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1.  Recent Insights Into the Genetics of Inflammatory Bowel Disease 
Gastroenterology  2011;140(6):1704-1712.
Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemio-logic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and anky-losing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying un common variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.
doi:10.1053/j.gastro.2011.02.046
PMCID: PMC4947143  PMID: 21530736
Crohn's Disease; Ulcerative Colitis; Genetics; Autophagy; Interleukin 23; Genome-Wide Association Studies
2.  Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans 
Gastroenterology  2015;149(6):1575-1586.
Background & Aims
Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci.
Methods
We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the US; additional controls were collected from 4 other immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease (CD), 361 with ulcerative colitis (UC), 62 with IBD type-unknown (IBDU), and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed.
Results
The strongest associations were observed between UC and HLA rs9271366 (P=7.5e–6), CD and 5p13.1 rs4286721 (P=3.0e–6), and IBD and KAT2A rs730086 (P=2.3e–6). Additional suggestive associations (P<4.2e-5) were observed between CD and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2 open reading frame 43; and between UC and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P<3.1e-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P<3.9e–4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2–15q23, and 16p12.2–16p12.1. Network analyses showed significant enrichment (false discovery rate <1e–5) in genes that encode members of the JAK–STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles.
Conclusions
In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we found evidence for loci and variants not previously associated with IBD. The complex genetic factors that determine risk for or protection from IBD in different populations require further study.
doi:10.1053/j.gastro.2015.07.065
PMCID: PMC4685036  PMID: 26278503
race; ethnicity; genetic variant; intestinal inflammation
3.  Genetics of Inflammatory Bowel Diseases 
Gastroenterology  2015;149(5):1163-1176.e2.
In this Review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and non-coding genetic variation. In the small minority of loci where major association signals correspond to non-synonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve non-coding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that expression of the large majority of human genes is regulated by non-coding genetic variation. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (i.e. odds ratios markedly deviating from one) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in very-early onset, more severe cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility, through emerging precision medicine initiatives. We discuss the rapidly evolving area of direct to consumer genetic testing, as well as the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect of partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.
doi:10.1053/j.gastro.2015.08.001
PMCID: PMC4915781  PMID: 26255561
Crohn's disease; Ulcerative Colitis; Epigenetics; Autophagy
5.  A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis 
Rivas, Manuel A. | Graham, Daniel | Sulem, Patrick | Stevens, Christine | Desch, A. Nicole | Goyette, Philippe | Gudbjartsson, Daniel | Jonsdottir, Ingileif | Thorsteinsdottir, Unnur | Degenhardt, Frauke | Mucha, Sören | Kurki, Mitja I. | Li, Dalin | D'Amato, Mauro | Annese, Vito | Vermeire, Severine | Weersma, Rinse K. | Halfvarson, Jonas | Paavola-Sakki, Paulina | Lappalainen, Maarit | Lek, Monkol | Cummings, Beryl | Tukiainen, Taru | Haritunians, Talin | Halme, Leena | Koskinen, Lotta L. E. | Ananthakrishnan, Ashwin N. | Luo, Yang | Heap, Graham A. | Visschedijk, Marijn C. | MacArthur, Daniel G. | Neale, Benjamin M. | Ahmad, Tariq | Anderson, Carl A. | Brant, Steven R. | Duerr, Richard H. | Silverberg, Mark S. | Cho, Judy H | Palotie, Aarno | Saavalainen, Päivi | Kontula, Kimmo | Färkkilä, Martti | McGovern, Dermot P. B. | Franke, Andre | Stefansson, Kari | Rioux, John D. | Xavier, Ramnik J. | Daly, Mark J. | Barrett, J. | de Lane, K. | Edwards, C. | Hart, A. | Hawkey, C. | Jostins, L. | Kennedy, N. | Lamb, C. | Lee, J. | Lees, C. | Mansfield, J. | Mathew, C. | Mowatt, C. | Newman, B. | Nimmo, E. | Parkes, M. | Pollard, M. | Prescott, N. | Randall, J. | Rice, D. | Satsangi, J. | Simmons, A. | Tremelling, M. | Uhlig, H. | Wilson, D. | Abraham, C. | Achkar, J. P. | Bitton, A. | Boucher, G. | Croitoru, K. | Fleshner, P. | Glas, J. | Kugathasan, S. | Limbergen, J. V. | Milgrom, R. | Proctor, D. | Regueiro, M. | Schumm, P. L. | Sharma, Y. | Stempak, J. M. | Targan, S. R. | Wang, M. H.
Nature Communications  2016;7:12342.
Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10−7, odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
While hundreds of loci are linked with inflammatory bowel diseases (IBDs), the functional consequences of the associated variants remain unclear. Here, the authors screened in ulcerative colitis (UC) patients' genomes for protein-truncating variants near IBD loci, and identify a protein truncating variant in RNF186 to be protective against UC.
doi:10.1038/ncomms12342
PMCID: PMC4980482  PMID: 27503255
6.  Improved integrative framework combining association data with gene expression features to prioritize Crohn's disease genes 
Human Molecular Genetics  2015;24(14):4147-4157.
Genome-wide association studies in Crohn's disease (CD) have identified 140 genome-wide significant loci. However, identification of genes driving association signals remains challenging. Furthermore, genome-wide significant thresholds limit false positives at the expense of decreased sensitivity. In this study, we explored gene features contributing to CD pathogenicity, including gene-based association data from CD and autoimmune (AI) diseases, as well as gene expression features (eQTLs, epigenetic markers of expression and intestinal gene expression data). We developed an integrative model based on a CD reference gene set. This integrative approach outperformed gene-based association signals alone in identifying CD-related genes based on statistical validation, gene ontology enrichment, differential expression between M1 and M2 macrophages and a validation using genes causing monogenic forms of inflammatory bowel disease as a reference. Besides gene-level CD association P-values, association with AI diseases was the strongest predictor, highlighting generalized mechanisms of inflammation, and the interferon-γ pathway particularly. Within the 140 high-confidence CD regions, 598 of 1328 genes had low prioritization scores, highlighting genes unlikely to contribute to CD pathogenesis. For select regions, comparably high integrative model scores were observed for multiple genes. This is particularly evident for regions having extensive linkage disequilibrium such as the IBD5 locus. Our analyses provide a standardized reference for prioritizing potential CD-related genes, in regions with both highly significant and nominally significant gene-level association P-values. Our integrative model may be particularly valuable in prioritizing rare, potentially private, missense variants for which genome-wide evidence for association may be unattainable.
doi:10.1093/hmg/ddv142
PMCID: PMC4560067  PMID: 25935003
7.  Inflammatory bowel disease: Genetic and epidemiologic considerations 
Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn’s disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.
doi:10.3748/wjg.14.338
PMCID: PMC2679123  PMID: 18200657
Crohn's disease; Ulcerative colitis; Interleukin 23; Autophagy; Complex genetics
8.  Relationship between proximal Crohn’s disease location and disease behavior and surgery: A cross-sectional study of the IBD Genetics Consortium 
Objectives
In classifying Crohn’s disease (CD) location, proximal (L4) disease includes esophagogastroduodenal (EGD) and jejunal disease. Our aim was to determine the influence of proximal disease on outcomes of behavior and need for surgery and to determine if there was significant clinical heterogeneity between EGD and jejunal disease.
Methods
We performed a cross-sectional query of the NIDDK IBD Genetics Consortium (IBDGC) database of patients with a confirmed diagnosis of CD and phenotyped per the IBDGC manual. Presence of any L4, L4-EGD, L4-jejunal and non-L4 disease (L1-ileal, L2-colonic, and L3-ileocolonic) was compared with demographic features including age, race, ethnicity, smoking and IBD family history, diagnosis age, disease duration, clinical outcomes of inflammatory, stricturing or penetrating behavior, and CD abdominal surgeries. Univariate and multivariable analyses were performed with R.
Results
Among 2105 patients with complete disease location data, 346 had L4 disease (175 L4-EGD, 115 L4-jejunal, and 56 EGD and jejunal) with 321 having concurrent L1-L3 disease. 1759 had only L1-L3 disease. L4 vs. non-L4 patients were more likely (p<0.001) to be younger at diagnosis, non-smokers, have co-existing ileal involvement and have stricturing disease. L4- jejunal vs. L4-EGD patients were at least twice as likely (p<0.001) to have had ileal disease, stricturing behavior, and any or multiple abdominal surgeries. Remarkably, L4-jejunal patients had more (p<0.001) stricturing behavior and multiple abdominal surgeries than non-L4 ileal disease patients. Logistic regression showed stricturing risks were ileal (without proximal) site (OR 3.18; 95% CI 2.23-4.64), longer disease duration (OR 1.33/decade; 1.19-1.49), jejunal site (OR 2.90; 1.89-4.45), and older age at diagnosis (OR 1.21/decade; 1.10-1.34). Multiple surgeries risks were disease duration (OR 3.74/decade; 3.05-4.64), penetrating disease (OR 2.60; 1.64-4.21), and jejunal site (OR 2.39; 1.36-4.20), with short duration from diagnosis to first surgery protective (OR 0.87/decade to 1st surgery; 0.84-0.90).
