Advertisement

Systemic Lupus Erythematosus

  • Susan K. Vester
  • Timothy J. VyseEmail author
Chapter
  • 307 Downloads
Part of the Rare Diseases of the Immune System book series (RDIS)

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with a strong genetic component. Monogenic causes of SLE, such as complement deficiencies, are rare but have high penetrance and have been able to shed light on some disease-related pathways. However, in a majority of SLE cases, the genetics underlying this disease are complex and not fully explored. The advent of genome-wide association studies has led to the discovery of over 80 common variants robustly associated with SLE risk. However, missing heritability is still observed. Next-generation sequencing approaches such as targeted resequencing, whole-exome sequencing, or whole-genome sequencing have been harnessed in the search for rare variants, which may account for some of the missing heritability observed. High-penetrant rare variants are likely to lead the way in pinpointing pathways for therapeutic targeting. Both common and rare variants cannot, however, be viewed entirely independently, as modified penetrance of protein-coding variants through regulatory haplotypes, as well as common variant haplotypes, has been observed in SLE.

Keywords

Systemic lupus erythematosus Missing heritability Common variants Rare variants De novo mutations Penetrance Haplotype 

References

  1. 1.
    Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, et al. Systemic lupus erythematosus. Nat Rev Dis Primers. 2016;2:16039.PubMedCrossRefGoogle Scholar
  2. 2.
    Pons-Estel GJ, Alarcón GS, Scofield L, Reinlib L, Cooper GS. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum. 2010;39(4):257–68.PubMedCrossRefGoogle Scholar
  3. 3.
    Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology. 2017;56(11):1945–61.PubMedCrossRefGoogle Scholar
  4. 4.
    Brunner HI, Gladman DD, Ibanez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum. 2008;58(2):556–62.PubMedCrossRefGoogle Scholar
  5. 5.
    Kuo C-F, Grainge MJ, Valdes AM, See L-C, Luo S-F, Yu K-H, et al. Familial aggregation of systemic lupus erythematosus and coaggregation of autoimmune diseases in affected families. JAMA Intern Med. 2015;175(9):1518–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Lawrence JS, Martins CL, Drake GL. A family survey of lupus erythematosus. 1. Heritability. J Rheumatol. 1987;14(5):913–21.PubMedGoogle Scholar
  7. 7.
    Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1982;35(3):311–8.Google Scholar
  8. 8.
    Block SR, Winfield JB, Lockshin MD, D’Angelo WA, Christian CL. Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets. Am J Med. 1975;59(4):533–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Alarcon-Segovia ME, Cardiel MH, Caeiro F, Massardo L, Villa AR, Pons-Estel BA. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 2005;52(4):1138–47.PubMedCrossRefGoogle Scholar
  10. 10.
    Webb R, Kelly JA, Somers EC, Hughes T, Kaufman KM, Sanchez E, et al. Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients. Ann Rheum Dis. 2011;70(1):151–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Parks CG, de Souza Espindola Santos A, Barbhaiya M, Costenbader KH. Understanding the role of environmental factors in the development of systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2017;31(3):306–20.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Crow YJ. Lupus: how much “complexity” is really (just) genetic heterogeneity? Arthritis Rheum. 2011;63(12):3661–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Glagov S, Gechman E. Familial occurence of disseminated lupus erythematosus. N Engl J Med. 1956;255(20):936–40.PubMedCrossRefGoogle Scholar
  14. 14.
    Marlow AA, Peabody HD, Nickel WR. Familial occurrence of systemic lupus erythematosus. JAMA. 1960;173(15):1641–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Agnello V, De Bracco MME, Kunkel HG. Hereditary C2 deficiency with some manifestations of systemic lupus erythematosus. J Immunol. 1972;108(3):837–40.PubMedGoogle Scholar
  16. 16.
    Moncada B, Day NKB, Good RA, Windhorst D. Lupus-erythematosus-like syndrome with a familial defect of complement. N Engl J Med. 1972;286(13):689–93.PubMedCrossRefGoogle Scholar
  17. 17.
    Lo MS, Tsokos GC. Monogenic lupus. Int J Clin Rheumtol. 2014;9(6):543–6.CrossRefGoogle Scholar
  18. 18.
