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1. Machine Learning to Predict Mortality and Critical Events in a Cohort of Patients With COVID-19 in New York City: Model Development and Validation

Author

Vaid, Akhil, Somani, Sulaiman, Russak, Adam J, De Freitas, Jessica K, Chaudhry, Fayzan F, Paranjpe, Ishan, Johnson, Kipp W, Lee, Samuel J, Miotto, Riccardo, Richter, Felix, Zhao, Shan, Beckmann, Noam D, Naik, Nidhi, Kia, Arash, Timsina, Prem, Lala, Anuradha, Paranjpe, Manish, Golden, Eddye, Danieletto, Matteo, Singh, Manbir, Meyer, Dara, O'Reilly, Paul F, Huckins, Laura, Kovatch, Patricia, Finkelstein, Joseph, Freeman, Robert M., Argulian, Edgar, Kasarskis, Andrew, Percha, Bethany, Aberg, Judith A, Bagiella, Emilia, Horowitz, Carol R, Murphy, Barbara, Nestler, Eric J, Schadt, Eric E, Cho, Judy H, Cordon-Cardo, Carlos, Fuster, Valentin, Charney, Dennis S, Reich, David L, Bottinger, Erwin P, Levin, Matthew A, Narula, Jagat, Fayad, Zahi A, Just, Allan C, Charney, Alexander W, Nadkarni, Girish N, and Glicksberg, Benjamin S

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

BackgroundCOVID-19 has infected millions of people worldwide and is responsible for several hundred thousand fatalities. The COVID-19 pandemic has necessitated thoughtful resource allocation and early identification of high-risk patients. However, effective methods to meet these needs are lacking. ObjectiveThe aims of this study were to analyze the electronic health records (EHRs) of patients who tested positive for COVID-19 and were admitted to hospitals in the Mount Sinai Health System in New York City; to develop machine learning models for making predictions about the hospital course of the patients over clinically meaningful time horizons based on patient characteristics at admission; and to assess the performance of these models at multiple hospitals and time points. MethodsWe used Extreme Gradient Boosting (XGBoost) and baseline comparator models to predict in-hospital mortality and critical events at time windows of 3, 5, 7, and 10 days from admission. Our study population included harmonized EHR data from five hospitals in New York City for 4098 COVID-19–positive patients admitted from March 15 to May 22, 2020. The models were first trained on patients from a single hospital (n=1514) before or on May 1, externally validated on patients from four other hospitals (n=2201) before or on May 1, and prospectively validated on all patients after May 1 (n=383). Finally, we established model interpretability to identify and rank variables that drive model predictions. ResultsUpon cross-validation, the XGBoost classifier outperformed baseline models, with an area under the receiver operating characteristic curve (AUC-ROC) for mortality of 0.89 at 3 days, 0.85 at 5 and 7 days, and 0.84 at 10 days. XGBoost also performed well for critical event prediction, with an AUC-ROC of 0.80 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. In external validation, XGBoost achieved an AUC-ROC of 0.88 at 3 days, 0.86 at 5 days, 0.86 at 7 days, and 0.84 at 10 days for mortality prediction. Similarly, the unimputed XGBoost model achieved an AUC-ROC of 0.78 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. Trends in performance on prospective validation sets were similar. At 7 days, acute kidney injury on admission, elevated LDH, tachypnea, and hyperglycemia were the strongest drivers of critical event prediction, while higher age, anion gap, and C-reactive protein were the strongest drivers of mortality prediction. ConclusionsWe externally and prospectively trained and validated machine learning models for mortality and critical events for patients with COVID-19 at different time horizons. These models identified at-risk patients and uncovered underlying relationships that predicted outcomes.

Published
2020
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2. Advancing genomics to improve health equity.

Author

Madden, Ebony, Hindorff, Lucia, Bonham, Vence, Akintobi, Tabia, Burchard, Esteban, Baker, Kellan, Begay, Rene, Carpten, John, Cox, Nancy, Di Francesco, Valentina, Dillard, Denise, Fletcher, Faith, Fullerton, Stephanie, Garrison, Nanibaa, Hammack-Aviran, Catherine, Hiratsuka, Vanessa, Hildreth, James, Horowitz, Carol, Hughes Halbert, Chanita, Inouye, Michael, Jackson, Amber, Landry, Latrice, Kittles, Rick, Leek, Jeff, Limdi, Nita, Lockhart, Nicole, Ofili, Elizabeth, Pérez-Stable, Eliseo, Sabatello, Maya, Saulsberry, Loren, Schools, Lorjetta, Troyer, Jennifer, Wilfond, Benjamin, Wojcik, Genevieve, Cho, Judy, Lee, Sandra, and Green, Eric

Subjects
Humans, Genomics, Health Equity, United States, Genome, Human, National Human Genome Research Institute (U.S.)
Abstract

Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.

Published
2024

3. Unraveling the Link between Periodontitis and Inflammatory Bowel Disease: Challenges and Outlook

Author

Tanwar, Himanshi, Gnanasekaran, Jeba Mercy, Allison, Devon, Chuang, Ling-shiang, He, Xuesong, Aimetti, Mario, Baima, Giacomo, Costalonga, Massimo, Cross, Raymond K., Sears, Cynthia, Mehandru, Saurabh, Cho, Judy, Colombel, Jean-Frederic, Raufman, Jean-Pierre, and Thumbigere-Math, Vivek

Subjects
Quantitative Biology - Tissues and Organs
Abstract

Periodontitis and Inflammatory Bowel Disease (IBD) are chronic inflammatory conditions, characterized by microbial dysbiosis and hyper-immunoinflammatory responses. Growing evidence suggest an interconnection between periodontitis and IBD, implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an Oral-Gut axis, marked by a higher prevalence of periodontitis in IBD patients and vice versa. The specific mechanisms linking periodontitis and IBD remain to be fully elucidated, but emerging evidence points to the ectopic colonization of the gut by oral bacteria, which promote intestinal inflammation by activating host immune responses. This review presents an in-depth examination of the interconnection between periodontitis and IBD, highlighting the shared microbiological and immunological pathways, and proposing a multi-hit hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare., Comment: Total Words: 7,016 Figures: 3 Tables: 2 Reference: 341

Published
2023

4. Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohns disease and leads to impaired CFB cleavage and phagocytosis.

Author

Akhlaghpour, Marzieh, Haritunians, Talin, More, Shyam, Thomas, Lisa, Stamps, Dalton, Dube, Shishir, Li, Dalin, Yang, Shaohong, Landers, Carol, Mengesha, Emebet, Hamade, Hussein, Murali, Ramachandran, Potdar, Alka, Wolf, Andrea, Botwin, Gregory, Khrom, Michelle, Ananthakrishnan, Ashwin, Faubion, William, Jabri, Bana, Lira, Sergio, Newberry, Rodney, Sandler, Robert, Sartor, R, Xavier, Ramnik, Brant, Steven, Cho, Judy, Duerr, Richard, Lazarev, Mark, Rioux, John, Schumm, L, Silverberg, Mark, Zaghiyan, Karen, Fleshner, Phillip, Melmed, Gil, Vasiliauskas, Eric, Ha, Christina, Rabizadeh, Shervin, Syal, Gaurav, Bonthala, Nirupama, Ziring, David, Targan, Stephan, Long, Millie, McGovern, Dermot, and Michelsen, Kathrin

Subjects
IBD - GENETICS, INFLAMMATORY BOWEL DISEASE, META-ANALYSIS, Humans, Complement Factor B, Crohn Disease, Quality of Life, Follow-Up Studies, Phagocytosis
Abstract

OBJECTIVE: Perianal Crohns disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

Published
2023

5. Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients.

