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Sequencing and Mapping IBD Genes to Individual Causative Variants and Their Clinical Relevance

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Molecular Genetics of Inflammatory Bowel Disease

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Abstract

Traditionally, IBD has been regarded as a polygenic disorder (Uhlig et al, Gastroenterology 147:990–1007.e3, 2014). Genetic association studies (Liu et al, Nat Genet 47:979–986, 2015; Jostins et al, Nature 491:119–124, 2012; Franke et al, Nat Genet 42:1118–1125, 2010; Anderson et al, Nat Genet 43:246–252, 2011) have identified over 200 IBD-associated genetic loci explaining an estimated 23–35% of genetic risk for CD (Franke et al, Nat Genet 42:1118–1125, 2010) and 17–25% for UC (Anderson et al, Nat Genet 43:246–252, 2011). In addition to the polygenicity, next-generation sequencing has allowed for the discovery of Mendelian disease-associated IBD, in the forms of VEOIBD and monogenic IBD (Uhlig, Muise, Trends Genet 33:629–641, 2017). These recent advances in genomic technologies enabled us to identify the IBD causal variants across both genetic architectures. In this chapter, we discuss the approaches and the knowledge gained through studying the IBD causal variants.

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Abbreviations

AF:

Allele frequency

ARPC:

Actin-related protein complex

CD:

Crohn’s disease

CGD:

Chronic granulomatous disease

CMPI:

Cow’s milk protein intolerance

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

DUOX:

Dual oxidase

GI:

Gastrointestinal

GWAS:

Genome-wide association studies

HLH:

Hemophagocytic lymphohistiocytosis

IBD:

Inflammatory bowel disease

IBDU:

IBD undetermined

IPEX:

Immunodysregulation, polyendocrinopathy, enteropathy X-linked

LD:

Linkage disequilibrium

LRBA:

Lipopolysaccharide-responsive and beige-like anchor

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor kappa B

NLRC4:

NOD-like receptors caspase containing 4

NO:

Nitric oxide

NOD2:

Nucleotide-binding oligomerization domain-containing protein 2

NOS:

Nitric oxide synthase

NOX:

NADPH oxidase

OR:

Odds ratio

PID:

Primary immunodeficiency

QC:

Quality control

ROS:

Reactive oxygen species

TRIM22:

Tripartite motif-containing 22

TTC7A:

Tetratricopeptide repeat domain 7

UC:

Ulcerative colitis

VEOIBD :

Very early onset inflammatory bowel disease

WES :

Whole-exome sequencing

WGS:

Whole-genome sequencing

XIAP:

X-linked inhibitor of apoptosis

References

  1. Uhlig HH, Schwerd T, Koletzko S et al (2014) The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147:990–1007.e3

    Article  PubMed  Google Scholar 

  2. Liu JZ, van Sommeren S, Huang H et al (2015) Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 47:979–986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jostins L, Ripke S, Weersma RK et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Franke A, McGovern DPB, Barrett JC et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Anderson CA, Boucher G, Lees CW et al (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43:246–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Uhlig HH, Muise AM (2017) Clinical genomics in inflammatory bowel disease. Trends Genet 33:629–641

    Article  CAS  PubMed  Google Scholar 

  7. Uhlig HH, Muise AM (2017) Clinical genomics in inflammatory bowel disease. Trends Genet: TIG 33:629–641

    Article  CAS  PubMed  Google Scholar 

  8. Crowley E, Muise A (2018) Inflammatory bowel disease: what very early onset disease teaches us. Gastroenterol Clin N Am 47:755–772

    Article  Google Scholar 

  9. Ruemmele FM, El Khoury MG, Talbotec C et al (2006) Characteristics of inflammatory bowel disease with onset during the first year of life. J Pediatr Gastroenterol Nutr 43:603–609

    Article  PubMed  Google Scholar 

  10. Paul T, Birnbaum A, Pal DK et al (2006) Distinct phenotype of early childhood inflammatory bowel disease. J Clin Gastroenterol 40:583–586

