Abstract
Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene–gene and gene–environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case–Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high-order interactions. Exploratory genotype correlations with UC sub-phenotypes [extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)] were conducted. The combination of 133 UC loci yielded good UC risk predictability [area under the curve (AUC) of 0.86]. A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P = 3.26E−05). Explained UC variance increased from 37 to 42 % after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high-order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene–gene and gene–environment interactions.
Similar content being viewed by others
References
Achkar JP, Klei L, Bakker PIW, Bellone G, Rebert N, Scott R, Lu Y, Regueiro M, Brzezinski A, Kamboh MI, Fiocchi C, Devlin B, Trucco M, Ringquist S, Roeder K, Duerr RH (2012) Amino acid position 11 of HLA-DR[beta]1 is a major determinant of chromosome 6p association with ulcerative colitis. Genes Immun 13:245–252
Aldhous MC, Drummond HE, Anderson N, Baneshi MR, Smith LA, Arnott ID, Satsangi J (2007) Smoking habit and load influence age at diagnosis and disease extent in ulcerative colitis. Am J Gastroenterol 102:589–597
Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A, Wesley E, Parnell K, Zhang H, Drummond H, Nimmo ER, Massey D, Blaszczyk K, Elliott T, Cotterill L, Dallal H, Lobo AJ, Mowat C, Sanderson JD, Jewell DP, Newman WG, Edwards C, Ahmad T, Mansfield JC, Satsangi J, Parkes M, Mathew CG, Donnelly P, Peltonen L, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Craddock N, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, McCarthy MI, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Samani N, Trembath RC, Viswanathan AC, Wood N, Spencer CC, Barrett JC, Bellenguez C, Davison D, Freeman C, Strange A, Donnelly P, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Perez ML, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, Deloukas P, Peltonen L, Mathew CG, Blackwell JM, Brown MA, Corvin A, McCarthy MI, Spencer CC, Attwood AP, Stephens J, Sambrook J, Ouwehand WH, McArdle WL, Ring SM, Strachan DP (2009) Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 41:1330–1334
Berzuini C, Berzuini P, Zhang H, Parkes M (2012) Analysis of interaction for identifying causal mechanisms. In: Berzuini C, Dawid P, Bernardinelli L (eds) Causality: statistical perspectives and applications. Wiley, New York, pp 192–207
Boyko EJ, Koepsell TD, Perera DR, Inui TS (1987) Risk of ulcerative colitis among former and current cigarette smokers. N Engl J Med 316:707–710
Browning BL, Browning SR (2009) A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals, 84 edn. pp 210–223
Damaj MI (2000) The involvement of spinal Ca(2+)/calmodulin-protein kinase II in nicotine-induced antinociception in mice. Eur J Pharmacol 404:103–110
Dambacher J, Beigel F, Zitzmann K, De Toni EN, Goke B, Diepolder HM, Auernhammer CJ, Brand S (2009) The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut 58:1207–1217
Danese S, Fiocchi C (2011) Ulcerative colitis. N Engl J Med 365:1713–1725
Dassopoulos T, Nguyen GC, Bitton A, Bromfield GP, Schumm LP, Wu Y, Elkadri A, Regueiro M, Siemanowski B, Torres EA, Gregory FJ, Kane SV, Harrell LE, Franchimont D, Achkar JP, Griffiths A, Brant SR, Rioux JD, Taylor KD, Duerr RH, Silverberg MS, Cho JH, Steinhart AH (2007) Assessment of reliability and validity of IBD phenotyping within the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium (IBDGC). Inflamm Bowel Dis 13:975–983
Deng GY, Muir A, Maclaren NK, She JX (1995) Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies. Am J Hum Genet 56:528–534
Donnelly RP, Sheikh F, Dickensheets H, Savan R, Young HA, Walter MR (2010) Interleukin-26: an IL-10-related cytokine produced by Th17 cells. Cytokine Growth Factor Rev 21:393–401
Duan MC, Huang Y, Zhong XN, Tang HJ (2012) Th17 cell enhances CD8 T-cell cytotoxicity via IL-21 production in emphysema mice. Mediators Inflamm 2012:898053
Ellinghaus D, Folseraas T, Holm K, Ellinghaus E, Melum E, Balschun T, Laerdahl JK, Shiryaev A, Gotthardt DN, Weismuller TJ, Schramm C, Wittig M, Bergquist A, Bjornsson E, Marschall HU, Vatn M, Teufel A, Rust C, Gieger C, Wichmann HE, Runz H, Sterneck M, Rupp C, Braun F, Weersma RK, Wijmenga C, Ponsioen CY, Mathew CG, Rutgeerts P, Vermeire S, Schrumpf E, Hov JR, Manns MP, Boberg KM, Schreiber S, Franke A, Karlsen TH (2013) Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology. doi:10.1002/hep.25977