Author

Wu, Yiming, Gettler, Kyle, Kars, Meltem, Giri, Mamta, Li, Dalin, Bayrak, Cigdem, Zhang, Peng, Jain, Aayushee, Maffucci, Patrick, Sabic, Ksenija, Van Vleck, Tielman, Nadkarni, Girish, Denson, Lee, Ostrer, Harry, Levine, Adam, Schiff, Elena, Segal, Anthony, Kugathasan, Subra, Stenson, Peter, Cooper, David, Philip Schumm, L, Snapper, Scott, Daly, Mark, Haritunians, Talin, Duerr, Richard, Silverberg, Mark, Rioux, John, Brant, Steven, McGovern, Dermot, Cho, Judy, and Itan, Yuval

Subjects
Adult, Humans, Jews, Exome, Inflammatory Bowel Diseases, Risk Assessment, Genetic Predisposition to Disease
Abstract

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Published
2023

7. Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease

Author

Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H, Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B, Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N, Faro, Valeria Lo, Lopera-Maya, Esteban A, Läll, Kristi, Favé, Marie-Julie, Partanen, Juulia J, Chapman, Sinéad B, Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M, Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A, Guare, Lindsay A, Gignoux, Christopher R, Graham, Sarah E, Hornsby, Whitney E, Ingold, Nathan, Ismail, Said I, Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y, Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H, Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M, Thani, Asma Al, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H, Damrauer, Scott M, Douville, Nicholas J, Finer, Sarah, Fritsche, Lars G, Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J, Guo, Yu, Hunt, Karen A, Ioannidis, Alexander, Jansonius, Nomdo M, Konuma, Takahiro, Lee, Ming Ta Michael, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E, Moatamed, Babak, Nava-Aguilar, Marco A, Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Muñoz, Agustin, Shortt, Jonathan A, Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C, Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K, Franke, Lude, Gamazon, Eric R, Ganna, Andrea, Gaunt, Tom R, Ge, Tian, Huang, Hailiang, and Huffman, Jennifer

Subjects
Human Genome, Genetics, Biotechnology, Generic health relevance, Good Health and Well Being, Biobank of the Americas, Biobank Japan Project, BioMe, BioVU, CanPath - Ontario Health Study, China Kadoorie Biobank Collaborative Group, Colorado Center for Personalized Medicine, deCODE Genetics, Estonian Biobank, FinnGen, Generation Scotland, Genes & Health Research Team, LifeLines, Mass General Brigham Biobank, Michigan Genomics Initiative, National Biobank of Korea, Penn Medicine BioBank, Qatar Biobank, QSkin Sun and Health Study, Taiwan Biobank, HUNT Study, UCLA ATLAS Community Health Initiative, Uganda Genome Resource, UK Biobank, GWAS, ancestry diversity, biobank, genetic association studies, meta-analysis, phenotype harmonization
Abstract

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.

Published
2022

9. Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

Author

Uhlig, Holm H., Booth, Claire, Cho, Judy, Dubinsky, Marla, Griffiths, Anne M., Grimbacher, Bodo, Hambleton, Sophie, Huang, Ying, Jones, Kelsey, Kammermeier, Jochen, Kanegane, Hirokazu, Koletzko, Sibylle, Kotlarz, Daniel, Klein, Christoph, Lenardo, Michael J., Lo, Bernice, McGovern, Dermot P. B., Özen, Ahmet, de Ridder, Lissy, Ruemmele, Frank, Shouval, Dror S., Snapper, Scott B., Travis, Simon P., Turner, Dan, Wilson, David C., and Muise, Aleixo M.

Published
2023
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11. Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease

Author

Khrom, Michelle, Long, Millie, Dube, Shishir, Robbins, Lori, Botwin, Gregory J., Yang, Shaohong, Mengesha, Emebet, Li, Dalin, Naito, Takeo, Bonthala, Nirupama N., Ha, Christina, Melmed, Gil, Rabizadeh, Shervin, Syal, Gaurav, Vasiliauskas, Eric, Ziring, David, Brant, Steven R., Cho, Judy, Duerr, Richard H., Rioux, John, Schumm, Phil, Silverberg, Mark, Ananthakrishnan, Ashwin N., Faubion, William A., Jabri, Bana, Lira, Sergio A., Newberry, Rodney D., Sandler, Robert S., Xavier, Ramnik J., Kugathasan, Subra, Hercules, David, Targan, Stephan R., Sartor, R. Balfour, Haritunians, Talin, and McGovern, Dermot P.B.

Published
2024
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13. Machine Learning Based Prediction of Incident Cases of Crohn’s Disease Using Electronic Health Records from a Large Integrated Health System

Author

Hugo, Julian, Ibing, Susanne, Borchert, Florian, Sachs, Jan Philipp, Cho, Judy, Ungaro, Ryan C., Böttinger, Erwin P., Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Juarez, Jose M., editor, Marcos, Mar, editor, Stiglic, Gregor, editor, and Tucker, Allan, editor

Published
2023
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14. Anti-integrin αvβ6 Autoantibodies are Increased in Primary Sclerosing Cholangitis Patients With Concomitant Inflammatory Bowel Disease and Correlate With Liver Disease Severity

Author

Bloemen, Hannah, Livanos, Alexandra E., Martins, Adrielly, Dean, Richard, Bravo, Ana Catarina, Bourgonje, Arno R., Tankelevich, Michael, Herb, Jake, Cho, Judy, Santos, André Anastácio, Rodrigues, Cecília M.P., Petralia, Francesca, Colombel, Jean-Frederic, Bowlus, Christopher L., Schiano, Thomas, Torres, Joana, Levy, Cynthia, and Mehandru, Saurabh

Published
2024
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15. After Surgically Induced Remission, Ileal and Colonic Mucosa-Associated Microbiota Predicts Crohn’s Disease Recurrence

Author

Hernández-Rocha, Cristian, Turpin, Williams, Borowski, Krzysztof, Stempak, Joanne M., Sabic, Ksenija, Gettler, Kyle, Tastad, Christopher, Chasteau, Colleen, Korie, Ujunwa, Hanna, Mary, Khan, Abdul, Mengesha, Emebet, Bitton, Alain, Schwartz, Marc B., Barrie, Arthur, Datta, Lisa W., Lazarev, Mark, Brant, Steven R., Rioux, John D., McGovern, Dermot P.B., Duerr, Richard H., Schumm, L. Phil, Cho, Judy H., and Silverberg, Mark S.

Published
2024
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17. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries

Author

Liu, Zhanju, Liu, Ruize, Gao, Han, Jung, Seulgi, Gao, Xiang, Sun, Ruicong, Liu, Xiaoming, Kim, Yongjae, Lee, Ho-Su, Kawai, Yosuke, Nagasaki, Masao, Umeno, Junji, Tokunaga, Katsushi, Kinouchi, Yoshitaka, Masamune, Atsushi, Shi, Wenzhao, Shen, Chengguo, Guo, Zhenglin, Yuan, Kai, Zhu, Shu, Li, Dalin, Liu, Jianjun, Ge, Tian, Cho, Judy, Daly, Mark J., McGovern, Dermot P. B., Ye, Byong Duk, Song, Kyuyoung, Kakuta, Yoichi, Li, Mingsong, and Huang, Hailiang

Published
2023
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20. Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression

Author

Mo, Angela, Nagpal, Sini, Gettler, Kyle, Haritunians, Talin, Giri, Mamta, Haberman, Yael, Karns, Rebekah, Prince, Jarod, Arafat, Dalia, Hsu, Nai-Yun, Chuang, Ling-Shiang, Argmann, Carmen, Kasarskis, Andrew, Suarez-Farinas, Mayte, Gotman, Nathan, Mengesha, Emebet, Venkateswaran, Suresh, Rufo, Paul A, Baker, Susan S, Sauer, Cary G, Markowitz, James, Pfefferkorn, Marian D, Rosh, Joel R, Boyle, Brendan M, Mack, David R, Baldassano, Robert N, Shah, Sapana, LeLeiko, Neal S, Heyman, Melvin B, Griffiths, Anne M, Patel, Ashish S, Noe, Joshua D, Davis Thomas, Sonia, Aronow, Bruce J, Walters, Thomas D, McGovern, Dermot PB, Hyams, Jeffrey S, Kugathasan, Subra, Cho, Judy H, Denson, Lee A, and Gibson, Greg

Subjects
Digestive Diseases, Inflammatory Bowel Disease, Human Genome, Autoimmune Disease, Clinical Research, Genetics, Patient Safety, Biotechnology, Prevention, Generic health relevance, Biological Specimen Banks, Cohort Studies, Colectomy, Colitis, Ulcerative, Colon, Crohn Disease, Datasets as Topic, Disease Progression, Gene Expression Profiling, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Prognosis, Quantitative Trait Loci, Risk Assessment, Transcriptome, United Kingdom, cell-type-specific gene expression, eQTLs, predicted polygenic transcriptional risk scores, prediction of disease progression, transcriptional risk scores, transcriptome-wide association studies, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.

Published
2021

21. Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target.