    Article  PubMed  Google Scholar 

  11. Griffiths AM (2004) Specificities of inflammatory bowel disease in childhood. Best Pract Res Clin Gastroenterol 18:509–523

    Article  PubMed  Google Scholar 

  12. Heyman MB, Kirschner BS, Gold BD et al (2005) Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 146:35–40

    Article  PubMed  Google Scholar 

  13. Muise AM, Xu W, Guo CH et al (2012) NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2. Gut 61:1028–1035

    Article  CAS  PubMed  Google Scholar 

  14. Dhillon SS, Fattouh R, Elkadri A et al (2014) Variants in nicotinamide adenine dinucleotide phosphate oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology 147:680–689 e2

    Article  CAS  PubMed  Google Scholar 

  15. Dhillon SS, Mastropaolo LA, Murchie R et al (2014) Higher activity of the inducible nitric oxide synthase contributes to very early onset inflammatory bowel disease. Clin Transl Gastroenterol 5:e46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hayes P, Dhillon S, O’Neill K et al (2015) Defects in NADPH oxidase genes and in very early onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 1:489–502

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ruel J, Ruane D, Mehandru S, Gower-Rousseau C, Colombel JF (2014) IBD across the age spectrum: is it the same disease? Nat Rev Gastroenterol Hepatol 11:88–98

    Article  PubMed  Google Scholar 

  18. Benchimol EI, Mack DR, Nguyen GC et al (2014) Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology 147:803–813 e7; quiz e14–5

    Article  PubMed  Google Scholar 

  19. Kotlarz D, Marquardt B, Baroy T et al (2018) Human TGF-beta1 deficiency causes severe inflammatory bowel disease and encephalopathy. Nat Genet 50:344–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Parlato M, Charbit-Henrion F, Pan J et al (2018) Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis. EMBO Mol Med (2018)10:e8483

    Google Scholar 

  21. Leung G, Muise AM (2018) Monogenic intestinal epithelium defects and the development of inflammatory bowel disease. Physiology (Bethesda) 33:360–369

    CAS  Google Scholar 

  22. Samuels ME, Majewski J, Alirezaie N et al (2013) Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia. J Med Genet 50:324–329

    Article  CAS  PubMed  Google Scholar 

  23. Chen R, Giliani S, Lanzi G et al (2013) Whole exome sequencing identifies TTC7A mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol 132:656–664 e17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Avitzur Y, Guo C, Mastropaolo LA et al (2014) Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146:1028–1039

    Article  CAS  PubMed  Google Scholar 

  25. Agarwal NS, Northrop L, Anyane-Yeboa K, Aggarwal VS, Nagy PL, Demirdag YY (2014) Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency. J Clin Immunol 34:607–610

    Article  PubMed  Google Scholar 

  26. Bigorgne AE, Farin HF, Lemoine R et al (2014) TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest 124:328–337

    Article  CAS  PubMed  Google Scholar 

  27. Lemoine R, Pachlopnik-Schmid J, Farin HF et al (2014) Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency. J Allergy Clin Immunol 134:1354–1364 e6

    Article  CAS  PubMed  Google Scholar 

  28. Guana R, Garofano S, Teruzzi E et al (2014) The complex surgical management of the first case of severe combined immunodeficiency and multiple intestinal atresias surviving after the fourth year of life. Pediatr Gastroenterol Hepatol Nutr 17:257–262

    Article  PubMed  PubMed Central  Google Scholar 

  29. Woutsas S, Aytekin C, Salzer E et al (2015) Hypomorphic mutation in TTC7A causes combined immunodeficiency with mild structural intestinal defects. Blood 125:1674–1676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang W, Lee PP, Thong MK et al (2015) Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency. Clin Genet 88:542–549

    Article  CAS  PubMed  Google Scholar 

  31. Kammermeier J, Lucchini G, Pai SY et al (2016) Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up. Blood 128:1306–1308

