We are currently in an exciting time when our understanding of genetic underpinnings of inflammatory bowel disease (IBD) has undergone a revolution, based in large part on novel genotyping and sequencing technologies. With >160 susceptible loci identified for IBD, the goal is now to understand at a fundamental level the function of these susceptibility alleles. Determining the clinical relevance of how these susceptible genes shape the development of IBD is also a high priority. The main challenge is to understand how the environment and microbiome play a role in triggering disease in genetically susceptible individuals, as the interactions may be complex. To advance the field, novel in vitro and mouse models that are designed to interrogate complex genetics and functionally test hypotheses are needed. Ultimately, the goal of genetics studies will be to translate genetics to patients with IBD and improve their care.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Baumgart DC, Sandborn WJ. 1.  2012. Crohn's disease. Lancet 380:1590–605 [Google Scholar]
  2. Ordas I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. 2.  2012. Ulcerative colitis. Lancet 380:1606–19 [Google Scholar]
  3. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP. 3.  et al. 2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–24 [Google Scholar]
  4. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M. 4.  et al. 2011. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43:246–52 [Google Scholar]
  5. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y. 5.  et al. 2011. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat. Genet. 43:1066–73 [Google Scholar]
  6. Ellinghaus D, Zhang H, Zeissig S, Lipinski S, Till A. 6.  et al. 2013. Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies. Gastroenterology 145:339–47 [Google Scholar]
  7. Christodoulou K, Wiskin AE, Gibson J, Tapper W, Willis C. 7.  et al. 2013. Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut 62:977–84 [Google Scholar]
  8. Khor B, Gardet A, Xavier RJ. 8.  2011. Genetics and pathogenesis of inflammatory bowel disease. Nature 474:307–17 [Google Scholar]
  9. Graham DB, Xavier RJ. 9.  2013. From genetics of inflammatory bowel disease towards mechanistic insights. Trends Immunol. 34:371–78 [Google Scholar]
  10. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J. 10.  et al. 2008. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9:356–69 [Google Scholar]
  11. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA. 11.  et al. 2009. Finding the missing heritability of complex diseases. Nature 461:747–53 [Google Scholar]
  12. Cho JH, Brant SR. 12.  2011. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 140:1704–12 [Google Scholar]
  13. Lee S, Abecasis GR, Boehnke M, Lin X. 13.  2014. Rare-variant association analysis: study designs and statistical tests. Am. J. Hum. Genet. 95:5–23 [Google Scholar]
  14. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS. 14.  et al. 2006. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–63 [Google Scholar]
  15. Orange JS, Glessner JT, Resnick E, Sullivan KE, Lucas M. 15.  et al. 2011. Genome-wide association identifies diverse causes of common variable immunodeficiency. J. Allergy Clin. Immunol. 127:1360–67.e6 [Google Scholar]
  16. Stray-Pedersen A, Backe PH, Sorte HS, Morkrid L, Chokshi NY. 16.  et al. 2014. PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia. Am. J. Hum. Genet. 95:96–107 [Google Scholar]
  17. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J. 17.  et al. 2014. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147:990–1007.e3 [Google Scholar]
  18. Muise AM, Walters T, Xu W, Shen-Tu G, Guo CH. 18.  et al. 2011. Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis. Gastroenterology 141:633–41 [Google Scholar]
  19. Muise AM, Xu W, Guo CH, Walters TD, Wolters VM. 19.  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 61:1028–35 [Google Scholar]
  20. Dhillon SS, Fattouh R, Elkadri A, Xu W, Murchie R. 20.  et al. 2014. Variants in nicotinamide adenine dinucleotide phosphate oxidase complex components determine susceptibility to very early onset inflammatory bowel disease. Gastroenterology 147:680–89.e2 [Google Scholar]
  21. Leoni G, Alam A, Neumann PA, Lambeth JD, Cheng G. 21.  et al. 2013. Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair. J. Clin. Investig. 123:443–54 [Google Scholar]