Author

Chen, Ernie, Chuang, Ling-Shiang, Giri, Mamta, Villaverde, Nicole, Hsu, Nai-Yun, Sabic, Ksenija, Joshowitz, Sari, Gettler, Kyle, Nayar, Shikha, Chai, Zhi, Alter, Isaac, Chasteau, Colleen, Korie, Ujunwa, Dzedzik, Siarhei, Thin, Tin, Jain, Aayushee, Moscati, Arden, Bongers, Gerardus, Duerr, Richard, Silverberg, Mark, Brant, Steven, Rioux, John, Peter, Inga, Schumm, L, Haritunians, Talin, McGovern, Dermot, Itan, Yuval, and Cho, Judy

Subjects
G-Protein Coupled Receptors, Mast Cells, Single Cell Sequencing, Ulcerative Colitis, Adrenomedullin, Animals, CHO Cells, Case-Control Studies, Cell Degranulation, Colitis, Ulcerative, Colon, Cricetulus, Extracellular Signal-Regulated MAP Kinases, Genetic Variation, Humans, Inositol Phosphates, Ligands, Mast Cells, Nerve Tissue Proteins, Phosphorylation, Receptors, G-Protein-Coupled, Receptors, Neuropeptide, beta-Arrestin 2
Abstract

BACKGROUND & AIMS: Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC. METHODS: Colon tissues were collected from patients with UC for bulk RNA sequencing and lamina propria cells were isolated for MRGPRX2 activation studies and single-cell RNA sequencing. Genetic association of all protein-altering G-protein coupled receptor single-nucleotide polymorphism was performed in an Ashkenazi Jewish UC case-control cohort. Variants of MRGPRX2 were transfected into Chinese hamster ovary (CHO) and human mast cell (HMC) 1.1 cells to detect genotype-dependent effects on β-arrestin recruitment, IP-1 accumulation, and phosphorylated extracellular signal-regulated kinase. RESULTS: Mast cell-specific mediators and adrenomedullin (proteolytic precursor of PAMP-12, an MRGPRX2 agonist) are up-regulated in inflamed compared to uninflamed UC. MRGPRX2 stimulation induces carboxypeptidase secretion from inflamed UC. Of all protein-altering GPCR alleles, a unique variant of MRGPRX2, Asn62Ser, was most associated with and was bioinformatically predicted to alter arrestin recruitment. We validated that the UC protective serine allele enhances β-arrestin recruitment, decreases IP-1, and increases phosphorylated extracellular signal-regulated kinase with MRGPRX2 agonists. Single-cell RNA sequencing defines that adrenomedullin is expressed by activated fibroblasts and epithelial cells and that interferon gamma is a key upstream regulator of mast cell gene expression. CONCLUSION: Inflamed UC regions are distinguished by MRGPRX2-mediated activation of mast cells, with decreased activation observed with a UC-protective genetic variant. These results define cell modules of UC activation and a new therapeutic target.

Published
2021

22. HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Author

Akar, Alaa, Flemming, Cornelius, Felix, Flomm, Flosbach, Markus, Jäger, Julia, Jeromin, Niklas, Jung, Johannes, Ohms, Mareike, Reinshagen, Konrad, Rische, Johann, Sagebiel, Adrian, Sandfort, Deborah, Steinert, Fenja, Tomuschat, Christian, Wesche, Jasmin, Shifteh Abedian, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Alberts, Rudi, Alizadeh, Behrooz, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Annese, Vito, Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Bampton, Peter A., Barclay, Murray, Barrett, Jeffrey C., Bethge, Johannes, Bewshea, Claire, Bis, Joshua C., Bitton, Alain, BK, Thelma, Boucher, Gabrielle, Brain, Oliver, Brand, Stephan, Brant, Steven R., Cheon, Jae Hee, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Cooney, Rachel, Croft, Anthony, Daly, Mark J., D'Amato, Mauro, Danese, Silvio, Daryani, Naser Ebrahim, Datta, Lisa Wu, Degenhardt, Frauke, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Drummond, Hazel E., Dubinsky, Marla, Duerr, Richard H., Edwards, Cathryn, Ellinghaus, David, Ellul, Pierre, Esaki, Motohiro, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Franke, Andre, Fuyuno, Yuta, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Goyette, Philippe, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Hold, Georgina L., Hong, Myhunghee, Hu, Xinli, Huang, Hailiang, Hugot, Jean-Pierre, Hui, Ken Y., Imielinski, Marcin, Jazayeri, Omid, Jonaitis, Laimas, Jostins, Luke, Juyal, Garima, Chandra Juyal, Ramesh, Kalla, Rahul, Karlsen, Tom H., Kennedy, Nicholas A., Khan, Mohammed Azam, Kim, Won Ho, Kitazono, Takanari, Kiudelis, Gediminas, Kubo, Michiaki, Kugathasan, Subra, Kupcinskas, Limas, Lamb, Christopher A., de Lange, Katrina M., Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Lewis, Nina, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Luo, Yang, Mahy, Gillian, Malekzadeh, Masoud Mohammad, Malekzadeh, Reza, Mansfield, John, Marriott, Suzie, Massey, Dunecan, Mathew, Christopher G., Matsui, Toshiyuki, McGovern, Dermot P.B., van der Meulen, Andrea, Midha, Vandana, Milgrom, Raquel, Mirzaei, Samaneh, Mitrovic, Mitja, Montgomery, Grant W., Mowat, Craig, Müller, Christoph, Newman, William G., Ng, Aylwin, Ng, Siew C., Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nöthen, Markus, Oikonomou, Ioannis, Okou, David, Orchard, Timothy R., Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Urõs, Poustchi, Hossein, Prescott, Natalie J., Proctor, Deborah D., Radford-Smith, Graham, Rahier, Jean- Francois, Regueiro, Miguel, Reinisch, Walter, Rieder, Florian, Rioux, John D., Roberts, Rebecca, Rogler, Gerhard, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Scharl, Michael, Schembri, John, Schreiber, Stefan, Schumm, L. Philip, Scott, Regan, Seielstad, Mark, Shah, Tejas, Sharma, Yashoda, Silverberg, Mark S., Simmons, Alison, Simms, Lisa A., Singh, Abhey, Skieceviciene, Jurgita, van Sommeren, Suzanne, Song, Kyuyoung, Sood, Ajit, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sung, Joseph J.Y., Targan, Stephan R., Taylor, Kirstin M., Theatre, Emilie, Torkvist, Leif, Torres, Esther A., Tremelling, Mark, Uhlig, Holm H., Umeno, Junji, Vahedi, Homayon, Vasiliauskas, Eric, Velde, Anje ter, Ventham, Nicholas T., Vermeire, Severine, Verspaget, Hein W., De Vos, Martine, Walters, Thomas, Wang, Kai, Wang, Ming-Hsi, Weersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Wong, Sunny H., Xavier, Ramnik J., Yamazaki, Keiko, Yang, Suk-Kyun, Ye, Byong Duk, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wei, Zhao, Hongyu, Zhao, Zhen Z., Baumdick, Martin E., Niehrs, Annika, Schwerk, Maria, Hinrichs, Ole, Jordan-Paiz, Ana, Padoan, Benedetta, Wegner, Lucy H.M., Schloer, Sebastian, Zecher, Britta F., Malsy, Jakob, Joshi, Vinita R., Illig, Christin, Schröder-Schwarz, Jennifer, Möller, Kimberly J., Martin, Maureen P., Yuki, Yuko, Ozawa, Mikki, Sauter, Jürgen, Schmidt, Alexander H., Perez, Daniel, Giannou, Anastasios D., Carrington, Mary, Davis, Randall S., Schumacher, Udo, Sauter, Guido, Huber, Samuel, Puelles, Victor G., Melling, Nathaniel, Altfeld, Marcus, and Bunders, Madeleine J.

Published
2023
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23. Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Author

Somineni, Hari, Nagpal, Sini, Venkateswaran, Suresh, Cutler, David, Okou, David, Haritunians, Talin, Simpson, Claire, Begum, Ferdouse, Datta, Lisa, Quiros, Antonio, Seminerio, Jenifer, Mengesha, Emebet, Alexander, Jonathan, Baldassano, Robert, Dudley-Brown, Sharon, Cross, Raymond, Dassopoulos, Themistocles, Denson, Lee, Dhere, Tanvi, Iskandar, Heba, Dryden, Gerald, Hou, Jason, Hussain, Sunny, Hyams, Jeffrey, Isaacs, Kim, Kader, Howard, Kappelman, Michael, Katz, Jeffry, Kellermayer, Richard, Kuemmerle, John, Lazarev, Mark, Li, Ellen, Mannon, Peter, Moulton, Dedrick, Newberry, Rodney, Patel, Ashish, Pekow, Joel, Saeed, Shehzad, Valentine, John, Wang, Ming-Hsi, McCauley, Jacob, Abreu, Maria, Jester, Traci, Molle-Rios, Zarela, Palle, Sirish, Scherl, Ellen, Kwon, John, Rioux, John, Duerr, Richard, Silverberg, Mark, Zwick, Michael, Stevens, Christine, Daly, Mark, Cho, Judy, Gibson, Greg, McGovern, Dermot, Brant, Steven, and Kugathasan, Subra

Subjects
CALB2, PTGER4, differential genetic architecture, polygenic risk scores, rare variants, trans-ethnic comparative analysis, understudied populations, whole-genome sequencing of African Americans, Black or African American, Aged, Aged, 80 and over, Calbindin 2, Colitis, Ulcerative, Crohn Disease, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Receptors, Prostaglandin E, EP4 Subtype, White People, Whole Genome Sequencing
Abstract