    Article  CAS  PubMed  Google Scholar 

  32. Lien R, Lin YF, Lai MW et al (2017) Novel mutations of the tetratricopeptide repeat domain 7A gene and phenotype/genotype comparison. Front Immunol 8:1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lawless D, Mistry A, Wood PM et al (2017) Bialellic mutations in tetratricopeptide repeat domain 7A (TTC7A) cause common variable immunodeficiency-like phenotype with enteropathy. J Clin Immunol 37:617–622

    Article  CAS  PubMed  Google Scholar 

  34. Neves JF, Afonso I, Borrego L et al (2018) Missense mutation of TTC7A mimicking tricho-hepato-enteric (SD/THE) syndrome in a patient with very-early onset inflammatory bowel disease. Eur J Med Genet 61:185–188

    Article  PubMed  Google Scholar 

  35. Mandiá N, Perez-Muñuzuri A, Lopez-Suarez O Congenital intestinal atresias with multiple episodes of sepsis. undefined 2018

    Google Scholar 

  36. Fayard J, Collardeau S, Bertrand Y et al (2018) TTC7A mutation must be considered in patients with repeated intestinal atresia associated with early inflammatory bowel disease: two new case reports and a literature review. Arch Pediatr 25:334–339

    Article  Google Scholar 

  37. Fullerton BS, Velazco CS, Hong CR, Carey AN, Jaksic T (2018) High rates of positive severe combined immunodeficiency screening among newborns with severe intestinal failure. JPEN J Parenter Enteral Nutr 42:239–246

    CAS  PubMed  Google Scholar 

  38. Jardine S, Dhingani N, Muise AM (2019) TTC7A: steward of intestinal health. Cell Mol Gastroenterol Hepatol 7:555–570

    Article  PubMed  Google Scholar 

  39. Glocker EO, Kotlarz D, Boztug K et al (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361:2033–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Glocker EO, Frede N, Perro M et al (2010) Infant colitis—it’s in the genes. Lancet 376:1272

    Article  PubMed  Google Scholar 

  41. Kotlarz D, Beier R, Murugan D et al (2012) Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143:347–355

    Article  CAS  PubMed  Google Scholar 

  42. Glocker EO, Kotlarz D, Klein C, Shah N, Grimbacher B (2011) IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci 1246:102–107

    Article  CAS  PubMed  Google Scholar 

  43. Engelhardt KR, Shah N, Faizura-Yeop I et al (2013) Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol 131:825–830 e9

    Article  CAS  PubMed  Google Scholar 

  44. Neven B, Mamessier E, Bruneau J et al (2013) A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency. Blood 122:3713–3722

    Article  CAS  PubMed  Google Scholar 

  45. Shouval DS, Ebens CL, Murchie R et al (2016) Large B-cell lymphoma in an adolescent patient with interleukin-10 receptor deficiency and history of infantile inflammatory bowel disease. J Pediatr Gastroenterol Nutr 63:e15–e17

    Article  PubMed  PubMed Central  Google Scholar 

  46. Marlow GJ, van Gent D, Ferguson LR (2013) Why interleukin-10 supplementation does not work in Crohn’s disease patients. World J Gastroenterol 19:3931–3941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nauseef WM (2008) Biological roles for the NOX family NADPH oxidases. J Biol Chem 283:16961–16965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Heyworth PG, Cross AR, Curnutte JT (2003) Chronic granulomatous disease. Curr Opin Immunol 15:578–584

    Article  CAS  PubMed  Google Scholar 

  49. Marks DJ, Miyagi K, Rahman FZ, Novelli M, Bloom SL, Segal AW (2009) Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn’s disease. Am J Gastroenterol 104:117–124

    Article  CAS  PubMed  Google Scholar 

  50. Schappi MG, Smith VV, Goldblatt D, Lindley KJ, Milla PJ (2001) Colitis in chronic granulomatous disease. Arch Dis Child 84:147–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Werlin SL, Chusid MJ, Caya J, Oechler HW (1982) Colitis in chronic granulomatous disease. Gastroenterology 82:328–331

