Genetic Architecture of Vitamin B and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets

English version České info

Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B₁₂ (B₁₂) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B₁₂ and folate measurements, respectively. We found six novel loci associating with serum B₁₂ (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B₁₂ and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B₁₂ or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.

Vyšlo v časopise: Genetic Architecture of Vitamin B and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets. PLoS Genet 9(6): e32767. doi:10.1371/journal.pgen.1003530
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003530

Souhrn

Zdroje

1. ScottJM (1999) Folate and vitamin B12. Proc Nutr Soc 58: 441–448.

2. MarkleHV, GreenwayDC (1996) Cobalamin. Crit Rev Clin Lab Sci 33: 247–356.

3. ClarkeR, DalyL, RobinsonK, NaughtenE, CahalaneS, et al. (1991) Hyperhomocysteinemia: An Independent Risk Factor for Vascular Disease. N Engl J Med 324: 1149–1155.

4. StampferMJ, MalinowMR, WillettWC, NewcomerLM, UpsonB, et al. (1992) A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 268: 877–881.

5. BirdCL, SwendseidME, WitteJS, ShikanyJM, HuntIF, et al. (1995) Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 4: 709–714.

6. GiovannucciE, StampferMJ, ColditzGA, RimmEB, TrichopoulosD, et al. (1993) Folate, Methionine, and Alcohol Intake and Risk of Colorectal Adenoma. J Natl Cancer Inst 85: 875–883.

7. ClarkeR (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55: 1449–1455.

8. NilssonSE, ReadS, BergS, JohanssonB (2009) Heritabilities for fifteen routine biochemical values: findings in 215 Swedish twin pairs 82 years of age or older. Scand J Clin Lab Invest 69: 562–569.

9. HazraA, KraftP, SelhubJ, GiovannucciEL, ThomasG, et al. (2008) Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet 40: 1160–1162.

10. HazraA, KraftP, LazarusR, ChenC, ChanockSJ, et al. (2009) Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum Mol Genet 18: 4677–4687.

11. TanakaT, ScheetP, GiustiB, BandinelliS, PirasMG, et al. (2009) Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet 84: 477–482.

12. LinX, LuD, GaoY, TaoS, YangX, et al. (2012) Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men. Hum Mol Genet 21: 2610–2617.

13. HustadS, MidttunO, SchneedeJ, VollsetSE, GrotmolT, et al. (2007) The methylenetetrahydrofolate reductase 677C→T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Am J Hum Genet 80: 846–855.

14. ThuesenBH, HusemoenLL, OvesenL, JorgensenT, FengerM, et al. (2010) Lifestyle and genetic determinants of folate and vitamin B12 levels in a general adult population. Br J Nutr 103: 1195–1204.

15. HindorffLA, SethupathyP, JunkinsHA, RamosEM, MehtaJP, et al. (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106: 9362–9367.

16. International HapMap Consortium (2007) FrazerKA, BallingerDG, CoxDR, HindsDA, et al. (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449: 851–861.

17. Genomes Project Consortium (2010) DurbinRM, AbecasisGR, AltshulerDL, AutonA, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.

18. TennessenJA, BighamAW, O'ConnorTD, FuW, KennyEE, et al. (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337: 64–69.

19. NelsonMR, WegmannD, EhmMG, KessnerD, StJP, et al. (2012) An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people. Science 337: 100–104.

20. KongA, MassonG, FriggeML, GylfasonA, ZusmanovichP, et al. (2008) Detection of sharing by descent, long-range phasing and haplotype imputation. Nat Genet 40: 1068–1075.

21. KongA, SteinthorsdottirV, MassonG, ThorleifssonG, SulemP, et al. (2009) Parental origin of sequence variants associated with complex diseases. Nature 462: 868–874.

22. HolmH, GudbjartssonDF, SulemP, MassonG, HelgadottirHT, et al. (2011) A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Genet 43: 316–320.

23. SulemP, GudbjartssonDF, WaltersGB, HelgadottirHT, HelgasonA, et al. (2011) Identification of low-frequency variants associated with gout and serum uric acid levels. Nat Genet 43: 1127–1130.

24. GudmundssonJ, SulemP, GudbjartssonDF, MassonG, AgnarssonBA, et al. (2012) A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nat Genet 44: 1326–1329.

25. RafnarT, GudbjartssonDF, SulemP, JonasdottirA, SigurdssonA, et al. (2011) Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet 43: 1104–1107.

