Pervasive Sharing of Genetic Effects in Autoimmune Disease
Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases—as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple—but not all—immune-mediated diseases (SNP-wise PCPMA<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.
Vyšlo v časopise:
Pervasive Sharing of Genetic Effects in Autoimmune Disease. PLoS Genet 7(8): e32767. doi:10.1371/journal.pgen.1002254
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002254
Souhrn
Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases—as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple—but not all—immune-mediated diseases (SNP-wise PCPMA<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.
Zdroje
1. VyseTToddJ 1996 Genetic analysis of autoimmune disease. Cell 85 311 318
2. BarrettJCHansoulSNicolaeDChoJDuerrRH 2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 955 962
3. GrahamRCotsapasCDaviesLHackettR 2008 Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 40 1059 1061
4. HuntKAZhernakovaATurnerGHeapGARFrankeL 2008 Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40 395 402
5. De JagerPLJiaXWangJDe BakkerPIWdOttoboniL 2009 Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41 776
6. NairRPDuffinKCHelmsCDingJStuartPE 2009 Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways. Nat Genet 41 199 204
7. StahlEARaychaudhuriSRemmersEFXieGEyreS 2010 Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42 508 514
8. CriswellLPfeifferKLumRGonzalesBNovitzkeJ 2005 Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. The American Journal of Human Genetics 76 561 571
9. WandstratAWakelandE 2001 The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nature immunology 2 802 809
10. EatonWRoseNKalaydjianAPedersenMMortensenP 2007 Epidemiology of autoimmune diseases in Denmark. Journal of Autoimmunity 29 1 9
11. MaierLLoweCCooperJDownesKAndersonD 2009 IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production. PLoS Genet 5 e1000322 doi:10.1371/journal.pgen.1000322
12. PlengeRMCotsapasCDaviesLPriceALDe BakkerPIWd 2007 Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 39 1477 1482
13. RemmersEFPlengeRMLeeATGrahamRHomG 2007 STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. The New England Journal of Medicine 357 977 986
14. 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
15. SmythDJPlagnolVWalkerNMCooperJDDownesK 2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. The New England Journal of Medicine 359 2767 2777
16. SirotaMSchaubMABatzoglouSRobinsonWHButteAJ 2009 Autoimmune disease classification by inverse association with SNP alleles. PLoS Genet 5 e1000792 doi:10.1371/journal.pgen.1000792
17. ZhernakovaAvan DiemenCWijmengaC 2009 Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10 43 55
18. de BakkerPIWdMcveanGSabetiPCMirettiMMGreenT 2006 A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38 1166 1172
19. RossinELageKRaychaudhuriSXavierRTatarD 2011 Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology. PLoS Genet 7 e1001273 doi:10.1371/journal.pgen.1001273
20. KhannaHDavisEEMurga-ZamalloaCAEstrada-CuzcanoALopezI 2009 A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat Genet 41 739 745
21. ToddJA 2010 Etiology of type 1 diabetes. Immunity 32 457 467
22. DuboisPCATrynkaGFrankeLHuntKARomanosJ 2010 Multiple common variants for celiac disease influencing immune gene expression. Nature Publishing Group 42 295 302
23. GatevaVSandlingJKHomGTaylorKEChungSA 2009 A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systematic lupus erythematosus. Nat Genet 41 1228 1233
24. BarrettJCClaytonDGConcannonPAkolkarBCooperJD 2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41 703
25. HindorffLSethupathyPJunkinsHRamosEMehtaJ 2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences 106 9362
26. JohnsonADHandsakerRPulitSNizzariMO'DonnellCJ 2008 SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24 2938 2939
27. GowerJ 1971 A general coefficient of similarity and some of its properties. Biometrics 27 857 874
28. WardJJr 1963 Hierarchical grouping to optimize an objective function. Journal of the American Statistical Association 236 244
29. Team RDC 2010 R: A Language and Environment for Statistical Computing. Vienna, Austria
30. LageKKarlbergEOStørlingZMÓlasonPÍPedersenAG 2007 A human phenome-interactome network of protein complexes implicated in genetic disorder. Nat Biotechnol 25 309 316
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 8
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- An EMT–Driven Alternative Splicing Program Occurs in Human Breast Cancer and Modulates Cellular Phenotype
- Chromosome Painting Reveals Asynaptic Full Alignment of Homologs and HIM-8–Dependent Remodeling of Chromosome Territories during Meiosis
- Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers
- Regulation of p53/CEP-1–Dependent Germ Cell Apoptosis by Ras/MAPK Signaling