    Morgan BP, Walport MJ. Complement deficiency and disease. Immunol Today. 1991;12(9):301–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Arason GJ, Jorgensen GH, Ludviksson BR. Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol. 2010;71(5):317–28.PubMedCrossRefGoogle Scholar
  20. 20.
    Atkinson JP, Yung Yu C. Genetic susceptibility and class III complement genes. In: Systemic lupus erythematosus. 5th ed. New York: Elsevier; 2011. p. 21–45.CrossRefGoogle Scholar
  21. 21.
    Costa-Reis P, Sullivan KE. Monogenic lupus: it’s all new! Curr Opin Immunol. 2017;49:87–95.PubMedCrossRefGoogle Scholar
  22. 22.
    Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C, Urushihara M, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet. 2001;28(4):313–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N, et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet. 2011;43(12):1186–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, et al. Protein kinase Cδ deficiency causes Mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013;65(8):2161–71.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Crow YJ, Chase DS, Schmidt JL, Szynkiewicz M, Forte GM, Gornall HL, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet Part A. 2015;167(A):296–312.CrossRefGoogle Scholar
  26. 26.
    Tsokos GC, Lo MS, Reis PC, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Publ Gr. 2016;12(12):716–30.Google Scholar
  27. 27.
    Lo MS. Monogenic lupus. Curr Rheumatol Rep. 2016;18:71.PubMedCrossRefGoogle Scholar
  28. 28.
    Grumet FC, Coukell A, Bodmer JG, Bodmer WF, McDevitt HO. Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. N Engl J Med. 1971;285(4):193–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Waters H, Konrad P, Walford RL. The distribution of HL-A histocompatibility factors and genes in patients with systemic lupus erythematosus. Tissue Antigens. 1971;1(2):68–73.PubMedCrossRefGoogle Scholar
  30. 30.
    Tsao BP. Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol. 2004;16(5):513–21.PubMedCrossRefGoogle Scholar
  31. 31.
    Harley JB, Alarcón-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40(2):204–10.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hom G, Ph D, Graham RR, Modrek B, Taylor KE, Ortmann W, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. 2008;358:900–9.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM, et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet. 2008;40(9):1059–61.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Fernando MMA, Stevens CR, Sabeti PC, Walsh EC, McWhinnie AJM, Shah A, et al. Identification of two independent risk factors for lupus within the MHC in United Kingdom families. PLoS Genet. 2007;3(11):2109–21.CrossRefGoogle Scholar
  35. 35.
    Rioux JD, Goyette P, Vyse TJ, Hammarstrom L, Fernando MMA, Green T, et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc Natl Acad Sci. 2009;106(44):18680–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Morris DL, Taylor KE, Fernando MMA, Nititham J, Alarcón-Riquelme ME, Barcellos LF, et al. Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans. Am J Hum Genet. 2012;91(5):778–93.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Morris DL, Fernando MMA, Taylor KE, Chung SA, Nititham J, Alarcón-Riquelme ME, et al. MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun. 2014;15(4):210–7.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Wakeland EK, Liu K, Graham RR, Behrens TW. Delineating the genetic basis of systemic lupus erythematosus. Immunity. 2001;15(3):397–408.PubMedCrossRefGoogle Scholar
  39. 39.
    Sestak AL, Nath SK, Sawalha AH, Harley JB. Current status of lupus genetics. Arthritis Res Ther. 2007;9(3):210.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Collins FS, Brooks LD, Chakravarti A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 1998;8(12):1229–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Zarrei M, MacDonald JR, Merico D, Scherer SW. A copy number variation map of the human genome. Nat Rev Genet. 2015;16(3):172–83.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001;17(9):502–10.CrossRefGoogle Scholar
  43. 43.
    Becker KG. The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses. 2004;62(2):309–17.PubMedCrossRefGoogle Scholar
  44. 44.
    Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest. 2008;118(5):1590–605.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Spencer CCA, Su Z, Donnelly P, Marchini J. Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip. PLoS Genet. 2009;5(5):e1000477.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MVP, Sanchez E, et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet. 2008;40(2):211–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Suarez-Gestal M, Calaza M, Endreffy E, Pullmann R, Ordi-Ros J, Domenico Sebastiani G, et al. Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study. Arthritis Res Ther. 2009;11(3):1–9.CrossRefGoogle Scholar
  48. 48.