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Published
2021

26. Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts

Author

Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Läll, Kristi, Favé, Marie-Julie, Chapman, Sinéad B., Karjalainen, Juha, Kurki, Mitja, Mutaamba, Maasha, Partanen, Juulia J., Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Palta, Priit, Pandit, Anita, Preuss, Michael H., Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Zawistowski, Matthew, Zhong, Xue, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Konuma, Takahiro, Marioni, Riccardo E., Nomdo, Jansonius, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J.F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Trembath, Richard C., Vonk, Judith M., Whiteman, David, Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Cox, Nancy J., Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lin, Yen-Feng, Mägi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno V., Pasaniuc, Bogdan, Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zöllner, Sebastian, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., Lopera, Esteban, Kerminen, Sini, Wu, Kuan-Han, Bhatta, Laxmi, Brumpton, Ben, Deelen, Patrick, Murakami, Yoshinori, Willer, Cristen, and Hirbo, Jibril

Published
2023
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28. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, Aleksejs, Stevens, Christine R., Venkataraman, Guhan R., Yuan, Kai, Avila, Brandon, Abreu, Maria T., Ahmad, Tariq, Allez, Matthieu, Ananthakrishnan, Ashwin N., Atzmon, Gil, Baras, Aris, Barrett, Jeffrey C., Barzilai, Nir, Beaugerie, Laurent, Beecham, Ashley, Bernstein, Charles N., Bitton, Alain, Bokemeyer, Bernd, Chan, Andrew, Chung, Daniel, Cleynen, Isabelle, Cosnes, Jacques, Cutler, David J., Daly, Allan, Damas, Oriana M., Datta, Lisa W., Dawany, Noor, Devoto, Marcella, Dodge, Sheila, Ellinghaus, Eva, Fachal, Laura, Farkkila, Martti, Faubion, William, Ferreira, Manuel, Franchimont, Denis, Gabriel, Stacey B., Ge, Tian, Georges, Michel, Gettler, Kyle, Giri, Mamta, Glaser, Benjamin, Goerg, Siegfried, Goyette, Philippe, Graham, Daniel, Hämäläinen, Eija, Haritunians, Talin, Heap, Graham A., Hiltunen, Mikko, Hoeppner, Marc, Horowitz, Julie E., Irving, Peter, Iyer, Vivek, Jalas, Chaim, Kelsen, Judith, Khalili, Hamed, Kirschner, Barbara S., Kontula, Kimmo, Koskela, Jukka T., Kugathasan, Subra, Kupcinskas, Juozas, Lamb, Christopher A., Laudes, Matthias, Lévesque, Chloé, Levine, Adam P., Lewis, James D., Liefferinckx, Claire, Loescher, Britt-Sabina, Louis, Edouard, Mansfield, John, May, Sandra, McCauley, Jacob L., Mengesha, Emebet, Mni, Myriam, Moayyedi, Paul, Moran, Christopher J., Newberry, Rodney D., O’Charoen, Sirimon, Okou, David T., Oldenburg, Bas, Ostrer, Harry, Palotie, Aarno, Paquette, Jean, Pekow, Joel, Peter, Inga, Pierik, Marieke J., Ponsioen, Cyriel Y., Pontikos, Nikolas, Prescott, Natalie, Pulver, Ann E., Rahmouni, Souad, Rice, Daniel L., Saavalainen, Päivi, Sands, Bruce, Sartor, R. Balfour, Schiff, Elena R., Schreiber, Stefan, Schumm, L. Philip, Segal, Anthony W., Seksik, Philippe, Shawky, Rasha, Sheikh, Shehzad Z., Silverberg, Mark S., Simmons, Alison, Skeiceviciene, Jurgita, Sokol, Harry, Solomonson, Matthew, Somineni, Hari, Sun, Dylan, Targan, Stephan, Turner, Dan, Uhlig, Holm H., van der Meulen, Andrea E., Vermeire, Séverine, Verstockt, Sare, Voskuil, Michiel D., Winter, Harland S., Young, Justine, Duerr, Richard H., Franke, Andre, Brant, Steven R., Cho, Judy, Weersma, Rinse K., Parkes, Miles, Xavier, Ramnik J., Rivas, Manuel A., Rioux, John D., McGovern, Dermot P. B., Huang, Hailiang, Anderson, Carl A., and Daly, Mark J.

Published
2022
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29. Genome-wide polygenic score to predict chronic kidney disease across ancestries

Author

Khan, Atlas, Turchin, Michael C., Patki, Amit, Srinivasasainagendra, Vinodh, Shang, Ning, Nadukuru, Rajiv, Jones, Alana C., Malolepsza, Edyta, Dikilitas, Ozan, Kullo, Iftikhar J., Schaid, Daniel J., Karlson, Elizabeth, Ge, Tian, Meigs, James B., Smoller, Jordan W., Lange, Christoph, Crosslin, David R., Jarvik, Gail P., Bhatraju, Pavan K., Hellwege, Jacklyn N., Chandler, Paulette, Torvik, Laura Rasmussen, Fedotov, Alex, Liu, Cong, Kachulis, Christopher, Lennon, Niall, Abul-Husn, Noura S., Cho, Judy H., Ionita-Laza, Iuliana, Gharavi, Ali G., Chung, Wendy K., Hripcsak, George, Weng, Chunhua, Nadkarni, Girish, Irvin, Marguerite R., Tiwari, Hemant K., Kenny, Eimear E., Limdi, Nita A., and Kiryluk, Krzysztof

Published
2022
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30. Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation

Author

Somineni, Hari K, Venkateswaran, Suresh, Kilaru, Varun, Marigorta, Urko M, Mo, Angela, Okou, David T, Kellermayer, Richard, Mondal, Kajari, Cobb, Dawayland, Walters, Thomas D, Griffiths, Anne, Noe, Joshua D, Crandall, Wallace V, Rosh, Joel R, Mack, David R, Heyman, Melvin B, Baker, Susan S, Stephens, Michael C, Baldassano, Robert N, Markowitz, James F, Dubinsky, Marla C, Cho, Judy, Hyams, Jeffrey S, Denson, Lee A, Gibson, Greg, Cutler, David J, Conneely, Karen N, Smith, Alicia K, and Kugathasan, Subra

Subjects
Autoimmune Disease, Digestive Diseases, Genetics, Human Genome, Clinical Research, Pediatric, Crohn's Disease, Inflammatory Bowel Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Adolescent, Age Factors, Case-Control Studies, Child, Child, Preschool, Crohn Disease, DNA Methylation, Disease Progression, Female, Follow-Up Studies, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Infant, Inflammation, Male, Mendelian Randomization Analysis, North America, Risk Assessment, Severity of Illness Index, Sex Factors, Children, Epigenetic Alteration, Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease (RISK) Study, Clinical Sciences, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

Background & aimsCrohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression.MethodsWe obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease.ResultsWe identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease.ConclusionsMethylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.

Published
2019

31. Genetic Factors and the Intestinal Microbiome Guide Development of Microbe-Based Therapies for Inflammatory Bowel Diseases

Author

Cohen, Louis J, Cho, Judy H, Gevers, Dirk, and Chu, Hiutung

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Nutrition, Biodefense, Vaccine Related, Infectious Diseases, Genetics, Digestive Diseases, Prevention, Human Genome, Emerging Infectious Diseases, Crohn's Disease, Autoimmune Disease, Inflammatory Bowel Disease, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Inflammatory and immune system, Animals, Drugs, Investigational, Gastrointestinal Microbiome, Genome, Human, Humans, Immunotherapy, Inflammatory Bowel Diseases, Mice, Models, Animal, Practice Guidelines as Topic, Prognosis, Treatment Outcome, Host Genetics, Microbiome, Mucosal Immunity, Preclinical Therapies, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

The intestinal microbiota is a dynamic community of bacteria, fungi, and viruses that mediates mucosal homeostasis and physiology. Imbalances in the microbiome and aberrant immune responses to gut bacteria can disrupt homeostasis and are associated with inflammatory bowel diseases (IBDs) in humans and colitis in mice. We review genetic variants associated with IBD and their effects on the intestinal microbiome, the immune response, and disease pathogenesis. The intestinal microbiome, which includes microbial antigens, adjuvants, and metabolic products, affects the development and function of the intestinal mucosa, influencing inflammatory responses in the gut. Therefore, strategies to manipulate the microbiome might be used in treatment of IBD. We review microbe-based therapies for IBD and the potential to engineer patients' intestinal microbiota. We discuss how studies of patients with IBD and mouse models have advanced our understanding of the interactions between genetic factors and the gut microbiome, and challenges to the development of microbe-based therapies for IBD.