Fausa O, Schrumpf E, Elgjo K (1991) Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis 11:31–39
Folseraas T, Melum E, Rausch P, Juran BD, Ellinghaus E, Shiryaev A, Laerdahl JK, Ellinghaus D, Schramm C, Weismuller TJ, Gotthardt DN, Hov JR, Clausen OP, Weersma RK, Janse M, Boberg KM, Bjornsson E, Marschall HU, Cleynen I, Rosenstiel P, Holm K, Teufel A, Rust C, Gieger C, Wichmann HE, Bergquist A, Ryu E, Ponsioen CY, Runz H, Sterneck M, Vermeire S, Beuers U, Wijmenga C, Schrumpf E, Manns MP, Lazaridis KN, Schreiber S, Baines JF, Franke A, Karlsen TH (2012) Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J Hepatol 57:366–375
Frisch M, Pedersen BV, Andersson RE (2009) Appendicitis, mesenteric lymphadenitis, and subsequent risk of ulcerative colitis: cohort studies in Sweden and Denmark. BMJ 338:b716
Gardenbroek TJ, Eshuis EJ, Ponsioen CI, Ubbink DT, D’Haens GR, Bemelman WA (2012) The effect of appendectomy on the course of ulcerative colitis: a systematic review. Colorectal Dis 14:545–553
Hallas J, Gaist D, Sorensen HT (2004) Does appendectomy reduce the risk of ulcerative colitis? Epidemiology 15:173–178
Hasler R, Feng Z, Backdahl L, Spehlmann ME, Franke A, Teschendorff A, Rakyan VK, Down TA, Wilson GA, Feber A, Beck S, Schreiber S, Rosenstiel P (2012) A functional methylome map of ulcerative colitis. Genome Res 22:2130–2137
Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E (2003) Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol 171:538–541
Hoffmann SC, Stanley EM, Darrin CE, Craighead N, DiMercurio BS, Koziol DE, Harlan DM, Kirk AD, Blair PJ (2001) Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation 72:1444–1450
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Buning C, Cohain A, Cichon S, D’Amato M, De JD, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De VM, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH (2012) Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124
Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, van der Helm-van Mil AH, Toes RE, Huizinga TW, Klareskog L, Alfredsson L (2007) Gene-gene and gene–environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 80:867–875
Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, Younkin SG, Saykin AJ, Jun G, Baldwin C, Logue MW, Buros J, Farrer L, Pericak-Vance MA, Haines JL, Sweet RA, Ganguli M, Feingold E, Dekosky ST, Lopez OL, Barmada MM (2012) Genome-wide association study of Alzheimer’s disease. Transl Psychiatry 2:e117
Kiss-Toth E, Bagstaff SM, Sung HY, Jozsa V, Dempsey C, Caunt JC, Oxley KM, Wyllie DH, Polgar T, Harte M, O’neill LA, Qwarnstrom EE, Dower SK (2004) Human tribbles, a protein family controlling mitogen-activated protein kinase cascades. J Biol Chem 279:42703–42708
Li Y, Willer C, Sanna S, Abecasis G (2009) Genotype imputation. Annu Rev Genomics Hum Genet 10:387–406
Li Y, Willer CJ, Ding J, Scheet P, GaR Abecasis (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834
Liu S, Song Y (2010) Building genetic scores to predict risk of complex diseases in humans: is it possible? Diabetes 59:2729–2731
Liu JZ, Hov JR, Folserras T (2013) Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 45:670–675
Mahid SS, Minor KS, Soto RE, Hornung CA, Galandiuk S (2006) Smoking and inflammatory bowel disease: a meta-analysis. Mayo Clin Proc 81:1462–1471
Makowsky R, Pajewski NM, Klimentidis YC, Vazquez AI, Duarte CW, Allison DB, de los Campos G (2011) Beyond missing heritability: prediction of complex traits. PLoS Genet 7:e1002051
Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39:906–913
McGill JM, Williams DM, Hunt CM (1996) Survey of cystic fibrosis transmembrane conductance regulator genotypes in primary sclerosing cholangitis. Dig Dis Sci 41:540–542
Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward DV, Reyes JA, Shah SA, LeLeiko N, Snapper SB, Bousvaros A, Korzenik J, Sands BE, Xavier RJ, Huttenhower C (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13:R79
Ouyang Y, Virasch N, Hao P, Aubrey MT, Mukerjee N, Bierer BE, Freed BM (2000) Suppression of human IL-1beta, IL-2, IFN-gamma, and TNF-alpha production by cigarette smoke extracts. J Allergy Clin Immunol 106:280–287
