The polygenic nature of rheumatoid arthritis

Cover Page

Cite item

Full Text

Abstract

Current advances in the genetic basis of rheumatoid arthritis (RA) were summarized in the review. Influence of gene polymorphisms involved in different cellular processes including cytokine-mediated signal transduction, immune and inflammatory responses to exogenous stimuli was discussed. The principal role of the major histocompatibility complex (MHC) and a shared epitope (SE), as well as contribution of non-HLA genes to susceptibility to RA was considered in terms of patients’ ethnicity and the serological status for the disease. The GWAS results for revealing candidate genes closely associated with RA risk were systematized as well as some aspects of epigenetics were mentioned. The findings indicated the polygenic nature of this complex disease. This problem was considered taking into account the recent results of mapping traits (eQTLs) with global gene expression. The novel “omnigenic” conception of heritability of complex traits/diseases was reported.

About the authors

Tat'yana D. Kuzhir

Institute of Genetics and Cytology, National Academy of Sciences of Belarus

Author for correspondence.
Email: T.Kuzhir@igc.by
Scopus Author ID: 6602670470

Main researcher, Doctor of Sciences in biology Laboratory of Molecular basis of Genomic Stability

Belarus, 220072, Minsk, Akademicheskaya st., 27

References

  1. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278(4):369-395. https://doi.org/10.1111/joim.12395.
  2. Angelotti F, Parma A, Cafaro G, et al. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2017;35(3):368-378.
  3. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46(2):183-196. https://doi.org/10.1016/j.immuni.2017.02.006.
  4. Кужир Т.Д. Ревматоидный артрит: исторические и современные аспекты // Молекулярная и прикладная генетика. – 2018. – Т. 24. – С. 55–73. [Kuzhir TD. Rheumatoid arthritis: historical and current aspects. Molekulyarnaya i prikladnaya genetika. 2018;24:55-73. (In Russ.)]
  5. Perricone C, Ceccarelli F, Valesini G. An overview on the genetic of rheumatoid arthritis: a never-ending story. Autoimmun Rev. 2011;10(10):599-608. https://doi.org/10.1016/j.autrev.2011.04.021.
  6. Mateen S, Zafar A, Moin S, et al. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta. 2016;455:161-171. https://doi.org/10.1016/j.cca.2016.02.010.
  7. Giaglis S, Hahn S, Hasler P. «The NET outcome»: are neutrophil extracellular traps of any relevance to the pathophysiology of autoimmune disorders in childhood? Front Pediatr. 2016;4:97. https://doi.org/10.3389/fped.2016.00097.
  8. Kurkó J, Besenyei T, Laki J, et al. Genetics of rheumatoid arthritis – comprehensive review. Clin Rev Allergy Immunol. 2013;45(2):170-179. https://doi.org/10.1007/s12016-012-8346-7.
  9. Hemminki K, Li X, Sundquist J, Sundquist K. Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis Rheum. 2009;60(3):661-668. https://doi.org/10.1002/art.24328.
  10. Kuo CF, Grainge MJ, Valdes AM, et al. Familial aggregation of rheumatoid arthritis and co-aggregation of autoimmune diseases in affected families: a nationwide population-based study. Rheumatology (Oxford). 2017;56(6):928-933. https://doi.org/10.1093/rheumatology/kew500.
  11. Choo SY. The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei Med J. 2007;48(1):11-23. https://doi.org/10.3349/ymj.2007.48.1.11.
  12. Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope. Curr Opin Rheumatol. 2010;22(3):293-298. https://doi.org/10.1097/BOR.0b013e328336ba63.
  13. Van Drongelen V, Holoshitz J. Human leukocyte antigen-disease associations in rheumatoid arthritis. Rheum Dis Clin North Am. 2017;43(3):363-376. https://doi.org/10.1016/j.rdc.2017.04.003.
  14. Huizinga TW, Amos CI, van der Helm-van Mil AH, et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 2005;52(11):3433-3438. https://doi.org/10.1002/art.21385.
  15. Kim K, Jiang X, Cui J, et al. Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis. Arthritis Rheum. 2015;67(10): 2611-2623. https://doi.org/10.1002/art.39228.
  16. Bettencourt A, Carvalho C, Leal B, et al. The protective role of HLA-DRB1(*)13 in autoimmune diseases. J Immunol Res. 2015;2015:948723. https://doi.org/10.1155/2015/948723.