Conclusion
Jejunal disease is a significantly greater risk factor for stricturing disease and multiple abdominal surgeries than either EGD or ileal (without proximal) disease. The Montreal site classification should be revised to include separate designations for jejunal and EGD disease.
doi:10.1038/ajg.2012.389
PMCID: PMC4059598  PMID: 23229423
9.  Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3 
Genes and immunity  2013;14(5):310-316.
The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease compared to non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to Crohn’s disease etiology in this population, most notably at NOD2, in which three causal, uncommon, and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes which showed significantly greater association to Crohn’s disease in the Ashkenazi Jewish population compared to a non-Jewish population (145 haplotypes and no haplotypes with P-value < 10−3, respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established Crohn’s disease loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare Crohn’s disease-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.
doi:10.1038/gene.2013.19
PMCID: PMC3785105  PMID: 23615072
haplotype association; Ashkenazi Jewish; Crohn’s disease; NF-κB signaling; synthetic association
10.  Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study 
Lancet (London, England)  2016;387(10014):156-167.
Summary
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).
doi:10.1016/S0140-6736(15)00465-1
PMCID: PMC4714968  PMID: 26490195
11.  The Influence of Depression on Quality of Life in Patients with Inflammatory Bowel Disease 
Inflammatory bowel diseases  2013;19(8):1732-1739.
Background
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that significantly impacts the health-related quality of life (HR-QOL). A decreased HR-QOL has been demonstrated in patients with active disease compared to patients in remission. In this cross-sectional study, we examined the role of depression and disease activity as independent factors in predicting patient's HR-QOL.
Methods
105 patients with either Crohn's disease (CD) or Ulcerative Colitis (UC) were enrolled. Disease activity was evaluated by the Crohn's disease activity index (CDAI) or Seo Activity Index (SAI). Depressive symptoms were evaluated by Beck's Depression Inventory II (BDI-II) and Primary Care (BDI-PC). HR-QOL was evaluated by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Simple and multiple regressions were performed on quality of life score with multiple demographic and clinical variables as predictors.
Results
The prevalence of depression in our study population is 25%. In both CD and UC patients, depression is the most significant predictor to a poor HR-QOL (in CD, P=8.22×10-6; in UC, P=2.02×10-6). HR-QOL is weakly affected by disease activity (in CD, P=0.110; in UC, P=0.00492). In CD, Biologic use displays positive effect on HR-QOL (P=0.00780). In total, the proportion of variance explained by all predictors is 61% for CD and 53% for UC, while the depression alone explains 44% and 36%.
Conclusion
Our study demonstrates the importance of depression toward the quality of life in IBD patients. The diagnosis of depression should be actively sought out and treated in outpatient IBD practices.
doi:10.1097/MIB.0b013e318281f395
PMCID: PMC4623582  PMID: 23669400
inflammatory bowel disease; depression; disease activity; health-related quality of life
12.  Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease 
Cell  2014;158(5):1000-1010.
SUMMARY
Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA−SEQ) and show that high IgA−coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA−SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with pre-defined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA−coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development.
doi:10.1016/j.cell.2014.08.006
PMCID: PMC4174347  PMID: 25171403
13.  Gene-centric Association Mapping of Chromosome 3p implicates MST1 in IBD pathogenesis 
Mucosal immunology  2008;1(2):131-138.
Association mapping and candidate gene studies within IBD linkage regions, as well as genome-wide association studies in CD have led to the discovery of multiple risk genes, but these only explain a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and UC using a gene-centric association mapping approach. We identified twelve functional candidate genes by searching for literature co-citations with relevant keywords and for gene expression patterns consistent with immune/intestinal function. We then performed an association study composed of a screening phase, where tagging SNPs were evaluated in 1020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association to IBD for four SNPs within a 1.2 Mb LD region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage stimulating 1 (MST1) gene (p-value 3.62×10−6) that accounts for the association signal, and shows association to both CD and UC. MST1 encodes MSP, a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.
doi:10.1038/mi.2007.15
PMCID: PMC4550306  PMID: 19079170
15.  Pattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk Allele 
Immunity  2014;40(5):734-746.