  22. Leoni G, Neumann PA, Kamaly N, Quiros M, Nishio H. 22.  et al. 2015. Annexin A1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair. J. Clin. Investig. 125:31215–27 [Google Scholar]
  23. Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H. 23.  et al. 2014. Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146:1028–39 [Google Scholar]
  24. Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N. 24.  et al. 2014. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J. Clin. Investig. 124:328–37 [Google Scholar]
  25. Zeissig Y, Petersen BS, Milutinovic S, Bosse E, Mayr G. 25.  et al. 2015. XIAP variants in male Crohn's disease. Gut 64:66–76 [Google Scholar]
  26. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA. 26.  et al. 2009. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361:2033–45 [Google Scholar]
  27. Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O. 27.  et al. 2012. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143:347–55 [Google Scholar]
  28. Olszak T, Neves JF, Dowds CM, Baker K, Glickman J. 28.  et al. 2014. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 509:497–502 [Google Scholar]
  29. Shouval DS, Biswas A, Goettel JA, McCann K, Conaway E. 29.  et al. 2014. Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. Immunity 40:706–19 [Google Scholar]
  30. Zigmond E, Bernshtein B, Friedlander G, Walker CR, Yona S. 30.  et al. 2014. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40:720–33 [Google Scholar]
  31. MacDuff DA, Reese TA, Kimmey JM, Weiss LA, Song C. 31.  et al. 2015. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection. eLife 4:e04494 [Google Scholar]
  32. Carmi S, Hui KY, Kochav E, Liu X, Xue J. 32.  et al. 2014. Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. Nat. Commun. 5:4835 [Google Scholar]
  33. Kenny EE, Pe'er I, Karban A, Ozelius L, Mitchell AA. 33.  et al. 2012. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLOS Genet. 8:e1002559 [Google Scholar]
  34. Zhang W, Hui KY, Gusev A, Warner N, Ng SM. 34.  et al. 2013. Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3. Genes Immun. 14:310–16 [Google Scholar]
  35. Yang SK, Hong M, Zhao W, Jung Y, Baek J. 35.  et al. 2014. Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 63:80–87 [Google Scholar]
  36. Yamazaki K, Umeno J, Takahashi A, Hirano A, Johnson TA. 36.  et al. 2013. A genome-wide association study identifies 2 susceptibility loci for Crohn's disease in a Japanese population. Gastroenterology 144:781–88 [Google Scholar]
  37. Hirano A, Yamazaki K, Umeno J, Ashikawa K, Aoki M. 37.  et al. 2013. Association study of 71 European Crohn's disease susceptibility loci in a Japanese population. Inflamm. Bowel Dis. 19:526–33 [Google Scholar]
  38. Hong SN, Park C, Park SJ, Lee CK, Ye BD. 38.  et al. 2015. Deep resequencing of 131 Crohn's disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants. Gut 65788–96 [Google Scholar]
  39. Yang SK, Hong M, Zhao W, Jung Y, Tayebi N. 39.  et al. 2013. Genome-wide association study of ulcerative colitis in Koreans suggests extensive overlapping of genetic susceptibility with Caucasians. Inflamm. Bowel Dis. 19:954–66 [Google Scholar]
  40. Ananthakrishnan AN, Huang H, Nguyen DD, Sauk J, Yajnik V, Xavier RJ. 40.  2014. Differential effect of genetic burden on disease phenotypes in Crohn's disease and ulcerative colitis: analysis of a North American cohort. Am. J. Gastroenterol. 109:395–400 [Google Scholar]
  41. Polychronakos C, Li Q. 41.  2011. Understanding type 1 diabetes through genetics: advances and prospects. Nat. Rev. Genet. 12:781–92 [Google Scholar]
  42. Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ. 42.  et al. 2014. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337–43 [Google Scholar]
  43. Parkes M, Cortes A, van Heel DA, Brown MA. 43.  2013. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14:661–73 [Google Scholar]
  44. Yang SK, Hong M, Choi H, Zhao W, Jung Y. 44.  et al. 2014. Immunochip analysis identification of 6 additional susceptibility loci for Crohn's disease in Koreans. Inflamm. Bowel Dis. 21:1–7 [Google Scholar]
  45. Cortes A, Brown MA. 45.  2011. Promise and pitfalls of the Immunochip. Arthritis Res. Ther. 13:101 [Google Scholar]
  46. Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V. 46.  et al. 2011. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43:1193–201 [Google Scholar]
