Genetics of Inflammatory Bowel Diseases

The Huang lab leads and contributes to inflammatory bowel diseases (IBD) genetics studies through collaborations with the international IBD genetics consortium (IIBDGC), the Daly Lab, the Xavier Lab and as a member of the Center for the Study of IBD at the Massachusetts General Hospital. Dr. Huang led the IIBDGC fine-mapping project which developed a novel fine-mapping method and applied it on ~ 70,000 European samples. This effort mapped 45 IBD associations to single variants with over 50% casual probabilities, significantly advancing our knowledge in IBD genetics (Huang et. al., Nature 2017). Following this study, the Huang lab focuses on understanding the tissue-specific gene regulations in the non-coding genome and their connections with IBD genetics, studies combining exome-sequencing and fine-mapping to reveal the genetic basis of IBD across the full allelic spectrum, and studies to understand the IBD genetic architecture cross major world populations.

Selected Publications

Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis
Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G, Graham DB, Herbst RH, Rogel N, Slyper M, Waldman J, Sud M, Andrews E, Velonias G, Haber AL, Jagadeesh K, Vickovic S, Yao J, Stevens C, Dionne D, Nguyen LT, Villani AC, Hofree M, Creasey EA, Huang H, Rozenblatt-Rosen O, Garber JJ, Khalili H, Desch AN, Daly MJ, Ananthakrishnan AN, Shalek AK, Xavier RJ, Regev A. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell. 2019 Jul 25;178(3):714-730.e22. [DOI] [PubMed] [PubMed Central]
Genetic variants in cellular transport do not affect mesalamine response in ulcerative colitis
Moran CJ, Huang H, Rivas M, Kaplan JL, Daly MJ, Winter HS. Genetic variants in cellular transport do not affect mesalamine response in ulcerative colitis. PLoS One. 2018;13(3):e0192806. eCollection 2018 [DOI] [PubMed] [PubMed Central]
Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population
Rivas MA, Avila BE, Koskela J, Huang H, Stevens C, Pirinen M, Haritunians T, Neale BM, Kurki M, Ganna A, Graham D, Glaser B, Peter I, Atzmon G, Barzilai N, Levine AP, Schiff E, Pontikos N, Weisburd B, Lek M, Karczewski KJ, Bloom J, Minikel EV, Petersen BS, Beaugerie L, Seksik P, Cosnes J, Schreiber S, Bokemeyer B, Bethge J, Heap G, Ahmad T, Plagnol V, Segal AW, Targan S, Turner D, Saavalainen P, Farkkila M, Kontula K, Palotie A, Brant SR, Duerr RH, Silverberg MS, Rioux JD, Weersma RK, Franke A, Jostins L, Anderson CA, Barrett JC, MacArthur DG, Jalas C, Sokol H, Xavier RJ, Pulver A, Cho JH, McGovern DPB, Daly MJ. Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 2018 May;14(5):e1007329.eCollection 2018 May [DOI] [PubMed] [PubMed Central]
Late-Onset Crohn’s Disease Is A Subgroup Distinct in Genetic and Behavioral Risk Factors With UC-Like Characteristics
Li D, Haritunians T, Landers C, Potdar AA, Yang S, Huang H, Schumm LP, Daly M, Targan SR, McGovern DPB. Late-Onset Crohn's Disease Is A Subgroup Distinct in Genetic and Behavioral Risk Factors With UC-Like Characteristics. Inflamm Bowel Dis. 2018 Oct 12;24(11):2413-2422. [DOI] [PubMed] [PubMed Central]
Fine-mapping inflammatory bowel disease loci to single-variant resolution