  17. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146(11):797-808. https://doi.org/10.7326/0003-4819-146-11-200706050-00008.
  18. Bovin LF, Rieneck K, Workman C, et al. Blood cell gene expression profiling in rheumatoid arthritis. Discriminative genes and effect of rheumatoid factor. Immunol Lett. 2004;93(2-3):217-226. https://doi.org/10.1016/j.imlet.2004.03.018.
  19. Ding B, Padyukov L, Lundström E, et al. Different patterns of associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in the extended major histocompatibility complex region. Arthritis Rheum. 2009;60(1):30-38. https://doi.org/10.1002/art.24135.
  20. Padyukov L, Seielstad M, Ong RT, et al. Epidemiological investigation of rheumatoid arthritis (EIRA) study group. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Annu Rheum Dis. 2011;70(2):259-265. https://doi.org/10.1136/ard.2009.126821.
  21. Viatte S, Plant D, Bowes J, et al. Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Annu Rheum Dis. 2012;71(12):1984-1990. https://doi.org/10.1136/annrheumdis-2011-201225.
  22. Mackie SL, Taylor JC, Martin SG, et al. A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population. Genes Immun. 2012;13(2): 120-128. https://doi.org/10.1038/gene.2011.60.
  23. Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, et al. Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum. 2005;52(10):3058-3062. https://doi.org/10.1002/art.21302.
  24. Terao C, Ohmura K, Ikari K, et al. ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Japanese. PLoS One. 2012;7(7): e40067. https://doi.org/10.1371/journal.pone.0040067.
  25. Van der Woude D, Houwing-Duistermaat JJ, Toes RE, et al. Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis. Arthritis Rheum. 2009;60(4):916-923. https://doi.org/10.1002/art. 24385.
  26. Plenge RM. Recent progress in rheumatoid arthritis genetics: one step towards improved patient care. Curr Opin Rheumatol. 2009;21(3):262-271. https://doi.org/10.1097/BOR.0b013e32832a2e2d.
  27. Ferucci ED, Templin DW, Lanier AP. Rheumatoid arthritis in American Indians and Alaska Natives: a review of the literature. Semin Arthritis Rheum. 2005;34(4):662-667. https://doi.org/10.1016/j.semarthrit.2004.08.003.
  28. Hughes LB, Morrison D, Kelley JM, et al. The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum. 2008;58(2): 349-358. https://doi.org/10.1002/art.23166.
  29. Traylor M, Curtis C, Patel H, et al. Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case-control study. Rheumatology (Oxford). 2017;56(8): 1282-1292. https://doi.org/10.1093/rheumatology/kex048.
  30. López Herráez D, Martínez-Bueno M, Riba L, et al. Rheumatoid arthritis in Latin Americans enriched for Amerindian ancestry is associated with loci in chromosomes 1, 12, and 13, and the HLA class II region. Arthritis Rheum. 2013;65(6):1457-1467. https://doi.org/10.1002/art.37923.
  31. Chun-Lai T, Padyukov L, Dhaliwal JS, et al. Shared epitope alleles remain a risk factor for anti-citrullinated proteins antibody (ACPA)-positive rheumatoid arthritis in three Asian ethnic groups. PLoS One. 2011;6(6): e21069. https://doi.org/10.1371/journal.pone.0021069.
  32. Korczowska I. Rheumatoid arthritis susceptibility genes: an overview. World J Orthop. 2014;5(4):544-549. https://doi.org/10.5312/wjo.v5.i4.544.
  33. Lee YH, Woo JH, Choi SJ, et al. Association between the rs7574865 polymorphism of STAT4 and rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2010;30(5):661-666. https://doi.org/10.1007/s00296-009-1051-z.
  34. Elshazli R, Settin A. Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: a meta-analysis update. Immunobiology. 2015;220(8):1012-1024. https://doi.org/10.1016/j.imbio.2015.04.003.
  35. Lee HS, Korman BD, Le JM, et al. Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations. Arthritis Rheum. 2009;60(2):364-371. https://doi.org/10.1002/art.24245.
  36. Kochi Y, Suzuki A, Yamada R, Yamamoto K. Genetics of rheumatoid arthritis: underlying evidence of ethnic differences. J Autoimmun. 2009;32(3-4):158-162. https://doi.org/10.1016/j.jaut.2009.02.020.
  37. Lee YH, Bae SC, Song GG. FCGR2A, FCGR3A, FCGR3B polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2015;33(5):647-654.