  47. Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L. 47.  et al. 2015. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat. Genet. 47:172–79 [Google Scholar]
  48. Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC. 48.  et al. 2015. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520:558–62 [Google Scholar]
  49. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V. 49.  et al. 2013. Super-enhancers in the control of cell identity and disease. Cell 155:934–47 [Google Scholar]
  50. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J. 50.  et al. 2001. Tuberculosis associated with infliximab, a tumor necrosis factor α–neutralizing agent. N. Engl. J. Med. 345:1098–104 [Google Scholar]
  51. Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J. 51.  et al. 2012. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N. Engl. J. Med. 367:1519–28 [Google Scholar]
  52. Sokol H, Conway KL, Zhang M, Choi M, Morin B. 52.  et al. 2013. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 145:591–601.e3 [Google Scholar]
  53. Vang T, Congia M, Macis MD, Musumeci L, Orru V. 53.  et al. 2005. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat. Genet. 37:1317–19 [Google Scholar]
  54. Diaz-Gallo LM, Espino-Paisan L, Fransen K, Gomez-Garcia M, van Sommeren S. 54.  et al. 2011. Differential association of two PTPN22 coding variants with Crohn's disease and ulcerative colitis. Inflamm. Bowel Dis. 17:2287–94 [Google Scholar]
  55. Rhee I, Veillette A. 55.  2012. Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nat. Immunol. 13:439–47 [Google Scholar]
  56. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. 56.  2014. NOD proteins: regulators of inflammation in health and disease. Nat. Rev. Immunol. 14:9–23 [Google Scholar]
  57. Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M. 57.  2009. Mapping complex disease traits with global gene expression. Nat. Rev. Genet. 10:184–94 [Google Scholar]
  58. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG. 58.  et al. 2004. Genetic analysis of genome-wide variation in human gene expression. Nature 430:743–47 [Google Scholar]
  59. Dixon AL, Liang L, Moffatt MF, Chen W, Heath S. 59.  et al. 2007. A genome-wide association study of global gene expression. Nat. Genet. 39:1202–7 [Google Scholar]
  60. Fairfax BP, Humburg P, Makino S, Naranbhai V, Wong D. 60.  et al. 2014. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343:1246949 [Google Scholar]
  61. Wang MH, Fiocchi C, Zhu X, Ripke S, Kamboh MI. 61.  et al. 2014. Gene-gene and gene-environment interactions in ulcerative colitis. Hum. Genet. 133:547–58 [Google Scholar]
  62. Wagner J, Sim WH, Ellis JA, Ong EK, Catto-Smith AG. 62.  et al. 2010. Interaction of Crohn's disease susceptibility genes in an Australian paediatric cohort. PLOS ONE 5:e15376 [Google Scholar]
  63. Hedl M, Lahiri A, Ning K, Cho JH, Abraham C. 63.  2014. Pattern recognition receptor signaling in human dendritic cells is enhanced by ICOS ligand and modulated by the Crohn's disease ICOSLG risk allele. Immunity 40:734–46 [Google Scholar]
  64. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Bock J. 64.  et al. 2013. Paneth cells as a site of origin for intestinal inflammation. Nature 503:272–76 [Google Scholar]
  65. Rogler G, Vavricka S. 65.  2014. Exposome in IBD: recent insights in environmental factors that influence the onset and course of IBD. Inflamm. Bowel Dis. 21:400–8 [Google Scholar]
  66. Ng SC, Bernstein CN, Vatn MH, Lakatos PL, Loftus EV Jr. 66.  et al. 2013. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut 62:630–49 [Google Scholar]
  67. Bloom SM, Bijanki VN, Nava GM, Sun L, Malvin NP. 67.  et al. 2011. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9:390–403 [Google Scholar]
  68. Ng SC, Tang W, Leong RW, Chen M, Ko Y. 68.  et al. 2014. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut 64:1063–71 [Google Scholar]
  69. Ananthakrishnan AN, Nguyen DD, Sauk J, Yajnik V, Xavier RJ. 69.  2014. Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases. Inflamm. Bowel Dis. 20:783–89 [Google Scholar]
  70. Verschuere S, De Smet R, Allais L, Cuvelier CA. 70.  2012. The effect of smoking on intestinal inflammation: What can be learned from animal models?. J. Crohn's Colitis 6:1–12 [Google Scholar]