Published
2019

32. Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Author

Zhou, Wei, Kanai, Masahiro, Wu, Kuan-Han H., Rasheed, Humaira, Tsuo, Kristin, Hirbo, Jibril B., Wang, Ying, Bhattacharya, Arjun, Zhao, Huiling, Namba, Shinichi, Surakka, Ida, Wolford, Brooke N., Lo Faro, Valeria, Lopera-Maya, Esteban A., Läll, Kristi, Favé, Marie-Julie, Partanen, Juulia J., Chapman, Sinéad B., Karjalainen, Juha, Kurki, Mitja, Maasha, Mutaamba, Brumpton, Ben M., Chavan, Sameer, Chen, Tzu-Ting, Daya, Michelle, Ding, Yi, Feng, Yen-Chen A., Guare, Lindsay A., Gignoux, Christopher R., Graham, Sarah E., Hornsby, Whitney E., Ingold, Nathan, Ismail, Said I., Johnson, Ruth, Laisk, Triin, Lin, Kuang, Lv, Jun, Millwood, Iona Y., Moreno-Grau, Sonia, Nam, Kisung, Palta, Priit, Pandit, Anita, Preuss, Michael H., Saad, Chadi, Setia-Verma, Shefali, Thorsteinsdottir, Unnur, Uzunovic, Jasmina, Verma, Anurag, Zawistowski, Matthew, Zhong, Xue, Afifi, Nahla, Al-Dabhani, Kawthar M., Al Thani, Asma, Bradford, Yuki, Campbell, Archie, Crooks, Kristy, de Bock, Geertruida H., Damrauer, Scott M., Douville, Nicholas J., Finer, Sarah, Fritsche, Lars G., Fthenou, Eleni, Gonzalez-Arroyo, Gilberto, Griffiths, Christopher J., Guo, Yu, Hunt, Karen A., Ioannidis, Alexander, Jansonius, Nomdo M., Konuma, Takahiro, Michael Lee, Ming Ta, Lopez-Pineda, Arturo, Matsuda, Yuta, Marioni, Riccardo E., Moatamed, Babak, Nava-Aguilar, Marco A., Numakura, Kensuke, Patil, Snehal, Rafaels, Nicholas, Richmond, Anne, Rojas-Muñoz, Agustin, Shortt, Jonathan A., Straub, Peter, Tao, Ran, Vanderwerff, Brett, Vernekar, Manvi, Veturi, Yogasudha, Barnes, Kathleen C., Boezen, Marike, Chen, Zhengming, Chen, Chia-Yen, Cho, Judy, Smith, George Davey, Finucane, Hilary K., Franke, Lude, Gamazon, Eric R., Ganna, Andrea, Gaunt, Tom R., Ge, Tian, Huang, Hailiang, Huffman, Jennifer, Katsanis, Nicholas, Koskela, Jukka T., Lajonchere, Clara, Law, Matthew H., Li, Liming, Lindgren, Cecilia M., Loos, Ruth J.F., MacGregor, Stuart, Matsuda, Koichi, Olsen, Catherine M., Porteous, David J., Shavit, Jordan A., Snieder, Harold, Takano, Tomohiro, Trembath, Richard C., Vonk, Judith M., Whiteman, David C., Wicks, Stephen J., Wijmenga, Cisca, Wright, John, Zheng, Jie, Zhou, Xiang, Awadalla, Philip, Boehnke, Michael, Bustamante, Carlos D., Cox, Nancy J., Fatumo, Segun, Geschwind, Daniel H., Hayward, Caroline, Hveem, Kristian, Kenny, Eimear E., Lee, Seunggeun, Lin, Yen-Feng, Mbarek, Hamdi, Mägi, Reedik, Martin, Hilary C., Medland, Sarah E., Okada, Yukinori, Palotie, Aarno V., Pasaniuc, Bogdan, Rader, Daniel J., Ritchie, Marylyn D., Sanna, Serena, Smoller, Jordan W., Stefansson, Kari, van Heel, David A., Walters, Robin G., Zöllner, Sebastian, Biobank of the Americas, Biobank Japan Project, BioMe, BioVU, CanPath - Ontario Health Study, China Kadoorie Biobank Collaborative Group, Colorado Center for Personalized Medicine, deCODE Genetics, Estonian Biobank, FinnGen, Generation Scotland, Genes & Health Research Team, LifeLines, Mass General Brigham Biobank, Michigan Genomics Initiative, National Biobank of Korea, Penn Medicine BioBank, Qatar Biobank, The Qskin Sun and Health Study, Taiwan Biobank, The Hunt Study, Ucla Atlas Community Health Initiative, Uganda Genome Resource, Uk Biobank, Martin, Alicia R., Willer, Cristen J., Daly, Mark J., Neale, Benjamin M., and Elzur, Roy

Published
2022
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33. Neutralizing Anti-Granulocyte Macrophage-Colony Stimulating Factor Autoantibodies Recognize Post-Translational Glycosylations on Granulocyte Macrophage-Colony Stimulating Factor Years Before Diagnosis and Predict Complicated Crohn’s Disease

Author

Mortha, Arthur, Remark, Romain, Del Valle, Diane Marie, Chuang, Ling-Shiang, Chai, Zhi, Alves, Inês, Azevedo, Catarina, Gaifem, Joana, Martin, Jerome, Petralia, Francesca, Tuballes, Kevin, Barcessat, Vanessa, Tai, Siu Ling, Huang, Hsin-Hui, Laface, Ilaria, Jerez, Yeray Arteaga, Boschetti, Gilles, Villaverde, Nicole, Wang, Mona D., Korie, Ujunwa M., Murray, Joseph, Choung, Rok-Seon, Sato, Takahiro, Laird, Renee M., Plevy, Scott, Rahman, Adeeb, Torres, Joana, Porter, Chad, Riddle, Mark S., Kenigsberg, Ephraim, Pinho, Salomé S., Cho, Judy H., Merad, Miriam, Colombel, Jean-Frederic, and Gnjatic, Sacha

Published
2022
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37. An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Author

Bolton, Chrissy, Smillie, Christopher S., Pandey, Sumeet, Elmentaite, Rasa, Wei, Gabrielle, Argmann, Carmen, Aschenbrenner, Dominik, James, Kylie R., McGovern, Dermot P.B., Macchi, Marina, Cho, Judy, Shouval, Dror S., Kammermeier, Jochen, Koletzko, Sibylle, Bagalopal, Krithika, Capitani, Melania, Cavounidis, Athena, Pires, Elisabete, Weidinger, Carl, McCullagh, James, Arkwright, Peter D., Haller, Wolfram, Siegmund, Britta, Peters, Lauren, Jostins, Luke, Travis, Simon P.L., Anderson, Carl A., Snapper, Scott, Klein, Christoph, Schadt, Eric, Zilbauer, Matthias, Xavier, Ramnik, Teichmann, Sarah, Muise, Aleixo M., Regev, Aviv, and Uhlig, Holm H.

Published
2022
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38. Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets

Author

Di'Narzo, Antonio F., Houten, Sander M., Kosoy, Roman, Huang, Ruiqi, Vaz, Frédéric M., Hou, Ruixue, Wei, Gabrielle, Wang, Wenhui, Comella, Phillip H., Dodatko, Tetyana, Rogatsky, Eduard, Stojmirovic, Aleksandar, Brodmerkel, Carrie, Perrigoue, Jacqueline, Hart, Amy, Curran, Mark, Friedman, Joshua R., Zhu, Jun, Agrawal, Manasi, Cho, Judy, Ungaro, Ryan, Dubinsky, Marla C., Sands, Bruce E., Suárez-Fariñas, Mayte, Schadt, Eric E., Colombel, Jean-Frédéric, Kasarskis, Andrew, Hao, Ke, and Argmann, Carmen

Published
2022
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39. Insights into the genetic epidemiology of Crohns and rare diseases in the Ashkenazi Jewish population.