    Bentham J, Morris DL, Cunninghame Graham DS, Pinder CL, Tombleson P, Behrens TW, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457–64.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Demirci FY, Wang X, Kelly JA, Morris DL, Barmada MM, Feingold E, et al. Identification of a new susceptibility locus for systemic lupus erythematosus on chromosome 12 in individuals of European ancestry. Arthritis Rheumatol. 2016;68(1):174–83.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Armstrong DL, Zidovetzki R, Alarcón-Riquelme ME, Tsao BP, Criswell LA, Kimberly RP, et al. GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun. 2014;15(6):347–54.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Han J-W, Zheng H-F, Cui Y, Sun L-D, Ye D-Q, Hu Z, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1234–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, Qian XX, et al. Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet. 2010;6(2):e1000841.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Okada Y, Shimane K, Kochi Y, Tahira T, Suzuki A, Higasa K, et al. A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus erythematosus in Japanese. PLoS Genet. 2012;8(1):e1002455.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Lee H-S, Kim T, Bang SY, Na YJ, Kim I, Kim K, et al. Ethnic specificity of lupus-associated loci identified in a genome-wide association study in Korean women. Ann Rheum Dis. 2014;73(6):1240–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Lessard CJ, Sajuthi S, Zhao J, Kim K, Ice JA, Li H, et al. Identification of a systemic lupus erythematosus risk locus spanning ATG16L2, FCHSD2, and P2RY2 in Koreans. Arthritis Rheumatol. 2016;68(5):1197–209.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Sun C, Molineros JE, Looger LL, Zhou XJ, Kim K, Okada Y, et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet. 2016;48(3):323–30.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Liu L, Zuo X, Zhu Z, Wen L, Yang C, Zhu C, et al. Genome-wide association study identifies three novel susceptibility loci for systemic lupus erythematosus in Han Chinese. Br J Dermatol. 2018;179(2):506–8.  https://doi.org/10.1111/bjd.16500.CrossRefPubMedGoogle Scholar
  58. 58.
    Alarcón-Riquelme ME, Ziegler JT, Molineros J, Howard TD, Moreno-Estrada A, Sánchez-Rodríguez E, et al. Genome-wide association study in an Amerindian ancestry population reveals novel systemic lupus erythematosus risk loci and the role of European admixture. Arthritis Rheumatol. 2016;68(4):932–43.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Kaiser R, Taylor KE, Deng Y, Zhao J, Li Y, Nititham J, et al. Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians. Arthritis Rheum. 2013;65(1):211–5.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Zhang J, Zhang L, Zhang Y, Yang J, Guo M, Sun L, et al. Gene-based meta-analysis of genome-wide association study data identifies independent single-nucleotide polymorphisms in ANXA6 as being associated with systemic lupus erythematosus in Asian populations. Arthritis Rheumatol. 2015;67(11):2966–77.PubMedCrossRefGoogle Scholar
  61. 61.
    Morris DL, Sheng Y, Zhang Y, Wang Y-F, Zhu Z, Tombleson P, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet. 2016;48(8):940–6.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Molineros JE, Yang W, jie ZX, Sun C, Okada Y, Zhang H, et al. Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci. Hum Mol Genet. 2017;26(6):1205–16.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Langefeld CD, Ainsworth HC, Cunninghame Graham DS, Kelly JA, Comeau ME, Harley JB, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8:16021.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cortes A, Brown MA. Promise and pitfalls of the immunochip. Arthritis Res Ther. 2011;13(1):101.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    So HC, Gui AHS, Cherny SS, Sham PC. Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet Epidemiol. 2011;35(5):310–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Chen L, Morris DL, Vyse TJ. Genetic advances in systemic lupus erythematosus: an update. Curr Opin Rheumatol. 2017;29(5):423–33.PubMedCrossRefGoogle Scholar
  67. 67.
    Boyle EA, Li YI, Pritchard JK. Perspective an expanded view of complex traits: From polygenic to omnigenic. Cell. 2017;169(7):1177–86.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Martin P, McGovern A, Orozco G, Duffus K, Yarwood A, Schoenfelder S, et al. Capture Hi-C reveals novel candidate genes and complex long-range interactions with related autoimmune risk loci. Nat Commun. 2015;6:1–7.Google Scholar
  69. 69.