  71. Ueno A, Jijon H, Traves S, Chan R, Ford K. 71.  et al. 2014. Opposing effects of smoking in ulcerative colitis and Crohn's disease may be explained by differential effects on dendritic cells. Inflamm. Bowel Dis. 20:800–10 [Google Scholar]
  72. Lee D, Albenberg L, Compher C, Baldassano R, Piccoli D. 72.  et al. 2015. Diet in the pathogenesis and treatment of inflammatory bowel diseases. Gastroenterology 148:1087–106 [Google Scholar]
  73. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH. 73.  et al. 2015. Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197–206 [Google Scholar]
  74. Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE. 74.  et al. 2015. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518:187–96 [Google Scholar]
  75. Chassaing B, Koren O, Goodrich JK, Poole AC, Srinivasan S. 75.  et al. 2015. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature 519:92–96 [Google Scholar]
  76. Martinez-Medina M, Denizot J, Dreux N, Robin F, Billard E. 76.  et al. 2014. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut 63:116–24 [Google Scholar]
  77. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H. 77.  et al. 2012. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10/− mice. Nature 487:104–8 [Google Scholar]
  78. Greenblum S, Turnbaugh PJ, Borenstein E. 78.  2012. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. PNAS 109:594–99 [Google Scholar]
  79. Hunter DJ. 79.  2005. Gene-environment interactions in human diseases. Nat. Rev. Genet. 6:287–98 [Google Scholar]
  80. Khoury MJ, Adams MJ Jr, Flanders WD. 80.  1988. An epidemiologic approach to ecogenetics. Am. J. Hum. Genet. 42:89–95 [Google Scholar]
  81. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A. 81.  et al. 2013. The Oslo definitions for coeliac disease and related terms. Gut 62:43–52 [Google Scholar]
  82. Khoury MJ, Flanders WD. 82.  1996. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls. ! Am. J. Epidemiol. 144:207–13 [Google Scholar]
  83. Smith PG, Day NE. 83.  1984. The design of case-control studies: the influence of confounding and interaction effects. Int. J. Epidemiol. 13:356–65 [Google Scholar]
  84. Belkaid Y, Hand TW. 84.  2014. Role of the microbiota in immunity and inflammation. Cell 157:121–41 [Google Scholar]
  85. Goodrich JK, Di Rienzi SC, Poole AC, Koren O, Walters WA. 85.  et al. 2014. Conducting a microbiome study. Cell 158:250–62 [Google Scholar]
  86. Kostic AD, Xavier RJ, Gevers D. 86.  2014. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146:1489–99 [Google Scholar]
  87. Knights D, Lassen KG, Xavier RJ. 87.  2013. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 62:1505–10 [Google Scholar]
  88. Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M. 88.  et al. 2010. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139:1844–54.e1 [Google Scholar]
  89. Joossens M, Huys G, Cnockaert M, De Preter V, Verbeke K. 89.  et al. 2011. Dysbiosis of the faecal microbiota in patients with Crohn's disease and their unaffected relatives. Gut 60:631–37 [Google Scholar]
  90. Gevers D, Kugathasan S, Denson LA, Vazquez-Baeza Y, Van Treuren W. 90.  et al. 2014. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15:382–92 [Google Scholar]
  91. Sadaghian Sadabad M, Regeling A, de Goffau MC, Blokzijl T, Weersma RK. 91.  et al. 2015. The ATG16L1-T300A allele impairs clearance of pathosymbionts in the inflamed ileal mucosa of Crohn's disease patients. Gut 64:1546–52 [Google Scholar]
  92. Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O. 92.  et al. 2014. Human genetics shape the gut microbiome. Cell 159:789–99 [Google Scholar]
  93. Machiels K, Joossens M, Sabino J, De Preter V, Arijs I. 93.  et al. 2014. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63:1275–83 [Google Scholar]
  94. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA. 94.  et al. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–73 [Google Scholar]
  95. Virgin HW, Todd JA. 95.  2011. Metagenomics and personalized medicine. Cell 147:44–56 [Google Scholar]
  96. Olszak T, An D, Zeissig S, Vera MP, Richter J. 96.  et al. 2012. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336:489–93 [Google Scholar]
  97. Moon C, Baldridge MT, Wallace MA, Burnham CA, Virgin HW, Stappenbeck TS. 97.  2015. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature 521:90–93 [Google Scholar]
