A Genome-Wide Meta-Analysis of Six Type 1 Diabetes Cohorts Identifies Multiple Associated Loci
Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10−11) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10−9) resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10−9) lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.
Vyšlo v časopise:
A Genome-Wide Meta-Analysis of Six Type 1 Diabetes Cohorts Identifies Multiple Associated Loci. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002293
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002293
Souhrn
Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10−11) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10−9) resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10−9) lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.
Zdroje
1. SteynNPLambertEVTabanaH 2009 Conference on "Multidisciplinary approaches to nutritional problems". Symposium on "Diabetes and health". Nutrition interventions for the prevention of type 2 diabetes. Proc Nutr Soc 68 55 70
2. EURODIAB ACE Study Group 2000 Variation and trends in incidence of childhood diabetes in Europe. EURODIAB ACE Study Group. Lancet 355 873 876
3. OnkamoPVaananenSKarvonenMTuomilehtoJ 1999 Worldwide increase in incidence of Type I diabetes-the analysis of the data on published incidence trends. Diabetologia 42 1395 1403
4. RedondoMJYuLHawaMMackenzieTPykeDA 2001 Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44 354 362
5. ClaytonDG 2009 Prediction and interaction in complex disease genetics: experience in type 1 diabetes. PLoS Genet 5 e1000540 doi:10.1371/journal.pgen.1000540
6. GuoDLiMZhangYYangPEckenrodeS 2004 A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet 36 837 841
7. MirelDBValdesAMLazzeroniLCReynoldsRLErlichHA 2002 Association of IL4R haplotypes with type 1 diabetes. Diabetes 51 3336 3341
8. Biason-LauberABoehmBLang-MuritanoMGauthierBRBrunT 2005 Association of childhood type 1 diabetes mellitus with a variant of PAX4: possible link to beta cell regenerative capacity. Diabetologia 48 900 905
9. BellGIHoritaSKaramJH 1984 A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33 176 183
10. BennettSTLucassenAMGoughSCPowellEEUndlienDE 1995 Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9 284 292
11. VafiadisPBennettSTToddJANadeauJGrabsR 1997 Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15 289 292
12. BarrattBJPayneFLoweCEHermannRHealyBC 2004 Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53 1884 1889
13. KristiansenOPLarsenZMPociotF 2000 CTLA-4 in autoimmune diseases-a general susceptibility gene to autoimmunity? Genes Immun 1 170 184
14. UedaHHowsonJMEspositoLHewardJSnookH 2003 Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423 506 511
15. AnjosSMTessierMCPolychronakosC 2004 Association of the cytotoxic T lymphocyte-associated antigen 4 gene with type 1 diabetes: evidence for independent effects of two polymorphisms on the same haplotype block. J Clin Endocrinol Metab 89 6257 6265
16. NisticoLBuzzettiRPritchardLEVan der AuweraBGiovanniniC 1996 The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet 5 1075 1080
17. BottiniNMusumeciLAlonsoARahmouniSNikaK 2004 A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36 337 338
18. SmythDCooperJDCollinsJEHewardJMFranklynJA 2004 Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53 3020 3023
19. VellaACooperJDLoweCEWalkerNNutlandS 2005 Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76 773 779
20. QuHQMontpetitAGeBHudsonTJPolychronakosC 2007 Toward further mapping of the association between the IL2RA locus and type 1 diabetes. Diabetes 56 1174 1176
21. LoweCECooperJDBruskoTWalkerNMSmythDJ 2007 Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 39 1074 1082
22. ConcannonPOnengut-GumuscuSToddJASmythDJPociotF 2008 A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 57 2858 2861
23. HakonarsonHGrantSFABradfieldJPMarchandLKimCE 2007 A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448 591 594
24. Wellcome Trust Case Control Consortium 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678
25. ToddJAWalkerNMCooperJDSmythDJDownesK 2007 Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39 857 864
