A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers

English version České info

While many large genetic association studies have identified genes playing a role in complex disorders, there is still concern over the amount of missing genetic heritability. With this in mind, we have used a data reduction approach alongside pedigree-based association to obtain highly heritable components which explain 'hidden' variance of multiphenotypes within a large pedigree from the Norfolk Island genetic isolate. The most heritable of these components involved 7 traits reflecting metabolic and renal functionality, association of which locates to an intergenic region on chromosome 1p22.2. By integrating gene expression information, we identified enrichment of a purine metabolism pathway, further strengthening the metabolic nature of the observed association. Adding additional support to our approach, we show association of the tagging SNP (rs1396315) in an independent US population. The findings presented here are of particular interest as they implicate pleiotropic effect loci and newly associated biological pathways underlying cardiovascular disease risk.

Vyšlo v časopise: A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers. PLoS Genet 11(10): e32767. doi:10.1371/journal.pgen.1005593
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005593

Souhrn

Zdroje

1. Laslett LJ, Alagona P, Clark BA, Drozda JP, Saldivar F, Wilson SR, et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol. 2012;60: S1–49. doi: 10.1016/j.jacc.2012.11.002 23257320

2. Avery CL, He Q, North KE, Ambite JL, Boerwinkle E, Fornage M, et al. A Phenomics-Based Strategy Identifies Loci on APOC1, BRAP, and PLCG1 Associated with Metabolic Syndrome Phenotype Domains. PLoS Genet. Public Library of Science; 2011;7: e1002322.

3. Kraja AT, Chasman DI, North KE, Reiner AP, Yanek LR, Kilpeläinen TO, et al. Pleiotropic genes for metabolic syndrome and inflammation. Mol Genet Metab. 2014;112 : 317–338. doi: 10.1016/j.ymgme.2014.04.007 24981077

4. Lowe JK, Maller JB, Pe’er I, Neale BM, Salit J, Kenny EE, et al. Genome-Wide Association Studies in an Isolated Founder Population from the Pacific Island of Kosrae. PLoS Genet. Public Library of Science; 2009;5: e1000365.

5. Sanna S, Li B, Mulas A, Sidore C, Kang HM, Jackson AU, et al. Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. Gibson G, editor. PLoS Genet. Public Library of Science; 2011;7: e1002198.

6. Traglia M, Sala C, Masciullo C, Cverhova V, Lori F, Pistis G, et al. Heritability and demographic analyses in the large isolated population of Val Borbera suggest advantages in mapping complex traits genes. PLoS One. 2009;4: e7554. doi: 10.1371/journal.pone.0007554 19847309

7. Shifman S, Darvasi A. The value of isolated populations. Nat Genet. 2001;28 : 309–310. <Go to ISI>://000170174800006 11479587

8. Heutink P, Oostra BA. Gene finding in genetically isolated populations. Hum Mol Genet. 2002;11 : 2507–2515. Available: <Go to ISI>://000178515900019 12351587

9. Bellis C, Hughes RM, Begley KN, Quinlan S, Lea RA, Heath SC, et al. Phenotypical characterisation of the isolated Norfolk Island population focusing on epidemiological indicators of cardiovascular disease. Hum Hered. 2006;60 : 211–219.

10. Hoare M. Norfolk Island: A Revised and Enlarged History 1774–1998. Rockhampton: Central Queensland University Press; 1999.

11. Edgecombe J. Norfolk Island—South Pacific: Island of History and Many Delights. Thornleigh: Australia: J.M. Edgecombe; 1999.

12. Macgregor S, Bellis C, Lea RA, Cox H, Dyer T, Blangero J, et al. Legacy of mutiny on the Bounty: founder effect and admixture on Norfolk Island. Eur J Hum Genet. 2010;18 : 67–72. doi: 10.1038/ejhg.2009.111 19584896

13. McEvoy BP, Zhao ZZ, Macgregor S, Bellis C, Lea RA, Cox H, et al. European and Polynesian admixture in the Norfolk Island population. Heredity (Edinb). 2010; 229–234.

14. Cox HC, Bellis C, Lea RA, Quinlan S, Hughes R, Dyer T, et al. Principal Component and Linkage Analysis of Cardiovascular Risk Traits in the Norfolk Isolate. Hum Hered. 2009;68 : 55–64. doi: 10.1159/000210449 19339786

15. Lotufo PA. Framingham score for cardiovascular diseases. Medicina (B Aires). 2008;87 : 232–237.

16. Lin J-P, Cupples LA, Wilson PWF, Heard-Costa N, O’Donnell CJ. Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a genomewide scan in the Framingham study. Am J Hum Genet. 2003;72 : 1029–34. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1180333&tool=pmcentrez&rendertype=abstract 12618960

17. Cox AJ, Ng MC-Y, Xu J, Langefeld CD, Koch KL, Dawson PA, et al. Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study. Atherosclerosis. 2013;229 : 155–60. doi: 10.1016/j.atherosclerosis.2013.04.008 23642732

18. Johnson AD, Kavousi M, Smith A V, Chen M-H, Dehghan A, Aspelund T, et al. Genome-wide association meta-analysis for total serum bilirubin levels. Hum Mol Genet. 2009;18 : 2700–10. doi: 10.1093/hmg/ddp202 19414484

19. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. Nature Publishing Group; 2007;449 : 851–61.