    Odhams CA, Cortini A, Chen L, Roberts AL, Buil A, Small KS, et al. Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus. Hum Mol Genet. 2017;26(5):1003–17.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Chen L, Ge B, Casale FP, Vasquez L, Kwan T, Garrido-Martín D, et al. Genetic drivers of epigenetic and transcriptional variation in human immune cells. Cell. 2016;167(5):1398–414.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.CrossRefGoogle Scholar
  72. 72.
    Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–29.CrossRefPubMedCentralGoogle Scholar
  73. 73.
    Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, Chakravarti A, Clark AG, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65.CrossRefGoogle Scholar
  75. 75.
    Keinan A, Clark AG. Recent explosive human population growth has resulted in an excess of rare genetic variants. Science. 2012;740:740–4.CrossRefGoogle Scholar
  76. 76.
    Bomba L, Walter K, Soranzo N. The impact of rare and low-frequency genetic variants in common disease. Genome Biol. 2017;18(1):1–17.CrossRefGoogle Scholar
  77. 77.
    Hunt KA, Mistry V, Bockett NA, Ahmad T, Ban M, Barker JN, et al. Negligible impact of rare autoimmune-locus coding-region variants on missing heritability. Nature. 2013;498(7453):232–5.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Torgerson DG, Capurso D, Mathias RA, Graves PE, Hernandez RD, Beaty TH, et al. Resequencing candidate genes implicates rare variants in asthma susceptibility. Am J Hum Genet. 2012;90(2):273–81.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Jordan CT, Cao L, Roberson EDO, Duan S, Helms CA, Nair RP, et al. Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet. 2012;90(5):796–808.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet. 2011;43(11):1066–73.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39(9):1065–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO, Adler A, et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun. 2011;12(4):270–9.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Bodaño A, Amarelo J, González A, Gómez-Reino JJ, Conde C. Novel DNASE I mutations related to systemic lupus erythematosus. Arthritis Rheum. 2004;50(12):4070–1.PubMedCrossRefGoogle Scholar
  84. 84.
    Roberts AL, Thomas ERA, Bhosle S, Game L, Obraztsova O, Aitman TJ, et al. Resequencing the susceptibility gene, ITGAM, identifies two functionally deleterious rare variants in systemic lupus erythematosus cases. Arthritis Res Ther. 2014;16(3):R114.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Lessard CJ, Adrianto I, Ice JA, Wiley GB, Kelly JA, Glenn SB, et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet. 2012;90(4):648–60.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Graham RR, Kyogoku C, Sigurdsson S, Vlasova IA, Davies LRL, Baechler EC, et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci. 2007;104(16):6758–63.PubMedCrossRefGoogle Scholar
  87. 87.
    Wang C, Ahlford A, Laxman N, Nordmark G, Eloranta ML, Gunnarsson I, et al. Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility. Genes Immun. 2013;14(4):217–22.PubMedCrossRefGoogle Scholar
  88. 88.
    Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13(8):565–75.PubMedCrossRefGoogle Scholar
  89. 89.
    Cooper GM, Shendure J. Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data. Nat Rev Genet. 2011;12(9):628–40.PubMedCrossRefGoogle Scholar
  90. 90.
    Belkadi A, Bolze A, Itan Y, Cobat A, Vincent QB, Antipenko A, et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci. 2015;112(17):5473–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V, Gaulton KJ, et al. The genetic architecture of type 2 diabetes. Nature. 2016;536(7614):41–7.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Luo Y, De Lange KM, Jostins L, Moutsianas L, Randall J, Kennedy NA, et al. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nat Genet. 2017;49(2):186–92.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Chakravarti A, Turner TN. Revealing rate-limiting steps in complex disease biology: the crucial importance of studying rare, extreme-phenotype families. Bioessays. 2016;38(6):578–86.PubMedCrossRefGoogle Scholar
  94. 94.