Hailiang Huang, Ming Fang, Luke Jostins, Maša Umićević Mirkov, Gabrielle Boucher, Carl A Anderson, Vibeke Andersen, Isabelle Cleynen, Adrian Cortes, François Crins, Mauro D'Amato, Valérie Deffontaine, Julia Dmitrieva, Elisa Docampo, Mahmoud Elansary, Kyle Kai-How Farh, Andre Franke, Ann-Stephan Gori, Philippe Goyette, Jonas Halfvarson, Talin Haritunians, Jo Knight, Ian C Lawrance, Charlie W Lees, Edouard Louis, Rob Mariman, Theo Meuwissen, Myriam Mni, Yukihide Momozawa, Miles Parkes, Sarah L Spain, Emilie Théâtre, Gosia Trynka, Jack Satsangi, Suzanne van Sommeren, Severine Vermeire, Ramnik J Xavier, Rinse K Weersma, Richard H Duerr, Christopher G Mathew, John D Rioux, Dermot PB McGovern, Judy H Cho, Michel Georges, Mark J Daly, and Jeffrey C Barrett. 2017. “Fine-mapping inflammatory bowel disease loci to single-variant resolution.” Nature, 547, 7662, Pp. 173-178. Abstract
Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
Characterization of candidate genes in inflammatory bowel disease-associated risk loci
Joanna M Peloquin, Gautam Goel, Lingjia Kong, Hailiang Huang, Talin Haritunians, Balfour R Sartor, Mark J Daly, Rodney D Newberry, Dermot P McGovern, Vijay Yajnik, Sergio A Lira, and Ramnik J Xavier. 2016. “Characterization of candidate genes in inflammatory bowel disease-associated risk loci.” JCI Insight, 1, 13, Pp. e87899. Abstract
GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD. Terminal ileal (TI) and colonic mucosal tissues were obtained from patients with Crohn's disease or ulcerative colitis and from healthy controls. We developed a NanoString code set to profile 678 genes within IBD risk loci. A subset of patients and controls were genotyped for IBD-associated risk SNPs. Analyses included differential expression and variance analysis, weighted gene coexpression network analysis, and eQTL analysis. We identified 116 genes that discriminate between healthy TI and colon samples and uncovered patterns in variance of gene expression that highlight heterogeneity of disease. We identified 107 coexpressed gene pairs for which transcriptional regulation is either conserved or reversed in an inflammation-independent or -dependent manner. We demonstrate that on average approximately 60% of disease-associated genes are differentially expressed in inflamed tissue. Last, we identified eQTLs with either genotype-only effects on expression or an interaction effect between genotype and inflammation. Our data reinforce tissue specificity of expression in disease-associated candidate genes, highlight genes and gene pairs that are regulated in disease-relevant tissue and inflammation, and provide a foundation to advance the understanding of IBD pathogenesis.
Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk
Kara G Lassen, Craig I McKenzie, Muriel Mari, Tatsuro Murano, Jakob Begun, Leigh A Baxt, Gautam Goel, Eduardo J Villablanca, Szu-Yu Kuo, Hailiang Huang, Laurence Macia, Atul K Bhan, Marcel Batten, Mark J Daly, Fulvio Reggiori, Charles R Mackay, and Ramnik J Xavier. 2016. “Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk.” Immunity, 44, 6, Pp. 1392-405. Abstract
Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense.
Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study
Isabelle Cleynen, Gabrielle Boucher, Luke Jostins, Philip L Schumm, Sebastian Zeissig, Tariq Ahmad, Vibeke Andersen, Jane M Andrews, Vito Annese, Stephan Brand, Steven R Brant, Judy H Cho, Mark J Daly, Marla Dubinsky, Richard H Duerr, Lynnette R Ferguson, Andre Franke, Richard B Gearry, Philippe Goyette, Hakon Hakonarson, Jonas Halfvarson, Johannes R Hov, Hailang Huang, Nicholas A Kennedy, Limas Kupcinskas, Ian C Lawrance, James C Lee, Jack Satsangi, Stephan Schreiber, Emilie Théâtre, Andrea E van der Meulen-de Jong, Rinse K Weersma, David C Wilson, Miles Parkes, Severine Vermeire, John D Rioux, John Mansfield, Mark S Silverberg, Graham Radford-Smith, Dermot PB McGovern, Jeffrey C Barrett, and Charlie W Lees. 2016. “Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.” Lancet, 387, 10014, Pp. 156-67. Abstract
BACKGROUND: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations
Jimmy Z Liu, Suzanne van Sommeren, Hailiang Huang, Siew C Ng, Rudi Alberts, Atsushi Takahashi, Stephan Ripke, James C Lee, Luke Jostins, Tejas Shah, Shifteh Abedian, Jae Hee Cheon, Judy Cho, Naser E Dayani, Lude Franke, Yuta Fuyuno, Ailsa Hart, Ramesh C Juyal, Garima Juyal, Won Ho Kim, Andrew P Morris, Hossein Poustchi, William G Newman, Vandana Midha, Timothy R Orchard, Homayon Vahedi, Ajit Sood, Joseph Y Sung, Reza Malekzadeh, Harm-Jan Westra, Keiko Yamazaki, Suk-Kyun Yang, Jeffrey C Barrett, Behrooz Z Alizadeh, Miles Parkes, Thelma Bk, Mark J Daly, Michiaki Kubo, Carl A Anderson, and Rinse K Weersma. 2015. “Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.” Nat Genet, 47, 9, Pp. 979-986. Abstract
Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.
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
Philippe Goyette, Gabrielle Boucher, Dermot Mallon, Eva Ellinghaus, Luke Jostins, Hailiang Huang, Stephan Ripke, Elena S Gusareva, Vito Annese, Stephen L Hauser, Jorge R Oksenberg, Ingo Thomsen, Stephen Leslie, Mark J Daly, Kristel Van Steen, Richard H Duerr, Jeffrey C Barrett, Dermot PB McGovern, Philip L Schumm, James A Traherne, Mary N Carrington, Vasilis Kosmoliaptsis, Tom H Karlsen, Andre Franke, and John D Rioux. 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, 2, Pp. 172-9. Abstract
Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.
Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation
Zhifang Cao, Kara L Conway, Robert J Heath, Jason S Rush, Elizaveta S Leshchiner, Zaida G Ramirez-Ortiz, Natalia B Nedelsky, Hailiang Huang, Aylwin Ng, Agnès Gardet, Shih-Chin Cheng, Alykhan F Shamji, John D Rioux, Cisca Wijmenga, Mihai G Netea, Terry K Means, Mark J Daly, and Ramnik J Xavier. 2015. “Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation.” Immunity, 43, 4, Pp. 715-26. Abstract
CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.
Differential effect of genetic burden on disease phenotypes in Crohn’s disease and ulcerative colitis: analysis of a North American cohort
Ashwin N Ananthakrishnan, Hailiang Huang, Deanna D Nguyen, Jenny Sauk, Vijay Yajnik, and Ramnik J Xavier. 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, 3, Pp. 395-400. Abstract
OBJECTIVES: Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown. METHODS: The data source for our study was a prospective cohort of CD and UC patients recruited from a tertiary referral center. All patients underwent genotyping on the Illumina Immunochip. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for each of the 163 inflammatory bowel disease (IBD) risk loci was calculated and phenotypic associations examined across GRS quartiles.
RESULTS: Our study cohort included 1,105 patients (697 CD, 408 UC). Increasing genetic burden was associated with earlier age of diagnosis of CD (Ptrend=0.008). Patients in the highest GRS quartile were likely to develop disease 5 years earlier than those in the lowest quartile. Increasing genetic burden was also associated with ileal involvement in CD (Ptrend <0.0001). The effect of genetic burden was independent of the NOD2 locus and was stronger among those with no NOD2 variants, and in never smokers. UC patients with an involved first-degree relative had a higher genetic burden, but GRS was not associated with disease phenotype in UC.
CONCLUSIONS: Increasing genetic burden is associated with early age of diagnosis in CD, but not UC. The expanded panel of IBD risk loci explains only a fraction of variance of disease phenotype, suggesting limited clinical utility of genetics in predicting natural history.