20. Cuellar-Partida G, Renteria ME, MacGregor S. LocusTrack: Integrated visualization of GWAS results and genomic annotation. Source Code Biol Med. 2015;10 : 1. doi: 10.1186/s13029-015-0032-8 25750659

21. Patel CJ, Sivadas A, Tabassum R, Preeprem T, Zhao J, Arafat D, et al. Whole genome sequencing in support of wellness and health maintenance. Genome Med. 2013;5 : 58. 23806097

22. Benton MC, Lea RA, Macartney-Coxson D, Carless MA, Göring HH, Bellis C, et al. Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits. Am J Hum Genet. Elsevier; 2013;93 : 1087–99.

23. D’Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117 : 743–53. doi: 10.1161/CIRCULATIONAHA.107.699579 18212285

24. Zabaneh D, Balding DJ. A Genome-Wide Association Study of the Metabolic Syndrome in Indian Asian Men. PLoS One. Public Library of Science; 2010;5: e11961.

25. Beck SR, Brown WM, Williams AH, Pierce J, Rich SS, Langefeld CD. Age-stratified QTL genome scan analyses for anthropometric measures. BMC Genet. 2003;4 Suppl 1: S31. 14975099

26. Hasstedt SJ, Hanis CL, Elbein SC. Univariate and bivariate linkage analysis identifies pleiotropic loci underlying lipid levels and type 2 diabetes risk. Ann Hum Genet. 2010;74 : 308–15. doi: 10.1111/j.1469-1809.2010.00589.x 20597901

27. Comuzzie AG, Cole SA, Laston SL, Voruganti VS, Haack K, Gibbs RA, et al. Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PLoS One. 2012;7: e51954. doi: 10.1371/journal.pone.0051954 23251661

28. Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 2011;43 : 1131–8. doi: 10.1038/ng.970 22001757

29. O’Donnell CJ, Cupples LA, D’Agostino RB, Fox CS, Hoffmann U, Hwang S-J, et al. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study. BMC Med Genet. 2007;8 Suppl 1: S4. 17903303

30. Wei S, Zhang L, Zhou X, Du M, Jiang Z, Hausman GJ, et al. Emerging roles of zinc finger proteins in regulating adipogenesis. Cell Mol Life Sci. 2013;

31. Kaestner KH. The hepatocyte nuclear factor 3 (HNF3 or FOXA) family in metabolism. Trends Endocrinol Metab. 2000;11 : 281–5. http://www.ncbi.nlm.nih.gov/pubmed/10920385 10920385

32. Welin M, Grossmann JG, Flodin S, Nyman T, Stenmark P, Trésaugues L, et al. Structural studies of tri-functional human GART. Nucleic Acids Res. 2010;38 : 7308–19. doi: 10.1093/nar/gkq595 20631005

33. Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol Genet Metab. 2005;86 : 25–33. 16176880

34. Li N, Florio SK, Pettenati MJ, Rao PN, Beavo JA, Baehr W. Characterization of human and mouse rod cGMP phosphodiesterase delta subunit (PDE6D) and chromosomal localization of the human gene. Genomics. 1998;49 : 76–82. 9570951

35. Tsang SH, Tsui I, Chou CL, Zernant J, Haamer E, Iranmanesh R, et al. A novel mutation and phenotypes in phosphodiesterase 6 deficiency. Am J Ophthalmol. 2008;146 : 780–8. doi: 10.1016/j.ajo.2008.06.017 18723146

36. Sherwin JC, Kearns LS, Hewitt AW, Ma Y, Kelly J, Griffiths LR, et al. Prevalence of Chronic Ocular Diseases in a Genetic Isolate: The Norfolk Island Eye Study (NIES). Ophthalmic Epidemiol. 2011;18 : 61–71. 21401413

37. Ng A, Uribe RA, Yieh L, Nuckels R, Gross JM. Zebrafish mutations in gart and paics identify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development. Development. 2009;136 : 2601–11. doi: 10.1242/dev.038315 19570845

38. Bellis C, Cox HC, Dyer TD, Charlesworth JC, Begley KN, Quinlan S, et al. Linkage mapping of CVD risk traits in the isolated Norfolk Island population. Hum Genet. 2008;124 : 543–552. doi: 10.1007/s00439-008-0580-y 18975005

39. Bellis C, Cox HC, Ovcaric M, Begley KN, Lea RA, Quinlan S, et al. Linkage disequilibrium analysis in the genetically isolated Norfolk Island population. Heredity (Edinb). 2008;100 : 366–373.

40. Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998;62 : 1198–1211. <Go to ISI>://000073487000025 9545414

41. Scharpf RB, Irizarry RA, Ritchie ME, Carvalho B, Ruczinski I. Using the R Package crlmm for Genotyping and Copy Number Estimation. J Stat Softw. 2011;40 : 1–32. <Go to ISI>://WOS:000290086900001 22523482

42. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses. Am J Hum Genet. University of Chicago Press; 2007;81 : 559–575. http://linkinghub.elsevier.com/retrieve/pii/S0002929707613524

43. Aulchenko YS, Ripke S, Isaacs A, Van Duijn CM. GenABEL: an R library for genorne-wide association analysis. Bioinformatics. 2007;23 : 1294–1296. 17384015

44. Manichaikul A, Mychaleckyj JC, Rich SS, Daly K, Sale M, Chen WM. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010;26 : 2867–2873. doi: 10.1093/bioinformatics/btq559 20926424

45. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21 : 263–265. 15297300