Author

Rivas, Manuel, Avila, Brandon, Koskela, Jukka, Huang, Hailiang, Stevens, Christine, Pirinen, Matti, Haritunians, Talin, Neale, Benjamin, Kurki, Mitja, Ganna, Andrea, Graham, Daniel, Glaser, Benjamin, Peter, Inga, Atzmon, Gil, Barzilai, Nir, Levine, Adam, Schiff, Elena, Pontikos, Nikolas, Weisburd, Ben, Lek, Monkol, Karczewski, Konrad, Bloom, Jonathan, Minikel, Eric, Petersen, Britt-Sabina, Beaugerie, Laurent, Seksik, Philippe, Cosnes, Jacques, Schreiber, Stefan, Bokemeyer, Bernd, Bethge, Johannes, Heap, Graham, Ahmad, Tariq, Plagnol, Vincent, Segal, Anthony, Targan, Stephan, Turner, Dan, Saavalainen, Paivi, Farkkila, Martti, Kontula, Kimmo, Palotie, Aarno, Brant, Steven, Duerr, Richard, Silverberg, Mark, Rioux, John, Weersma, Rinse, Franke, Andre, Jostins, Luke, Anderson, Carl, Barrett, Jeffrey, MacArthur, Daniel, Jalas, Chaim, Sokol, Harry, Xavier, Ramnik, Pulver, Ann, Cho, Judy, McGovern, Dermot, and Daly, Mark

Subjects
Algorithms, Crohn Disease, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Haplotypes, Humans, Jews, Models, Genetic, Molecular Epidemiology, Polymorphism, Single Nucleotide, Rare Diseases
Abstract

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with pathogenic ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohns disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohns disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p

Published
2018

40. Functional variants in the LRRK2 gene confer shared effects on risk for Crohns disease and Parkinsons disease.

Author

Hui, Ken, Fernandez-Hernandez, Heriberto, Hu, Jianzhong, Schaffner, Adam, Pankratz, Nathan, Hsu, Nai-Yun, Chuang, Ling-Shiang, Carmi, Shai, Villaverde, Nicole, Li, Xianting, Rivas, Manual, Levine, Adam, Bao, Xiuliang, Labrias, Philippe, Haritunians, Talin, Ruane, Darren, Gettler, Kyle, Chen, Ernie, Li, Dalin, Schiff, Elena, Pontikos, Nikolas, Barzilai, Nir, Brant, Steven, Bressman, Susan, Cheifetz, Adam, Clark, Lorraine, Daly, Mark, Desnick, Robert, Duerr, Richard, Katz, Seymour, Lencz, Todd, Myers, Richard, Ostrer, Harry, Ozelius, Laurie, Payami, Haydeh, Peter, Yakov, Rioux, John, Segal, Anthony, Scott, William, Silverberg, Mark, Vance, Jeffery, Ubarretxena-Belandia, Iban, Foroud, Tatiana, Atzmon, Gil, Peer, Itsik, Ioannou, Yiannis, McGovern, Dermot, Yue, Zhenyu, Schadt, Eric, Cho, Judy, and Peter, Inga

Subjects
Alleles, Autophagy, Crohn Disease, Cytoskeleton, Exome, Gene Frequency, Gene Regulatory Networks, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Macrophages, Odds Ratio, Open Reading Frames, Parkinson Disease, Phenotype, Reproducibility of Results, Risk Factors, Exome Sequencing
Abstract

Crohns disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10-10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10-8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinsons disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.

Published
2018

41. Clinical impact and financial feasibility of remote oncology pharmacists' roles in community oncology practices.

Author

Roman, Andrea, primary, Cho, Judy, additional, Jovani, Juna, additional, Farag, Caroline, additional, Carroll, Melissa, additional, Conkling, Hilary, additional, Greisl, Natalie, additional, Hale, Brittney, additional, Kendzierski, Daniel, additional, Keisler, Meredith, additional, Koselke, Beth, additional, and Hough, Shannon, additional

Published
2024
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43. Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension

Author

Argmann, Carmen, Tokuyama, Minami, Ungaro, Ryan C., Huang, Ruiqi, Hou, Ruixue, Gurunathan, Sakteesh, Kosoy, Roman, Di’Narzo, Antonio, Wang, Wenhui, Losic, Bojan, Irizar, Haritz, Peters, Lauren, Stojmirovic, Aleksandar, Wei, Gabrielle, Comella, Phillip H., Curran, Mark, Brodmerkel, Carrie, Friedman, Joshua R., Hao, Ke, Schadt, Eric E., Zhu, Jun, Cho, Judy, Harpaz, Noam, Dubinsky, Marla C., Sands, Bruce E., Kasarskis, Andrew, Mehandru, Saurabh, Colombel, Jean-Frederic, and Suárez-Fariñas, Mayte

Published
2021
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44. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author