Quigley EM (2012) Epigenetics: filling in the ‘heritability gap’ and identifying gene–environment interactions in ulcerative colitis. Genome Med 4:72
Riley BE, Xu Y, Zoghbi HY, Orr HT (2004) The effects of the polyglutamine repeat protein ataxin-1 on the UbL-UBA protein A1Up. J Biol Chem 279:42290–42301
Rubino SJ, Geddes K, Girardin SE (2012) Innate IL-17 and IL-22 responses to enteric bacterial pathogens. Trends Immunol 33:112–118
Ruczinski I, Kooperberg C, LeBlanc L (2003) Logic regression. J Comput Graph Stat 12:475–511
Ruczinski I, Kooperberg C, LeBlanc L (2004) Exploring interactions in high-dimensional genomic data: an overview of logic regression, with applications. J Multivar Anal 90:178–195
Satsangi J, Welsh KI, Bunce M, Julier C, Farrant JM, Bell JI, Jewell DP (1996) Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 347:1212–1217
Schwender H, Ruczinski I (2010) Logic regression and its extensions. Adv Genet 72:25–45
Selby WS, Janossy G, Mason DY, Jewell DP (1983) Expression of HLA-DR antigens by colonic epithelium in inflammatory bowel disease. Clin Exp Immunol 53:614–618
Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD (2003) Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 113:286–292
Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Pare P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH (2009) Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 41:216–220
Stokes ME, Davis C, Koch G (2000) Categorical data analysis using the SAS system, second edn. SAS Institute Inc., Philadelphia
Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118:534–544
Szamosi T, Banai J, Lakatos L, Czegledi Z, David G, Zsigmond F, Pandur T, Erdelyi Z, Gemela O, Papp M, Papp J, Lakatos PL (2010) Early azathioprine/biological therapy is associated with decreased risk for first surgery and delays time to surgery but not reoperation in both smokers and nonsmokers with Crohn’s disease, while smoking decreases the risk of colectomy in ulcerative colitis. Eur J Gastroenterol Hepatol 22:872–879
Timmer A (2003) Environmental influences on inflammatory bowel disease manifestations. Lessons from epidemiology. Dig Dis 21:91–104
Toyoda H, Wang SJ, Yang HY, Redford A, Magalong D, Tyan D, McElree CK, Pressman SR, Shanahan F, Targan SR (1993) Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology 104:741–748
Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA 105:20858–20863
Wang MH, Fiocchi C, Zhu X, Duerr RH, Ripke S, Achkar JP (2013) A novel approach to detect cumulative genetic effects and genetic interactions in Crohn’s disease. Inflamm Bowel Dis. doi:10.1097/MIB.0b013e31828706a0
Wray NR, Goddard ME, Visscher PM (2007) Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res 17:1520–1528
Yang Q, Khoury MJ, Botto L, Friedman JM, Flanders WD (2003) Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes. Am J Hum Genet 72:636–649
Acknowledgments
We thank the patients and the controls for participating in this study. We acknowledge the Feinstein Institute for Medical Research of the North Shore-Long Island Jewish Health System for Illumina Genotyping BeadChip processing. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113.
Funding
T32 DK083251, NIH—National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (M-H W, CF); DK068112 (J-PA), DK062420 (RHD) and DK076025 (RHD); AG030653 (MIK); a Crohn’s and Colitis Foundation of America Senior Research Award (RHD); and funds generously provided by Kenneth and Jennifer Rainin, the Wesley Roj and Douglas Durham Roj Endowed Fund, and Gerald and Nancy Goldberg.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
439_2013_1395_MOESM1_ESM.tif
Supplementary Figure 2A Tree1 and its genetic interactions illustrated by further pairwise stratified analyses (TIFF 89 kb)
439_2013_1395_MOESM3_ESM.tif
Supplementary Figure 2C Tree3 and its genetic interactions illustrated by further pairwise stratified analyses (TIFF 91 kb)
439_2013_1395_MOESM5_ESM.tif
Supplementary Figure 2E Tree5 and its gene–gene and gene-smoking interactions illustrated by further stratified analyses (TIFF 77 kb)
Rights and permissions
About this article
Cite this article
Wang, MH., Fiocchi, C., Zhu, X. et al. Gene–gene and gene–environment interactions in ulcerative colitis. Hum Genet 133, 547–558 (2014). https://doi.org/10.1007/s00439-013-1395-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-013-1395-z