26. JonssonT, AtwalJK, SteinbergS, SnaedalJ, JonssonPV, et al. (2012) A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 488: 96–99.

27. LiY, VinckenboschN, TianG, Huerta-SanchezE, JiangT, et al. (2010) Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet 42: 969–972.

28. AlbrechtsenA, GrarupN, LiY, SparsoT, TianG, et al. (2013) Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia 56: 298–310.

29. EmilssonV, ThorleifssonG, ZhangB, LeonardsonAS, ZinkF, et al. (2008) Genetics of gene expression and its effect on disease. Nature 452: 423–428.

30. BalasubramanianS, HabeggerL, FrankishA, MacArthurDG, HarteR, et al. (2011) Gene inactivation and its implications for annotation in the era of personal genomics. Genes Dev 25: 1–10.

31. PareG, ChasmanDI, ParkerAN, ZeeRR, MalarstigA, et al. (2009) Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study. Circ Cardiovasc Genet 2: 142–150.

32. LangeLA, Croteau-ChonkaDC, MarvelleAF, QinL, GaultonKJ, et al. (2010) Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults. Hum Mol Genet 19: 2050–2058.

33. ChambersJC, ZhangW, SehmiJ, LiX, WassMN, et al. (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 43: 1131–1138.

34. TeslovichTM, MusunuruK, SmithAV, EdmondsonAC, StylianouIM, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707–713.

35. FrankeA, McGovernDP, BarrettJC, WangK, Radford-SmithGL, et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42: 1118–1125.

36. McGovernDP, JonesMR, TaylorKD, MarcianteK, YanX, et al. (2010) Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. Hum Mol Genet 19: 3468–3476.

37. EllinghausD, EllinghausE, NairRP, StuartPE, EskoT, et al. (2012) Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci. Am J Hum Genet 90: 636–647.

38. IkramMK, SimX, JensenRA, CotchMF, HewittAW, et al. (2010) Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. PLoS Genet 6: e1001184.

39. SmythDJ, CooperJD, HowsonJMM, ClarkeP, DownesK, et al. (2011) FUT2 Nonsecretor Status Links Type 1 Diabetes Susceptibility and Resistance to Infection. Diabetes 60: 3081–3084.

40. CarlssonB, KindbergE, BuesaJ, RydellGE, LidónMF, et al. (2009) The G428A Nonsense Mutation in FUT2 Provides Strong but Not Absolute Protection against Symptomatic GII.4 Norovirus Infection. PLoS ONE 4: e5593.

41. HegnhojJ, HansenCP, RannemT, SobirkH, AndersenLB, et al. (1990) Pancreatic function in Crohn's disease. Gut 31: 1076–1079.

42. WarsiAA, DaviesB, Morris-StiffG, HullinD, LewisMH (2004) Abdominal Aortic Aneurysm and its Correlation to Plasma Homocysteine, and Vitamins. Eur J Vasc Endovasc Surg 27: 75–79.

43. CoelhoD, KimJC, MiousseIR, FungS, duMM, et al. (2012) Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet 44: 1152–1155.

44. KorotkovaN, LidstromME (2004) MeaB is a component of the methylmalonyl-CoA mutase complex required for protection of the enzyme from inactivation. J Biol Chem 279: 13652–13658.

45. JørgensenT, Borch-JohnsenK, ThomsenTF, IbsenH, GlumerC, et al. (2003) A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: Baseline results Inter99 (1). Eur J Cardiovasc Prev Rehab 10: 377–386.

46. BoesgaardTW, GrarupN, JørgensenT, Borch-JohnsenK (2010) Meta-Analysis of Glucose and Insulin-Related Trait Consortium (MAGIC), (2010) et al. Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people. Diabetologia 53: 1647–1655.

47. GlümerC, JørgensenT, Borch-JohnsenK (2003) Prevalences of diabetes and impaired glucose regulation in a Danish population: the Inter99 study. Diabetes Care 26: 2335–2340.

48. ThyssenJP, LinnebergA, MenneT, NielsenNH, JohansenJD (2009) The prevalence and morbidity of sensitization to fragrance mix I in the general population. Br J Dermatol 161: 95–101.

49. KimSY, LohmuellerKE, AlbrechtsenA, LiY, KorneliussenT, et al. (2011) Estimation of allele frequency and association mapping using next-generation sequencing data. BMC Bioinformatics 12: 231.

50. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191.