  38. Tang GP, Hu L, Zhang QH. [PTPN22 1858C/T polymorphism is associated with rheumatoid arthritis susceptibility in Caucasian population: a meta-analysis. (In Chinese)]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2014;43(4):466-473.
  39. Nabi G, Akhter N, Wahid M, et al. Meta-analysis reveals PTPN22 1858C/T polymorphism confers susceptibility to rheumatoid arthritis in Caucasian but not in Asian population. Autoimmunity. 2016;49(3):197-210. https://doi.org/10.3109/08916934.2015.1134514.
  40. El-Lebedy D, Raslan H, Ibrahim A, et al. Association of STAT4 rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoid arthritis and non-systemically reacting antibodies in Egyptian patients. Clin Rheumatol. 2017;36(9):1981-1987. https://doi.org/10.1007/s10067-017-3632-7.
  41. Vernerova L, Spoutil F, Vlcek M, et al. A combination of CD28 (rs1980422) and IRF5 (rs10488631) polymorphisms is associated with seropositivity in rheumatoid arthritis: a case control study. PLoS One. 2016;11(4): e0153316. https://doi.org/10.1371/journal.pone.0153316.
  42. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296(5573):1634-1635. https://doi.org/10.1126/science.1071924.
  43. Chen X, Oppenheim JJ. Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity. FEBS letters. 2011;585(23):3611-3618. https://doi.org/10.1016/j.febslet.2011.04.025.
  44. Hehlgans T, Pfeffer K. The intriguing biology of the tumor necrosis factor/tumor necrosis factor receptor superfamily: players, rules and the games. Immunology. 2005;115(1):1-20. https://doi.org/10.1111/j.1365-2567.2005.02143.x.
  45. Nedwin GE, Naylor SL, Sakaguchi AY, et al. Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985;13(17):6361-6373. https://doi.org/10.1093/nar/13.17.6361.
  46. Udalova IA, Nedospasov SA, Webb GC, et al. Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics. 1993;16(1): 180-186. https://doi.org/10.1006/geno.1993. 1156.
  47. Рыдловская А.В., Симбирцев А.С. Функциональный полиморфизм гена TNF-α и патология // Цитокины и воспаление. – 2005. – Т. 4. – № 3. – С. 1–10. [Rydlovskaia AV, Simbirtsev AS. TNF-α functional gene polymorphism and pathology. Cytokines and inflammation. 2005;4(3):1-10. (In Russ.)]
  48. Lee YH, Ji JD, Song GG. Tumor necrosis factor-alpha promoter-308 A/G polymorphism and rheumatoid arthritis susceptibility: a meta-analysis. J Rheumatol. 2007;34(1):43-49.
  49. Chatzikyriakidou A, Voulgari PV, Lambropoulos A, Drosos AA. Genetics in rheumatoid arthritis beyond HLA genes: what meta-analyses have shown? Semin Arthritis Rheum. 2013;43(1):29-38. https://doi.org/10.1016/j.semarthrit.2012.12.003.
  50. Miterski B, Drynda S, Böschow G, et al. Complex genetic predisposition in adult and juvenile rheumatoid arthritis. BMC Genet. 2004;5:2. https://doi.org/10.1186/1471-2156-5-2.
  51. Khanna D, Wu H, Park G, et al. Association of tumor necrosis factor alpha polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort. Arthritis Rheum. 2006;54(4):1105-1116. https://doi.org/10.1002/art.21750.
  52. Lacki JK, Moser R, Korczowska I, et al. TNF-α gene polymorphism does not affect the clinical and radiological outcome of rheumatoid arthritis. Rheumatol Int. 2000;19(4):137-140. https://doi.org/10.1007/s002960050117.
  53. Савина Н.В. Изучение аллельного полиморфизма гена TNF-α при раке мочевого пузыря // Молекулярная и прикладная генетика. – 2013. – Т. 15. – С. 33–38. [Savina NV. The study of the gene TNF-α polymorphism in the bladder cancer. Molekulyarnaya i prikladnaya genetika. 2013;15:33-38. (In Russ.)]
  54. Левданский О.Д., Родькин М.С., Данилов Д.Е., и др. Полиморфизм генов IL28B и TNF-α среди коренного населения Беларуси, а также у пациентов с хроническим гепатитом С // Молекулярная и прикладная генетика. – 2016. – Т. 20. – С. 80–86. [Liaudanski AD, Rodzkin MS, Danilau DE, et al. IL28B and TNF-α gene polymorphism in native Belarusians and patients with chronic hepatitis C. Molekulyarnaya i prikladnaya genetika. 2016;20:80-86. (In Russ.)]