Summary
Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune homeostasis and cytokine secretion. Multiple loci are associated with IBD, but a functional explanation is missing for most. Here we found that pattern-recognition receptor (PRR)-induced cytokine secretion was diminished in human monocyte-derived dendritic cells (MDDC) from rs7282490 ICOSLG GG risk-carriers. Homotypic interactions between the co-stimulatory molecule ICOS and the ICOS ligand on MDDCs amplified nucleotide-binding oligomerization domain 2 (NOD2)-initiated cytokine secretion. This amplification required arginine residues in the ICOSL cytoplasmic tail that recruited the adaptor protein RACK1 and the kinases PKC and JNK leading to PKC, MAPK and NFκB activation. MDDC from rs7282490 GG risk-carriers had reduced ICOSL expression and PRR-initiated signaling and this loss-of-function ICOSLG risk allele associated with an ileal Crohn’s disease phenotype, similar to polymorphisms in NOD2. Taken together, ICOSL amplifies PRR-initiated outcomes, which may contribute to immune homeostasis.
doi:10.1016/j.immuni.2014.04.011
PMCID: PMC4157904  PMID: 24837102
16.  Celiac disease in a child with ulcerative colitis. A possible genetic association 
Celiac disease and Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease are both immune-mediated enteropathies. It is rare for both celiac disease and IBD to occur together in an individual patient. This association has been reported in adults, but very rarely in children. Here, we report an unusual case of an eight-year-old child with a history of anemia and failure to thrive who presented with bloody diarrhea. His evaluation showed anemia, elevated inflammatory markers and positive celiac antibodies. Endoscopic evaluation revealed partial duodenal villous atrophy and pancolitis. He was diagnosed with celiac disease and UC and responded well to a gluten-free diet and steroid/mesalamine therapy. The patient’s genetic testing revealed markers showing susceptibility for both celiac disease and UC. It is important to be aware of this association as both conditions can present with similar clinical features, but require different therapeutic approaches.
doi:10.1097/MCG.0b013e318250e468
PMCID: PMC4425271  PMID: 23314669
celiac disease; Crohn’s disease; ulcerative colitis
17.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene 
Science (New York, N.Y.)  2006;314(5804):1461-1463.
The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
doi:10.1126/science.1135245
PMCID: PMC4410764  PMID: 17068223
18.  Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins 
Nature Communications  2014;5:4835.
The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈12–25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.
Ashkenazi Jews are a genetically isolated population with distinct patterns of genetic diversity. Here, the authors sequence the genomes of 128 Ashkenazi Jewish individuals and use the sequence information to provide insight into the population's European and Middle Eastern origins.
doi:10.1038/ncomms5835
PMCID: PMC4164776  PMID: 25203624
19.  Granulocyte-Macrophage Colony-Stimulating Factor Auto-Antibodies: A Marker of Aggressive Crohn’s Disease 
Inflammatory bowel diseases  2013;19(8):1671-1680.
Background & Aims
Neutralizing auto-antibodies (Ab) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) have been associated with stricturing ileal Crohn’s disease (CD) in a largely pediatric patient cohort (total 394, adult CD 57). The aim of this study was to examine this association in two independent predominantly adult inflammatory bowel disease patient cohorts.
Methods
Serum samples from 745 subjects from the NIDDK IBD Genetics Consortium and 737 patients from Australia were analyzed for GM-CSF Ab and genetic markers. We conducted multiple regression analysis with backwards elimination to assess the contribution of GM-CSF Ab levels, established CD risk alleles and smoking on ileal disease location in the 477 combined CD subjects from both cohorts. We also determined associations of GM-CSF Ab levels with complications requiring surgical intervention in combined CD subjects in both cohorts.
Results
Serum samples from CD patients expressed significantly higher concentrations of GM-CSF Ab when compared to Ulcerative Colitis or controls in each cohort. Non-smokers with ileal CD expressed significantly higher GM-CSF Ab concentrations in the Australian cohort (p= 0.002). Elevated GM-CSF Ab, ileal disease location and disease duration greater than 3 years were independently associated with stricturing/penetrating behavior and intestinal resection for CD.
Conclusions
The expression of high GM-CSF Ab is a risk marker for aggressive CD behavior and complications including surgery. Modifying factors include environmental exposure to smoking and genetic risk markers.
doi:10.1097/MIB.0b013e318281f506
PMCID: PMC3707315  PMID: 23749272
Inflammatory bowel disease; granulocyte-macrophage colony-stimulating factor antibody; Crohn’s Disease, smoking
20.  Empirical Bayes Correction for the Winner's Curse in Genetic Association Studies 
Genetic epidemiology  2012;37(1):60-68.
We consider an Empirical Bayes method to correct for the Winner's Curse phenomenon in genome-wide association studies. Our method utilizes the collective distribution of all odds ratios (ORs) to determine the appropriate correction for a particular single-nucleotide polymorphism (SNP). We can show that this approach is squared error optimal provided that this collective distribution is accurately estimated in its tails. To improve the performance when correcting the OR estimates for the most highly associated SNPs, we develop a second estimator that adaptively combines the Empirical Bayes estimator with a previously considered Conditional Likelihood estimator. The applications of these methods to both simulated and real data suggest improved performance in reducing selection bias.
doi:10.1002/gepi.21683
PMCID: PMC4048064  PMID: 23012258
GWAS; Empirical Bayes; Winner's Curse
21.  Contribution of higher risk genes and European admixture to Crohn's disease in African Americans 
Inflammatory bowel diseases  2012;18(12):10.1002/ibd.22931.
Background & Aims
African Americans (AA) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD.
Methods
Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 SNPs in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry.
Results
Mean EA was similar among the CD cases and controls (20.9% and 20.4, respectively, p=0.58). No significant admixture differences were observed among cases (211 to 227) stratified by phenotypic sub-classifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, p = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, p=0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (L503F [10.6% CD, 7.6% Controls, p=0.05] and g-207c [41.3% CD, 35.7% Controls, p=0.03], respectively) and IL23R rs2201841 (18.2% CD, 13.8% Controls, p=0.03), but not IRGM variants nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (p=0.05), whereas a more common haplotype isolating g-207c was not.
Conclusions
Specific functional gene variations significantly contribute to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 in recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls.
doi:10.1002/ibd.22931
PMCID: PMC3810419  PMID: 22411504
genetics; epidemiology; Crohn's disease
22.  NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2 
Gut  2011;61(7):1028-1035.
Objective
The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohn's colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD).
Methods
Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts.
Results
Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3×10−5, OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67phox to RAC2. This study found a novel genetic association of RAC2 with Crohn's disease (CD) and replicated the previously reported association of NCF4 with ileal CD.
Conclusion
These studies suggest that the rare novel p67phox variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.
doi:10.1136/gutjnl-2011-300078
PMCID: PMC3806486  PMID: 21900546
23.  Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis 
PLoS Genetics  2013;9(9):e1003723.
Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.
Author Summary
Genetic studies of common diseases have seen tremendous progress in the last half-decade primarily due to recent technologies that enable a systematic examination of genetic markers across the entire genome in large numbers of patients and healthy controls. The studies, while identifying genomic regions that influence a person's risk for developing disease, often do not pinpoint the actual gene or gene variants that account for this risk (called a causal gene/variant). A prime example of this can be seen with the 163 genetic risk factors that have recently been associated with the chronic inflammatory bowel diseases known as Crohn's disease and ulcerative colitis. For less than a handful of these 163 is the causative change in the genetic code known. The current study used an approach to directly look at the genetic code for a subset of these and identified a causative change in the genetic code for eight risk factors for ulcerative colitis. This finding is particularly important because it directs biological studies to understand the mechanisms that lead to this chronic life-long inflammatory disease.
doi:10.1371/journal.pgen.1003723
PMCID: PMC3772057  PMID: 24068945
24.  A New Approach for the Joint Analysis of Multiple Chip-Seq Libraries with Application to Histone Modification 
Most approaches for analyzing ChIP-Seq data are focused on inferring exact protein binding sites from a single library. However, frequently multiple ChIP-Seq libraries derived from differing cell lines or tissue types from the same individual may be available. In such a situation, a separate analysis for each tissue or cell line may be inefficient. Here, we describe a novel method to analyze such data that intelligently uses the joint information from multiple related ChIP-Seq libraries. We present our method as a two-stage procedure. First, separate single cell line analysis is performed for each cell line. Here, we use a novel mixture regression approach to infer the subset of genes that are most likely to be involved in protein binding in each cell line. In the second step, we combine the separate single cell line analyses using an Empirical Bayes algorithm that implicitly incorporates inter-cell line correlation. We demonstrate the usefulness of our method using both simulated data, as well as real H3K4me3 and H3K27me3 histone methylation libraries.
doi:10.1515/1544-6115.1660
PMCID: PMC3770480  PMID: 22499701
Empirical Bayes; EM; ChIP-Seq; histone methylation
25.  Genome-wide Association Study of N370S Homozygous Gaucher Disease Reveals the Candidacy of CLN8 gene as a Genetic Modifier Contributing to Extreme Phenotypic Variation 
American journal of hematology  2012;87(4):377-383.
Mutations in GBA1 gene result in defective acid β-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesized that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate or severe disease category using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for associations using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at p value 1.26 × 10−6. Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients in whom CLN8 risk alleles were over-represented. In an in vitro cell model of GD, CLN8 expression was increased which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.
doi:10.1002/ajh.23118
PMCID: PMC3684025  PMID: 22388998
Gaucher disease; GWAS; genotype/phenotype correlations; phenotypic diversity; modifier genes; CLN8; N370S; GBA mutations

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