Neale, Benjamin M., Daly, Mark, Ganna, Andrea, Stevens, Christine, Pathak, Gita A., Andrews, Shea J., Kanai, Masahiro, Cordioli, Mattia, Karjalainen, Juha, Polimanti, Renato, Pirinen, Matti, Harerimana, Nadia, Veerapen, Kumar, Wolford, Brooke, Nguyen, Huy, Solomonson, Matthew, Liao, Rachel G., Chwialkowska, Karolina, Trankiem, Amy, Balaconis, Mary K., Hayward, Caroline, Richmond, Anne, Campbell, Archie, Morris, Marcela, Fawns-Ritchie, Chloe, Glessner, Joseph T., Shaw, Douglas M., Chang, Xiao, Polikowski, Hannah, Lauren, Petty E., Chen, Hung-Hsin, Wanying, Zhu, Hakonarson, Hakon, Porteous, David J., Below, Jennifer, North, Kari, McCormick, Joseph B., Timmers, Paul R.H.J., Wilson, James F., Tenesa, Albert, D’Mellow, Kenton, Kerr, Shona M., Niemi, Mari E.K., Nkambul, Lindokuhle, Aprile von Hohenstaufen, Kathrin, Sobh, Ali, Eltoukhy, Madonna M., Yassen, Amr M., Hegazy, Mohamed A.F., Okasha, Kamal, Eid, Mohammed A., Moahmed, Hanteera S., Shahin, Doaa, El-Sherbiny, Yasser M., Elhadidy, Tamer A., Abd Elghafar, Mohamed S., El-Jawhari, Jehan J., Mohamed, Attia A.S., Elnagdy, Marwa H., Samir, Amr, Abdel-Aziz, Mahmoud, Khafaga, Walid T., El-Lawaty, Walaa M., Torky, Mohamed S., El-shanshory, Mohamed R., Batini, Chiara, Lee, Paul H., Shrine, Nick, Williams, Alexander T., Tobin, Martin D., Guyatt, Anna L., John, Catherine, Packer, Richard J., Ali, Altaf, Free, Robert C., Wang, Xueyang, Wain, Louise V., Hollox, Edward J., Venn, Laura D., Bee, Catherine E., Adams, Emma L., Niavarani, Ahmadreza, Sharififard, Bahareh, Aliannejad, Rasoul, Amirsavadkouhi, Ali, Naderpour, Zeinab, Tadi, Hengameh Ansari, Aleagha, Afshar Etemadi, Ahmadi, Saeideh, Mohseni Moghaddam, Seyed Behrooz, Adamsara, Alireza, Saeedi, Morteza, Abdollahi, Hamed, Hosseini, Abdolmajid, Chariyavilaskul, Pajaree, Chamnanphon, Monpat, Suttichet, Thitima B., Shotelersuk, Vorasuk, Pongpanich, Monnat, Phokaew, Chureerat, Chetruengchai, Wanna, Jantarabenjakul, Watsamon, Putchareon, Opass, Torvorapanit, Pattama, Puthanakit, Thanyawee, Suchartlikitwong, Pintip, Hirankarn, Nattiya, Nilaratanakul, Voraphoj, Sodsai, Pimpayao, Brumpton, Ben M., Hveem, Kristian, Willer, Cristen, Zhou, Wei, Rogne, Tormod, Solligard, Erik, Åsvold, Bjørn Olav, Abedalthagafi, Malak, Alaamery, Manal, Alqahtani, Saleh, Baraka, Dona, Al Harthi, Fawz, Alsolm, Ebtehal, Safieh, Leen Abu, Alowayn, Albandary M., Alqubaishi, Fatimah, Al Mutairi, Amal, Mangul, Serghei, Alshareef, Abdulraheem, Sawaji, Mona, Almutairi, Mansour, Aljawini, Nora, Albesher, Nour, Arabi, Yaseen M., Mahmoud, Ebrahim S., Khattab, Amin K., Halawani, Roaa T., Alahmadey, Ziab Z., Albakri, Jehad K., Felemban, Walaa A., Suliman, Bandar A., Hasanato, Rana, Al-Awdah, Laila, Alghamdi, Jahad, AlZahrani, Deema, AlJohani, Sameera, Al-Afghani, Hani, Alrashed, May, AlDhawi, Nouf, AlBardis, Hadeel, Alkwai, Sarah, Alswailm, Moneera, Almalki, Faisal, Albeladi, Maha, Almohammed, Iman, Barhoush, Eman, Albader, Anoud, Massadeh, Salam, AlMalik, Abdulaziz, Alotaibi, Sara, Alghamdi, Bader, Jung, Junghyun, Fawzy, Mohammad S., Lee, Yunsung, Magnus, Per, Trogstad, Lill-Iren S., Helgeland, Øyvind, Harris, Jennifer R., Mangino, Massimo, Spector, Tim D., Emma, Duncan, Smieszek, Sandra P., Przychodzen, Bartlomiej P., Polymeropoulos, Christos, Polymeropoulos, Vasilios, Polymeropoulos, Mihael H., Fernandez-Cadenas, Israel, Perez-Tur, Jordi, Llucià-Carol, Laia, Cullell, Natalia, Muiño, Elena, Cárcel-Márquez, Jara, DeDiego, Marta L., Iglesias, Lara Lloret, Planas, Anna M., Soriano, Alex, Rico, Veronica, Agüero, Daiana, Bedini, Josep L., Lozano, Francisco, Domingo, Carlos, Robles, Veronica, Ruiz-Jaén, Francisca, Márquez, Leonardo, Gomez, Juan, Coto, Eliecer, Albaiceta, Guillermo M., García-Clemente, Marta, Dalmau, David, Arranz, Maria J., Dietl, Beatriz, Serra-Llovich, Alex, Soler, Pere, Colobrán, Roger, Martín-Nalda, Andrea, Martínez, Alba Parra, Bernardo, David, Rojo, Silvia, Fiz-López, Aida, Arribas, Elisa, Cal-Sabater, Paloma de la, Segura, Tomás, González-Villa, Esther, Serrano-Heras, Gemma, Martí-Fàbregas, Joan, Jiménez-Xarrié, Elena, de Felipe Mimbrera, Alicia, Masjuan, Jaime, García-Madrona, Sebastian, Domínguez-Mayoral, Anna, Villalonga, Joan Montaner, Menéndez-Valladares, Paloma, Chasman, Daniel I., Buring, Julie E., Ridker, Paul M., Franco, Giulianini, Sesso, Howard D., Manson, JoAnn E., Glessner, Joseph R., Medina-Gomez, Carolina, Uitterlinden, Andre G., Ikram, M. Arfan, Kristiansson, Kati, Koskelainen, Sami, Perola, Markus, Donner, Kati, Kivinen, Katja, Palotie, Aarno, Ripatti, Samuli, Ruotsalainen, Sanni, Kaunisto, Mari, FinnGen, Nakanishi, Tomoko, Butler-Laporte, Guillaume, Forgetta, Vincenzo, Morrison, David R., Ghosh, Biswarup, Laurent, Laetitia, Belisle, Alexandre, Henry, Danielle, Abdullah, Tala, Adeleye, Olumide, Mamlouk, Noor, Kimchi, Nofar, Afrasiabi, Zaman, Branka Vulesevic, Nardin Rezk, Bouab, Meriem, Guzman, Charlotte, Petitjean, Louis, Tselios, Chris, Xue, Xiaoqing, Schurr, Erwin, Afilalo, Jonathan, Afilalo, Marc, Oliveira, Maureen, Brenner, Bluma, Lepage, Pierre, Ragoussis, Jiannis, Auld, Daniel, Brassard, Nathalie, Durand, Madeleine, Chassé, Michaël, Kaufmann, Daniel E., Lathrop, G. Mark, Mooser, Vincent, Richards, J. Brent, Li, Rui, Adra, Darin, Rahmouni, Souad, Georges, Michel, Moutschen, Michel, Misset, Benoit, Darcis, Gilles, Guiot, Julien, Guntz, Julien, Azarzar, Samira, Gofflot, Stéphanie, Beguin, Yves, Claassen, Sabine, Malaise, Olivier, Huynen, Pascale, Meuris, Christelle, Thys, Marie, Jacques, Jessica, Léonard, Philippe, Frippiat, Frederic, Giot, Jean-Baptiste, Sauvage, Anne-Sophie, Von Frenckell, Christian, Belhaj, Yasmine, Lambermont, Bernard, Pigazzini, Sara, Nkambule, Lindokuhle, Daya, Michelle, Shortt, Jonathan, Rafaels, Nicholas, Wicks, Stephen J., Crooks, Kristy, Barnes, Kathleen C., Gignoux, Christopher R., Chavan, Sameer, Laisk, Triin, Läll, Kristi, Lepamets, Maarja, Mägi, Reedik, Esko, Tõnu, Reimann, Ene, Milani, Lili, Alavere, Helene, Metsalu, Kristjan, Puusepp, Mairo, Metspalu, Andres, Naaber, Paul, Laane, Edward, Pesukova, Jaana, Peterson, Pärt, Kisand, Kai, Tabri, Jekaterina, Allos, Raili, Hensen, Kati, Starkopf, Joel, Ringmets, Inge, Tamm, Anu, Kallaste, Anne, Bochud, Pierre-Yves, Rivolta, Carlo, Bibert, Stéphanie, Quinodoz, Mathieu, Kamdar, Dhryata, Boillat, Noémie, Nussle, Semira Gonseth, Albrich, Werner, Suh, Noémie, Neofytos, Dionysios, Erard, Véronique, Voide, Cathy, FHoGID, RegCOVID, P-PredictUs, SeroCOVID, CRiPSI, de Cid, Rafael, Galván-Femenía, Iván, Blay, Natalia, Carreras, Anna, Cortés, Beatriz, Farré, Xavier, Sumoy, Lauro, Moreno, Victor, Mercader, Josep Maria, Guindo-Martinez, Marta, Torrents, David, Kogevinas, Manolis, Garcia-Aymerich, Judith, Castaño-Vinyals, Gemma, Dobaño, Carlota, Renieri, Alessandra, Mari, Francesca, Fallerini, Chiara, Daga, Sergio, Benetti, Elisa, Baldassarri, Margherita, Fava, Francesca, Frullanti, Elisa, Valentino, Floriana, Doddato, Gabriella, Giliberti, Annarita, Tita, Rossella, Amitrano, Sara, Bruttini, Mirella, Croci, Susanna, Meloni, Ilaria, Mencarelli, Maria Antonietta, Lo Rizzo, Caterina, Pinto, Anna Maria, Beligni, Giada, Tommasi, Andrea, Di Sarno, Laura, Palmieri, Maria, Carriero, Miriam Lucia, Alaverdian, Diana, Busani, Stefano, Bruno, Raffaele, Vecchia, Marco, Belli, Mary Ann, Picchiotti, Nicola, Sanarico, Maurizio, Gori, Marco, Furini, Simone, Mantovani, Stefania, Ludovisi, Serena, Mondelli, Mario Umberto, Castelli, Francesco, Quiros-Roldan, Eugenia, Antoni, Melania Degli, Zanella, Isabella, Vaghi, Massimo, Rusconi, Stefano, Siano, Matteo, Montagnani, Francesca, Emiliozzi, Arianna, Fabbiani, Massimiliano, Rossetti, Barbara, Bargagli, Elena, Bergantini, Laura, D’Alessandro, Miriana, Cameli, Paolo, Bennett, David, Anedda, Federico, Marcantonio, Simona, Scolletta, Sabino, Franchi, Federico, Mazzei, Maria Antonietta, Guerrini, Susanna, Conticini, Edoardo, Cantarini, Luca, Frediani, Bruno, Tacconi, Danilo, Spertilli, Chiara, Feri, Marco, Donati, Alice, Scala, Raffaele, Guidelli, Luca, Spargi, Genni, Corridi, Marta, Nencioni, Cesira, Croci, Leonardo, Bandini, Maria, Caldarelli, Gian Piero, Piacentini, Paolo, Desanctis, Elena, Cappelli, Silvia, Canaccini, Anna, Verzuri, Agnese, Anemoli, Valentina, Ognibene, Agostino, Pancrazzi, Alessandro, Lorubbio, Maria, D’Arminio Monforte, Antonella, Miraglia, Federica Gaia, Girardis, Massimo, Venturelli, Sophie, Cossarizza, Andrea, Antinori, Andrea, Vergori, Alessandra, Gabrieli, Arianna, Riva, Agostino, Francisci, Daniela, Schiaroli, Elisabetta, Paciosi, Francesco, Scotton, Pier Giorgio, Andretta, Francesca, Panese, Sandro, Scaggiante, Renzo, Gatti, Francesca, Parisi, Saverio Giuseppe, Baratti, Stefano, Della Monica, Matteo, Piscopo, Carmelo, Capasso, Mario, Russo, Roberta, Andolfo, Immacolata, Iolascon, Achille, Fiorentino, Giuseppe, Carella, Massimo, Castori, Marco, Merla, Giuseppe, Squeo, Gabriella Maria, Aucella, Filippo, Raggi, Pamela, Marciano, Carmen, Perna, Rita, Bassetti, Matteo, Di Biagio, Antonio, Sanguinetti, Maurizio, Masucci, Luca, Valente, Serafina, Mandalà, Marco, Giorli, Alessia, Salerni, Lorenzo, Zucchi, Patrizia, Parravicini, Pierpaolo, Menatti, Elisabetta, Trotta, Tullio, Giannattasio, Ferdinando, Coiro, Gabriella, Lena, Fabio, Coviello, Domenico A., Mussini, Cristina, Martinelli, Enrico, Mancarella, Sandro, Tavecchia, Luisa, Crotti, Lia, Gabbi, Chiara, Rizzi, Marco, Maggiolo, Franco, Ripamonti, Diego, Bachetti, Tiziana, La Rovere, Maria Teresa, Sarzi-Braga, Simona, Bussotti, Maurizio, Ceri, Stefano, Pinoli, Pietro, Raimondi, Francesco, Biscarini, Filippo, Stella, Alessandra, Zguro, Kristina, Capitani, Katia, Suardi, Claudia, Dei, Simona, Parati, Gianfranco, Ravaglia, Sabrina, Artuso, Rosangela, Bottà, Giordano, Di Domenico, Paolo, Rancan, Ilaria, Francesco Bianchi, Antonio Perrella, Romani, Davide, Bergomi, Paola, Catena, Emanuele, Colombo, Riccardo, Tanfoni, Marco, Vincenti, Antonella, Ferri, Claudio, Grassi, Davide, Pessina, Gloria, Tumbarello, Mario, Di Pietro, Massimo, Sabrina, Ravaglia, Luchi, Sauro, Barbieri, Chiara, Acquilini, Donatella, Andreucci, Elena, Segala, Francesco Vladimiro, Tiseo, Giusy, Falcone, Marco, Lista, Mirjam, Poscente, Monica, De Vivo, Oreste, Petrocelli, Paola, Guarnaccia, Alessandra, Baroni, Silvia, Smith, Albert V., Boughton, Andrew P., Li, Kevin W., LeFaive, Jonathon, Annis, Aubrey, Justice, Anne E., Mirshahi, Tooraj, Chittoor, Geetha, Josyula, Navya Shilpa, Kosmicki, Jack A., Ferreira, Manuel A.R., Leader, Joseph B., Carey, Dave J., Gass, Matthew C., Horowitz, Julie E., Cantor, Michael N., Yadav, Ashish, Baras, Aris, Abecasis, Goncalo R., van Heel, David A., Hunt, Karen A., Mason, Dan, Huang, Qin Qin, Finer, Sarah, Genes & Health Research Team, Trivedi, Bhavi, Griffiths, Christopher J., Martin, Hilary C., Wright, John, Trembath, Richard C., Soranzo, Nicole, Zhao, Jing Hua, Butterworth, Adam S., Danesh, John, Di Angelantonio, Emanuele, Marike Boezen, Lude Franke, Deelen, Patrick, Claringbould, Annique, Lopera, Esteban, Warmerdam, Robert, Vonk, Judith.M., van Blokland, Irene, Lanting, Pauline, Ori, Anil P.S., Sebastian Zöllner, Brooke Wolford, Wang, Jiongming, Beck, Andrew, Peloso, Gina, Ho, Yuk-Lam, Sun, Yan V., Huffman, Jennifer E., O’Donnell, Christopher J., Cho, Kelly, Tsao, Phil, Gaziano, J. Michael, Nivard, Michel (M.G.), de geus, Eco (E.J.C.), Bartels, Meike, Hottenga, Jouke Jan, Weiss, Scott T., Karlson, Elizabeth W., Smoller, Jordan W., Green, Robert C., Anne Feng, Yen-Chen, Mercader, Josep, Murphy, Shawn N., Meigs, James B., Woolley, Ann E., Perez, Emma F., Rader, Daniel, Verma, Anurag, Ritchie, Marylyn D., Li, Binglan, Verma, Shefali S., Lucas, Anastasia, Bradford, Yuki, Zeberg, Hugo, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklos, Nkambul, Lindo, Tardif, Nicolas, Rooyackers, Olav, Grip, Jonathan, Maricic, Tomislav, Karczewski, Konrad J., Atkinson, Elizabeth G., Tsuo, Kristin, Baya, Nikolas, Turley, Patrick, Gupta, Rahul, Callier, Shawneequa, Walters, Raymond K., Palmer, Duncan S., Sarma, Gopal, Cheng, Nathan, Lu, Wenhan, Bryant, Sam, Churchhouse, Claire, Cusick, Caroline, Goldstein, Jacqueline I., King, Daniel, Seed, Cotton, Finucane, Hilary, Martin, Alicia R., Satterstrom, F. Kyle, Wilson, Daniel J., Armstrong, Jacob, Rudkin, Justine K., Band, Gavin, Earle, Sarah G., Lin, Shang-Kuan, Arning, Nicolas, Crook, Derrick W., Wyllie, David H., O’Connell, Anne Marie, Spencer, Chris C.A., Koelling, Nils, Caulfield, Mark J., Scott, Richard H., Fowler, Tom, Moutsianas, Loukas, Kousathanas, Athanasios, Pasko, Dorota, Walker, Susan, Rendon, Augusto, Stuckey, Alex, Odhams, Christopher A., Rhodes, Daniel, Chan, Georgia, Arumugam, Prabhu, Ball, Catherine A., Hong, Eurie L., Rand, Kristin, Girshick, Ahna, Guturu, Harendra, Baltzell, Asher Haug, Roberts, Genevieve, Park, Danny, Coignet, Marie, McCurdy, Shannon, Knight, Spencer, Partha, Raghavendran, Rhead, Brooke, Zhang, Miao, Berkowitz, Nathan, Gaddis, Michael, Noto, Keith, Ruiz, Luong, Pavlovic, Milos, Sloofman, Laura G., Charney, Alexander W., Beckmann, Noam D., Schadt, Eric E., Jordan, Daniel M., Thompson, Ryan C., Gettler, Kyle, Abul-Husn, Noura S., Ascolillo, Steven, Buxbaum, Joseph D., Chaudhary, Kumardeep, Cho, Judy H., Itan, Yuval, Kenny, Eimear E., Belbin, Gillian M., Sealfon, Stuart C., Sebra, Robert P., Salib, Irene, Collins, Brett L., Levy, Tess, Britvan, Bari, Keller, Katherine, Tang, Lara, Peruggia, Michael, Hiester, Liam L., Niblo, Kristi, Aksentijevich, Alexandra, Labkowsky, Alexander, Karp, Avromie, Zlatopolsky, Menachem, Preuss, Michael, Loos, Ruth J.F., Nadkarni, Girish N., Do, Ron, Hoggart, Clive, Choi, Sam, Underwood, Slayton J., O’Reilly, Paul, Huckins, Laura M., Zyndorf, Marissa, D’Antonio, Matteo, Nguyen, Jennifer P., Arthur, Timothy D., Matsui, Hiroko, D’Antonio-Chronowska, Agnieszka, and Frazer, Kelly A.