26. HakonarsonHQuHQBradfieldJPMarchandLKimCE 2008 A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. Diabetes 57 1143 1146
27. CooperJDSmythDJSmilesAMPlagnolVWalkerNM 2008 Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40 1399 1401
28. GrantSFQuHQBradfieldJPMarchandLKimCE 2009 Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. Diabetes 58 290 295
29. BarrettJCClaytonDGConcannonPAkolkarBCooperJD 2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41 703 707
30. QuHQBradfieldJPLiQKimCFrackeltonE 2010 In silico replication of the genome-wide association results of the Type 1 Diabetes Genetics Consortium. Hum Mol Genet 19 2534 2538
31. WangKBaldassanoRZhangHQuHQImielinskiM 2010 Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Hum Mol Genet 19 2059 2067
32. CooperJDWalkerNMSmythDJDownesKHealyBC 2009 Follow-up of 1715 SNPs from the Wellcome Trust Case Control Consortium genome-wide association study in type I diabetes families. Genes Immun 10 Suppl 1 S85 94
33. BarrettJCClaytonDGConcannonPAkolkarBCooperJD 2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet
34. SmythDJPlagnolVWalkerNMCooperJDDownesK 2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359 2767 2777
35. FungEYSmythDJHowsonJMCooperJDWalkerNM 2009 Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 10 188 191
36. CooperJDWalkerNMHealyBCSmythDJDownesK 2009 Analysis of 55 autoimmune disease and type II diabetes loci: further confirmation of chromosomes 4q27, 12q13.2 and 12q24.13 as type I diabetes loci, and support for a new locus, 12q13.3-q14.1. Genes Immun 10 Suppl 1 S95 120
37. PriceALPattersonNJPlengeRMWeinblattMEShadickNA 2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909
38. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
39. LiYWillerCSannaSAbecasisG 2009 Genotype imputation. Annu Rev Genomics Hum Genet 10 387 406
40. BarrettJCFryBMallerJDalyMJ 2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 263 265
41. PruimRJWelchRPSannaSTeslovichTMChinesPS 2010 LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26 2336 2337
42. PruittKDTatusovaTMaglottDR 2005 NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 33 D501 504
43. SemenovaEWangXJablonskiMMLevorseJTilghmanSM 2003 An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse chromosome 14 causes defects in viability, postnatal growth and degeneration of muscle and retina. Hum Mol Genet 12 1301 1312
44. KutluBBurdickDBaxterDRasschaertJFlamezD 2009 Detailed transcriptome atlas of the pancreatic beta cell. BMC Med Genomics 2 3
45. HolaskaJMRais-BahramiSWilsonKL 2006 Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes. Hum Mol Genet 15 3459 3472
46. FrankeAMcGovernDPBarrettJCWangKRadford-SmithGL 2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42 1118 1125
47. Lango AllenHEstradaKLettreGBerndtSIWeedonMN 2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467 832 838
48. GudbjartssonDFWaltersGBThorleifssonGStefanssonHHalldorssonBV 2008 Many sequence variants affecting diversity of adult human height. Nat Genet 40 609 615
49. SpeliotesEKWillerCJBerndtSIMondaKLThorleifssonG 2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42 937 948
50. RichardsJBRivadeneiraFInouyeMPastinenTMSoranzoN 2008 Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371 1505 1512
51. RivadeneiraFStyrkarsdottirUEstradaKHalldorssonBVHsuYH 2009 Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41 1199 1206
52. GatevaVSandlingJKHomGTaylorKEChungSA 2009 A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41 1228 1233
53. PurcellSChernySSShamPC 2003 Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19 149 150
54. BaileyRCooperJDZeitelsLSmythDJYangJH 2007 Association of the vitamin D metabolism gene CYP27B1 with type 1 diabetes. Diabetes 56 2616 2621
55. HeinigMPetrettoEWallaceCBottoloLRotivalM A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467 460 464
56. WallaceCSmythDJMaisuria-ArmerMWalkerNMToddJA The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet 42 68 71
57. QuHQGrantSFBradfieldJPKimCFrackeltonE 2009 Association of RASGRP1 with type 1 diabetes is revealed by combined follow-up of two genome-wide studies. J Med Genet 46 553 554
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
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