  55. Савина Н.В., Никитченко Н.В., Кужир Т.Д., и др. Частоты генотипов и аллелей полиморфных локусов генов воспалительного ответа PTPN22, TNF-α и MIF у детского контингента Республики Беларусь // Молекулярная и прикладная генетика. – 2017. – Т. 22. – С. 14–24. [Savina NV, Nikitchenko NV, Kuzhir TD, et al. Frequencies of genotypes and alleles of polymorphic loci of inflammatory response genes PTPN22, TNF-α and MIF in children and adolescents in the Republic of Belarus. Molekulyarnaya i prikladnaya genetika. 2017;22:14-24. (In Russ.)]
  56. Lee YH, Bae SC, Choi SJ, et al. The association between interleukin-6 polymorphisms and rheumatoid arthritis: a meta-analysis. Inflamm Res. 2012;61(7):665-671. https://doi.org/10.1007/s00011-012-0459-1.
  57. Яцкив А.А., Большакова Д.В., Чичко А.М., и др. Влияние полиморфизма -174 G/C гена IL-6 на вероятность развития ревматоидного артрита у детского и взрослого населения Республики Беларусь // Доклады Национальной академии наук Беларуси. – 2018. – Т. 62. – № 5. – С. 608–614. [Yatskiu HA, Balshakova DV, Tchitchko AM, et al. Influence of -l74 G/C IL-6 gene polymorphism on the susceptibility to rheumatoid arthritis in children and adults in the Republic of Belarus. Doklady of the National Academy of Sciences of Belarus. 2018;62(5):608-614. (In Russ.)]. https://doi.org/10.29235/1561-8323-2018-62-5-608-614.
  58. Magyari L, Varszegi D, Kovesdi E, et al. Interleukins and interleukin receptors in rheumatoid arthritis: research, diagnostics and clinical implications. World J Orthop. 2014;5(4):516-536. https://doi.org/10.5312/wjo.v5.i4.516.
  59. Ge L, Huang Y, Zhang H, et al. Association between polymorphisms of interleukin 10 with inflammatory biomarkers in East Chinese Han patients with rheumatoid arthritis. Joint Bone Spine. 2015;82(3):182-186. https://doi.org/10.1016/j.jbspin.2014.11.007.
  60. Zhang TP, Lv TT, Xu SZ, et al. Association of interleukin-10 gene single nucleotide polymorphisms with rheumatoid arthritis in a Chinese population. Postgrad Med J. 2018;94(1111):284-288. https://doi.org/10.1136/postgradmedj-2017-135441.
  61. Pearson TA, Manolio TA. How to interpret a genome-wide association study. JAMA. 2008;299(11): 1335-1344. https://doi.org/10.1001/jama.299.11. 1335.
  62. Welter D, MacArthur J, Morales J, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42 (Database issue): D1001-D1006. https://doi.org/10.1093/nar/gkt1229.
  63. Ricaño-Ponce I, Zhernakova DV, Deelen P, et al. Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs. J Autoimmun. 2016;68:62-74. https://doi.org/10.1016/j.jaut.2016.01.002.
  64. Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376-381. https://doi.org/10.1038/nature12873.
  65. Zhu H, Xia W, Mo XB, et al. Gene-based genome-wide association analysis in European and Asian populations identified novel genes for rheumatoid arthritis. PLoS One. 2016;11(11): e0167212. https://doi.org/10.1371/journal.pone.0167212.
  66. Stahl EA, Raychaudhuri S, Remmers EF, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42(6):508-514. https://doi.org/10.1038/ ng.582.
  67. Zhang L, Yuan X, Zhou Q, et al. Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis risk: a meta-analysis. Arch Med Res. 2017;48(4): 386-392. https://doi.org/10.1016/j.arcmed.2017. 08.003.
  68. Golka K, Selinski S, Lehmann ML, et al. Genetic variants in urinary bladder cancer: collective power of the “wimp SNPs”. Arch Toxicol. 2011;85(6):539-554. https://doi.org/10.1007/s00204-011-0676-3.
  69. Ernst J, Kheradpour P, Mikkelsen TS, et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature. 2011;473(7345):43-49. https://doi.org/10.1038/nature09906.
  70. Viatte S, Plant D, Raychaudhuri S. Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol. 2013;9(3):141-153. https://doi.org/10.1038/nrrheum.2012.237.
  71. Klein K, Gay S. Epigenetics in rheumatoid arthritis. Curr Opin Rheumatol. 2015;27(1):76-82. https://doi.org/10.1097/BOR.0000000000000128.
  72. Firestein GS. Pathogenesis of rheumatoid arthritis: the intersection of genetics and epigenetics. Trans Am Clin Climatol Assoc. 2018;129:171-182.
  73. Nakano K, Whitaker JW, Boyle DL, et al. DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis. 2013;72(1):110-117. https://doi.org/10.1136/annrheumdis-2012-201526.
  74. Ham S, Bae JB, Lee S, et al. Epigenetic analysis in rheumatoid arthritis synoviocytes. Exp Mol Med. 2019;51(2):22. https://doi.org/10.1038/s12276-019-0215-5.