    Article  CAS  PubMed  Google Scholar 

  52. Bennett CL, Christie J, Ramsdell F et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21

    Article  CAS  PubMed  Google Scholar 

  53. Okou DT, Mondal K, Faubion WA et al (2014) Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 58:561–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rigaud S, Fondaneche MC, Lambert N et al (2006) XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:110–114

    Article  CAS  PubMed  Google Scholar 

  55. Worthey EA, Mayer AN, Syverson GD et al (2011) Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13:255–262

    Article  PubMed  Google Scholar 

  56. Aguilar C, Lenoir C, Lambert N et al (2014) Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J Allergy Clin Immunol 134:1131–1141

    Article  CAS  PubMed  Google Scholar 

  57. Zeissig Y, Petersen BS, Milutinovic S et al (2015) XIAP variants in male Crohn’s disease. Gut 64:66–76

    Article  CAS  PubMed  Google Scholar 

  58. Ashton JJ, Andreoletti G, Coelho T et al (2016) Identification of variants in genes associated with single-gene inflammatory bowel disease by whole-exome sequencing. Inflamm Bowel Dis 22:2317–2327

    Article  PubMed  Google Scholar 

  59. Schubert D, Bode C, Kenefeck R et al (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 20:1410–1416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gamez-Diaz L, August D, Stepensky P et al (2016) The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol 137:223–230

    Article  CAS  PubMed  Google Scholar 

  61. Serwas NK, Kansu A, Santos-Valente E et al (2015) Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel Dis 21:40–47

    Article  PubMed  Google Scholar 

  62. Lo B, Zhang K, Lu W et al (2015) Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349:436–440

    Article  CAS  PubMed  Google Scholar 

  63. van de Geer A, Nieto-Patlan A, Kuhns DB et al (2018) Inherited p40phox deficiency differs from classic chronic granulomatous disease. J Clin Invest 28:3957–3975

    Article  Google Scholar 

  64. Lehle AS, Farin HF, Marquardt B et al (2019) Intestinal inflammation and dysregulated immunity in patients with inherited caspase-8 deficiency. Gastroenterology 156:275–278

    Article  PubMed  Google Scholar 

  65. Cuchet-Lourenco D, Eletto D, Wu C et al (2018) Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science (New York, NY) 361:810–813

    Article  CAS  Google Scholar 

  66. Li Y, Fuhrer M, Bahrami E et al (2019) Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc Natl Acad Sci U S A 116:970–975

    Article  CAS  PubMed  Google Scholar 

  67. Kammermeier J, Dziubak R, Pescarin M et al (2017) Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years. J Crohns Colitis 11:60–69

    Article  PubMed  Google Scholar 

  68. Kammermeier J, Drury S, James CT et al (2014) Targeted gene panel sequencing in children with very early onset inflammatory bowel disease--evaluation and prospective analysis. J Med Genet 51:748–755

    Article  CAS  PubMed  Google Scholar 

  69. Ostrowski J, Paziewska A, Lazowska I et al (2016) Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population. Sci Rep 6:39831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Murugan D, Albert MH, Langemeier J et al (2014) Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation. J Clin Immunol 34:331–339

    Article  CAS  PubMed  Google Scholar 

  71. Charbit-Henrion F, Jeverica AK, Begue B et al (2017) Deficiency in mucosa-associated lymphoid tissue lymphoma translocation 1: a novel cause of IPEX-Like syndrome. J Pediatr Gastroenterol Nutr 64:378–384

    Article  CAS  PubMed  Google Scholar 

  72. Booth C, Gilmour KC, Veys P et al (2011) X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 117:53–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rohr J, Pannicke U, Doring M et al (2010) Chronic inflammatory bowel disease as key manifestation of atypical ARTEMIS deficiency. J Clin Immunol 30:314–320

    Article  CAS  PubMed  Google Scholar 

  74. Cuvelier GD, Rubin TS, Wall DA, Schroeder ML (2016) Long-term outcomes of hematopoietic stem cell transplantation for ZAP70 deficiency. J Clin Immunol 36:713–724

    Article  CAS  PubMed  Google Scholar 

  75. Ngwube A, Hanson IC, Orange J et al (2018) Outcomes after allogeneic transplant in patients with Wiskott-Aldrich syndrome. Biol Blood Marrow Transplant 24:537–554

    Article  PubMed  Google Scholar 

  76. Chiriaco M, Salfa I, Di Matteo G, Rossi P, Finocchi A (2016) Chronic granulomatous disease: clinical, molecular, and therapeutic aspects. Pediatr Allergy Immunol 27:242–253

    Article  PubMed  Google Scholar 

  77. Kato K, Kojima Y, Kobayashi C et al (2011) Successful allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease with inflammatory complications and severe infection. Int J Hematol 94:479–482

    Article  PubMed  Google Scholar 

  78. Freudenberg F, Wintergerst U, Roesen-Wolff A et al (2010) Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease. J Allergy Clin Immunol 125:943–946 e1

    Article  CAS  PubMed  Google Scholar 

  79. Uzel G, Orange JS, Poliak N, Marciano BE, Heller T, Holland SM (2010) Complications of tumor necrosis factor-alpha blockade in chronic granulomatous disease-related colitis. Clin Infect Dis 51:1429–1434

    Article  PubMed  PubMed Central  Google Scholar 

  80. Canna SW, Girard C, Malle L et al (2017) Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol 139:1698–1701

    Article  CAS  PubMed  Google Scholar 

  81. Weinacht KG, Charbonnier LM, Alroqi F et al (2017) Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol 139:1629–1640 e2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schaid DJ, Chen W, Larson NB (2018) From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet 19:491–504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Goode EL (2011) Linkage disequilibrium. In: Schwab M (ed) Encyclopedia of cancer. Springer Berlin Heidelberg, Berlin, Heidelberg, pp 2043–2048

    Chapter  Google Scholar 

  84. Farh KK-H, Marson A, Zhu J et al (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337–343

    Article  CAS  PubMed  Google Scholar 

  85. Huang H, Fang M, Jostins L et al (2017) Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547:173–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mahajan A, Taliun D, Thurner M et al (2018) Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet 50:1505–1513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Davey JW, Hohenlohe PA, Etter PD, Boone JQ, Catchen JM, Blaxter ML (2011) Genome-wide genetic marker discovery and genotyping using next-generation sequencing. Nat Rev Genet 12:499

    Article  CAS  PubMed  Google Scholar 

  88. Marchini J, Howie B (2010) Genotype imputation for genome-wide association studies. Nat Rev Genet 11:499–511

    Article  CAS  PubMed  Google Scholar 

  89. Jostins L (2012) Using next-generation genomic datasets in disease association. The University of Cambridge

    Google Scholar 

  90. Lam M, Chen C-Y, Li Z et al (2018) Comparative genetic architectures of schizophrenia in East Asian and European populations. bioRxiv:445874

    Google Scholar 

  91. Kichaev G, Pasaniuc B (2015) Leveraging functional-annotation data in trans-ethnic fine-mapping studies. Am J Hum Genet 97:260–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hormozdiari F, van de Bunt M, Segrè Ayellet V et al (2016) Colocalization of GWAS and eQTL signals detects target genes. Am J Hum Genet 99:1245–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Caruso R, Warner N, Inohara N, Nunez G (2014) NOD1 and NOD2: signaling, host defense, and inflammatory disease. Immunity 41:898–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ogura Y, Bonen DK, Inohara N et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603

    Article  CAS  PubMed  Google Scholar 

  95. Hugot JP, Chamaillard M, Zouali H et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603

    Article  CAS  PubMed  Google Scholar 

  96. Zhong X, Chen B, Yang L, Yang Z (2018) Molecular and physiological roles of the adaptor protein CARD9 in immunity. Cell Death Dis 9:52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cao Z, Conway KL, Heath RJ et al (2015) Ubiquitin ligase TRIM62 regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. Immunity 43:715–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rivas MA, Beaudoin M, Gardet A et al (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Leshchiner ES, Rush JS, Durney MA et al (2017) Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease. Proc Natl Acad Sci U S A 114:11392–11397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Buonocore S, Ahern PP, Uhlig HH et al (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464:1371–1375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Duerr RH, Taylor KD, Brant SR et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sivanesan D, Beauchamp C, Quinou C et al (2016) IL23R (interleukin 23 receptor) variants protective against inflammatory bowel diseases (IBD) display loss of function due to impaired protein stability and intracellular trafficking. J Biol Chem 291:8673–8685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Takeuchi O, Akira S (2008) MDA5/RIG-I and virus recognition. Curr Opin Immunol 20:17–22

    Article  CAS  PubMed  Google Scholar 

  104. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324:387–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chistiakov DA, Voronova NV, Savost’Anov KV, Turakulov RI (2010) Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-beta production in peripheral blood mononuclear cells of type 1 diabetes patients. Hum Immunol 71:1128–1134

    Article  CAS  PubMed  Google Scholar 

  106. Peisley A, Lin C, Wu B et al (2011) Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc Natl Acad Sci U S A 108:21010–21015

    Article  PubMed  PubMed Central  Google Scholar 

  107. Liao W, Lin JX, Leonard WJ (2013) Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38:13–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Huang J, Ellinghaus D, Franke A, Howie B, Li Y (2012) 1000 Genomes-based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data. Eur J Hum Genet 20:801–805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Orru V, Steri M, Sole G et al (2013) Genetic variants regulating immune cell levels in health and disease. Cell 155:242–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Roberts AB, Russo A, Felici A, Flanders KC (2003) Smad3: a key player in pathogenetic mechanisms dependent on TGF-beta. Ann N Y Acad Sci 995:1–10

    Article  CAS  PubMed  Google Scholar 

  111. Consortium EP (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74

    Article  CAS  Google Scholar 

  112. Nica AC, Montgomery SB, Dimas AS et al (2010) Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet 6:e1000895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lappalainen T, Sammeth M, Friedlander MR et al (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501:506–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rivas MA, Graham D, Sulem P et al (2016) A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun 7:12342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hatzikotoulas K, Gilly A, Zeggini E (2014) Using population isolates in genetic association studies. Brief Funct Genomics 13:371–377

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kenny EE, Pe’er I, Karban A et al (2012) A genome-wide scan of Ashkenazi Jewish Crohn’s disease suggests novel susceptibility loci. PLoS Genet 8:e1002559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Popejoy AB, Fullerton SM (2016) Genomics is failing on diversity. Nature 538:161–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Cell Biology, Research Institute, Hospital for Sick Children, Toronto, ON, Canada

    Aleixo Muise

  2. IMS, and Pediatrics, University of Toronto, Toronto, ON, Canada

    Aleixo Muise

  3. SickKids Inflammatory Bowel Disease Centre, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada

    Aleixo Muise

  4. Massachusetts General Hospital, Boston, MA, USA

    Hailiang Huang

  5. Harvard Medical School, Boston, MA, USA

    Hailiang Huang

  6. Broad Institute of MIT, Harvard, Cambridge, MA, USA

    Hailiang Huang

Authors
  1. Aleixo Muise
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  2. Hailiang Huang
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Correspondence to Hailiang Huang .

Editor information

Editors and Affiliations

  1. Gastroenterology unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden

    Charlotte Hedin

  2. Montreal Heart Institute and Université de Montréal, Montréal, QC, Canada

    John D. Rioux

  3. School of Biological Sciences, Monash University, Clayton, VIC, Australia

    Mauro D'Amato

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Muise, A., Huang, H. (2019). Sequencing and Mapping IBD Genes to Individual Causative Variants and Their Clinical Relevance. In: Hedin, C., Rioux, J., D'Amato, M. (eds) Molecular Genetics of Inflammatory Bowel Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-28703-0_6

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