  98. Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY. 98.  et al. 2015. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160:447–60 [Google Scholar]
  99. Palm NW, de Zoete MR, Cullen TW, Barry NA, Stefanowski J. 99.  et al. 2014. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158:1000–10 [Google Scholar]
  100. Lassen KG, Kuballa P, Conway KL, Patel KK, Becker CE. 100.  et al. 2014. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. PNAS 111:7741–46 [Google Scholar]
  101. Murthy A, Li Y, Peng I, Reichelt M, Katakam AK. 101.  et al. 2014. A Crohn's disease variant in Atg16l1 enhances its degradation by caspase 3. Nature 506:456–62 [Google Scholar]
  102. Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC. 102.  et al. 2010. Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell 141:1135–45 [Google Scholar]
  103. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J. 103.  et al. 2008. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456:259–63 [Google Scholar]
  104. VanDussen KL, Liu TC, Li D, Towfic F, Modiano N. 104.  et al. 2014. Genetic variants synthesize to produce Paneth cell phenotypes that define subtypes of Crohn's disease. Gastroenterology 146:200–9 [Google Scholar]
  105. Marchiando AM, Ramanan D, Ding Y, Gomez LE, Hubbard-Lucey VM. 105.  et al. 2013. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 14:216–24 [Google Scholar]
  106. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA. 106.  et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–57 [Google Scholar]
  107. Conway KL, Kuballa P, Song JH, Patel KK, Castoreno AB. 107.  et al. 2013. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology 145:1347–57 [Google Scholar]
  108. Pelletier S, Gingras S, Green DR. 108.  2015. Mouse genome engineering via CRISPR-Cas9 for study of immune function. Immunity 42:18–27 [Google Scholar]
  109. Kim SC, Tonkonogy SL, Albright CA, Tsang J, Balish EJ. 109.  et al. 2005. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology 128:891–906 [Google Scholar]
  110. Liu B, Tonkonogy SL, Sartor RB. 110.  2011. Antigen-presenting cell production of IL-10 inhibits T-helper 1 and 17 cell responses and suppresses colitis in mice. Gastroenterology 141:653–62, 662.e1–4 [Google Scholar]
  111. Im E, Jung J, Pothoulakis C, Rhee SH. 111.  2014. Disruption of Pten speeds onset and increases severity of spontaneous colitis in Il10−/− mice. Gastroenterology 147:667–79.e10 [Google Scholar]
  112. VanDussen KL, Marinshaw JM, Shaikh N, Miyoshi H, Moon C. 112.  et al. 2015. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 64:911–20 [Google Scholar]
  113. van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F. 113.  et al. 2015. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161:933–45 [Google Scholar]
  114. Plevy S, Silverberg MS, Lockton S, Stockfisch T, Croner L. 114.  et al. 2013. Combined serological, genetic, and inflammatory markers differentiate non-IBD, Crohn's disease, and ulcerative colitis patients. Inflamm. Bowel Dis. 19:1139–48 [Google Scholar]
  115. van Schaik FD, Oldenburg B, Hart AR, Siersema PD, Lindgren S. 115.  et al. 2013. Serological markers predict inflammatory bowel disease years before the diagnosis. Gut 62:683–88 [Google Scholar]
  116. Cleynen I, Gonzalez JR, Figueroa C, Franke A, McGovern D. 116.  et al. 2013. Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project. Gut 62:1556–65 [Google Scholar]
  117. Alonso A, Domenech E, Julia A, Panes J, Garcia-Sanchez V. 117.  et al. 2015. Identification of risk loci for Crohn's disease phenotypes using a genome-wide association study. Gastroenterology 148:794–805 [Google Scholar]
  118. Haritunians T, Taylor KD, Targan SR, Dubinsky M, Ippoliti A. 118.  et al. 2010. Genetic predictors of medically refractory ulcerative colitis. Inflamm. Bowel Dis. 16:1830–40 [Google Scholar]
  119. Ryan JD, Silverberg MS, Xu W, Graff LA, Targownik LE. 119.  et al. 2013. Predicting complicated Crohn's disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population-based cohort. Aliment. Pharmacol. Ther. 38:274–83 [Google Scholar]
  120. Yang SK, Hong M, Baek J, Choi H, Zhao W. 120.  et al. 2014. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat. Genet. 46:1017–20 [Google Scholar]
  121. Stessman HA, Bernier R, Eichler EE. 121.  2014. A genotype-first approach to defining the subtypes of a complex disease. Cell 156:872–77 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error