  75. Pieper J, Johansson S, Snir O, et al. Peripheral and site-specific CD4(+) CD28(Null) T cells from rheumatoid arthritis patients show distinct characteristics. Scand J Immunol. 2014;79(2):149-155. https://doi.org/10.1111/sji.12139.
  76. Karouzakis E, Gay RE, Gay S, Neidhart M. Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2012;64(6):1809-1817. https://doi.org/10.1002/art.34340.
  77. Liu Y, Aryee MJ, Padyukov L, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31(2):142-147. https://doi.org/10.1038/nbt.2487.
  78. Cribbs A, Feldmann M, Oppermann U. Towards an understanding of the role of DNA methylation in rheumatoid arthritis: therapeutic and diagnostic implications. Ther Adv Musculoskelet Dis. 2015;7(5): 206-219. https://doi.org/10.1177/1759720X15598307.
  79. Neidhart M., Karouzakis E., Jüngel A., et al. Inhibition of spermidine/spermine N1-acetyltransferase activity: a new therapeutic concept in rheumatoid arthritis. Arthritis Rheumatol. 2014; 66(7):1723-1733. https://doi.org/10.1002/art.38574.
  80. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747-753. https://doi.org/10.1038/nature08494.
  81. Ricaño-Ponce I, Wijmenga C. Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet. 2013;14:325-353. https://doi.org/10.1146/annurev-genom-091212-153450.
  82. GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348(6235): 648-660. https://doi.org/10.1126/science.1262110.
  83. Pai AA, Pritchard JK, Gilad Y. The genetic and mechanistic basis for variation in gene regulation. PLoS Genet. 2015;11(1): e1004857. https://doi.org/10.1371/journal.pgen.1004857.
  84. Joehanes R, Zhang X, Huan T, et al. Integrated genome-wide analysis of expression quantitative trait loci aids interpretation of genomic association studies. Genome Biol. 2017;18(1):16. https://doi.org/10.1186/s13059-016-1142-6.
  85. Albert FW, Kruglyak L. The role of regulatory variation in complex traits and disease. Nat Rev Genet. 2015;16(4):197-212. https://doi.org/10.1038/nrg3891.
  86. Cookson W, Liang L, Abecasis G, et al. Mapping complex disease traits with global gene expression. Nat Rev Genet. 2009;10(3):184-94. https://doi.org/10.1038/nrg2537.
  87. Fairfax BP, Makino S, Radhakrishnan J, et al. Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat Genet. 2012;44(5):502-510. https://doi.org/10.1038/ng.2205.
  88. Van Dongen J, Jansen R, Smit D, et al. The contribution of the functional IL6R polymorphisms 2228145, eQTLs and other genome-wide SNPs to the heritability of plasma sIL-6R levels. Behav Genet. 2014;44(4):368-382. https://doi.org/10.1007/s10519-014-9656-8.
  89. Farh KK, Marson A, Zhu J, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518(7539):337-343. https://doi.org/10.1038/nature13835.
  90. Ishigaki K, Kochi Y, Suzuki A, et al. Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis. Nat Genet. 2017;49(7):1120-1125. https://doi.org/10.1038/ng.3885.
  91. McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis – shaping the immunological landscape. Nat Rev Rheumatol. 2016;12(1):63-68. https://doi.org/10.1038/nrrheum.2015.171.
  92. Boyle EA, Li YI, Pritchard JK. An expanded view of complex traits: from polygenic to omnigenic. Cell. 2017;169(7):1177-1186. https://doi.org/10.1016/j.cell.2017.05.038.
  93. Pullabhatla V, Roberts AL, Lewis MJ, et al. De novo mutations implicate novel genes in systemic lupus erythematosus. Hum Mol Genet. 2018;27(3):421-429. https://doi.org/10.1093/hmg/ddx407.
  94. Curtis D. The «omnigenic» model for schizophrenia – why it’s even worse than you think [Accessed 2019 April 14]. Available from: http://davenomiddlenamecurtis.blogspot.com/2017/06/the-omnigenic-model-for-schizophrenia.html.
  95. Wray NR, Wijmenga C, Sullivan PF, et al. Common disease is more complex than implied by the core gene omnigenic model. Cell. 2018;173(7): 1573-1580. https://doi.org/10.1016/j.cell.2018.05. 051.
  96. Barton NH, Etheridge AM, Véber A. The infinitesimal model: definition, derivation, and implications. Theor Popul Biol. 2017;118:50-73. https://doi.org/10.1016/j.tpb.2017.06.001.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2019 Kuzhir T.D.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies