–205.
Article
38. Jiang X, O’Reilly PF, Aschard H, Hsu YH, Richards JB, Dupuis J, et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun. 2018; 9:260.
39. Manousaki D, Mitchell R, Dudding T, Haworth S, Harroud A, Forgetta V, et al. Genome-wide association study for vitamin D levels reveals 69 independent loci. Am J Hum Genet. 2020; 106:327–37.
Article
40. Bouillon R. Genetic and racial differences in the vitamin D endocrine system. Endocrinol Metab Clin North Am. 2017; 46:1119–35.
Article
41. Jiang X, Kiel DP, Kraft P. The genetics of vitamin D. Bone. 2019; 126:59–77.
Article
42. Yao P, Sun L, Lu L, Ding H, Chen X, Tang L, et al. Effects of genetic and nongenetic factors on total and bioavailable 25(OH)D responses to vitamin D supplementation. J Clin Endocrinol Metab. 2017; 102:100–10.
Article
43. Delanghe JR, Speeckaert R, Speeckaert MM. Behind the scenes of vitamin D binding protein: more than vitamin D binding. Best Pract Res Clin Endocrinol Metab. 2015; 29:773–86.
Article
44. Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, Medina-Gomez C, et al. Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis. Am J Hum Genet. 2017; 101:227–38.
Article
45. Thakkinstian A, Anothaisintawee T, Chailurkit L, Ratanachaiwong W, Yamwong S, Sritara P, et al. Potential causal associations between vitamin D and uric acid: bidirectional mediation analysis. Sci Rep. 2015; 5:14528.
Article
46. Howles SA, Wiberg A, Goldsworthy M, Bayliss AL, Gluck AK, Ng M, et al. Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nat Commun. 2019; 10:5175.
Article
47. Zheng JS, Luan J, Sofianopoulou E, Sharp SJ, Day FR, Imamura F, et al. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: a meta-analysis and Mendelian randomisation analysis. PLoS Med. 2020; 17:e1003394.
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