    Pullabhatla V, Roberts AL, Lewis MJ, Mauro D, Morris DL, Odhams CA, et al. De novo mutations implicate novel genes in systemic lupus erythematosus. Hum Mol Genet. 2018;27(3):421–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Ruderfer DM, Hamamsy T, Lek M, Karczewski KJ, Kavanagh D, Samocha KE, et al. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nat Genet. 2016;48(10):1107–11.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Desachy G, Croen LA, Torres AR, Kharrazi M, Delorenze GN, Windham GC, et al. Increased female autosomal burden of rare copy number variants in human populations and in autism families. Mol Psychiatry. 2015;20(2):170–5.PubMedCrossRefGoogle Scholar
  98. 98.
    Fanciulli M, Norsworthy PJ, Petretto E, Dong R, Harper L, Kamesh L, et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet. 2007;39(6):721–3.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Morris DL, Roberts AL, Witherden AS, Tarzi R, Barros P, Whittaker JC, et al. Evidence for both copy number and allelic (NA1/NA2) risk at the FCGR3B locus in systemic lupus erythematosus. Eur J Hum Genet. 2010;18(9):1027–31.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Mueller M, Barros P, Witherden AS, Roberts AL, Zhang Z, Schaschl H, et al. Genomic pathology of SLE-associated copy-number variation at the FCGR2C/FCGR3B/FCGR2B locus. Am J Hum Genet. 2013;92(1):28–40.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Boteva L, Morris DL, Cortés-Hernández J, Martin J, Vyse TJ, Fernando MMA. Genetically determined partial complement C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Am J Hum Genet. 2012;90(3):445–56.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Hedrich CM. Epigenetics in SLE. Curr Rheumatol Rep. 2017;19(9):58.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Long H, Yin H, Wang L, Gershwin ME, Lu Q. The critical role of epigenetics in systemic lupus erythematosus and autoimmunity. J Autoimmun. 2016;74:118–38.PubMedCrossRefGoogle Scholar
  104. 104.
    Wen ZK, Xu W, Xu L, Cao QH, Wang Y, Chu YW, et al. DNA hypomethylation is crucial for apoptotic DNA to induce systemic lupus erythematosus-like autoimmune disease in SLE-non-susceptible mice. Rheumatology. 2007;46(12):1796–803.PubMedCrossRefGoogle Scholar
  105. 105.
    Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M, et al. Klinefelter’s syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008;58(8):2511–7.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Liu K, Kurien BT, Zimmerman SL, Kaufman KM, Taft DH, Kottyan LC, et al. X chromosome dose and sex bias in autoimmune diseases: increased prevalence of 47,XXX in systemic lupus erythematosus and Sjögren’s syndrome. Arthritis Rheumatol. 2016;68(5):1290–300.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Cooney CM, Bruner GR, Aberle T, Namjou-Khales B, Myers LK, Feo L, et al. 46,X,del(X)(q13) Turner’s syndrome women with systemic lupus erythematosus in a pedigree multiplex for SLE. Genes Immun. 2009;10(5):478–81.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Zhang Y, Zhang J, Yang J, Wang Y, Zhang L, Zuo X, et al. Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus. Hum Mol Genet. 2015;24(1):274–84.PubMedCrossRefGoogle Scholar
  109. 109.
    Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, et al. Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci. 2010;107(36):15838–43.PubMedCrossRefGoogle Scholar
  110. 110.
    Zhu Z, Liang Z, Liany H, Yang C, Wen L, Lin Z, et al. Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus. Arthritis Res Ther. 2015;17(1):349.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Jacob CO, Zhu J, Armstrong DL, Yan M, Han J, Zhou XJ, et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci. 2009;106(15):6256–61.PubMedCrossRefGoogle Scholar
  112. 112.
    Castel SE, Cervera A, Mohammadi P, Aguet F, Reverter F, Wolman A, et al. Modified penetrance of coding variants by cis-regulatory variation shapes human traits. bioRxiv. 2018;190397.Google Scholar
  113. 113.
    Demirkaya E, Zhou Q, Smith CK, Ombrello MJ, Deuitch N, Tsai WL, et al. Brief report: deficiency of complement 1r subcomponent in early-onset systemic lupus erythematosus: the role of disease-modifying alleles in a monogenic disease. Arthritis Rheumatol. 2017;69(9):1832–9.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Medical and Molecular GeneticsKing’s College LondonLondonUK
  2. 2.Department of Medical and Molecular GeneticsKing’s College London, Guy’s HospitalLondonUK

Personalised recommendations