Published
2021
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45. Novel ultra-rare exonic variants identified in a founder population implicate cadherins in schizophrenia

Author

Lencz, Todd, Yu, Jin, Khan, Raiyan Rashid, Flaherty, Erin, Carmi, Shai, Lam, Max, Ben-Avraham, Danny, Barzilai, Nir, Bressman, Susan, Darvasi, Ariel, Cho, Judy H., Clark, Lorraine N., Gümüş, Zeynep H., Vijai, Joseph, Klein, Robert J., Lipkin, Steven, Offit, Kenneth, Ostrer, Harry, Ozelius, Laurie J., Peter, Inga, Malhotra, Anil K., Maniatis, Tom, Atzmon, Gil, and Pe’er, Itsik

Published
2021
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46. Toward a fine-scale population health monitoring system

Author

Belbin, Gillian M., Cullina, Sinead, Wenric, Stephane, Soper, Emily R., Glicksberg, Benjamin S., Torre, Denis, Moscati, Arden, Wojcik, Genevieve L., Shemirani, Ruhollah, Beckmann, Noam D., Cohain, Ariella, Sorokin, Elena P., Park, Danny S., Ambite, Jose-Luis, Ellis, Steve, Auton, Adam, Bottinger, Erwin P., Cho, Judy H., Loos, Ruth J.F., Abul-Husn, Noura S., Zaitlen, Noah A., Gignoux, Christopher R., and Kenny, Eimear E.

Published
2021
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47. Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort

Author

Gettler, Kyle, Levantovsky, Rachel, Moscati, Arden, Giri, Mamta, Wu, Yiming, Hsu, Nai-Yun, Chuang, Ling-Shiang, Sazonovs, Aleksejs, Venkateswaran, Suresh, Korie, Ujunwa, Chasteau, Colleen, Duerr, Richard H., Silverberg, Mark S., Snapper, Scott B., Daly, Mark J., McGovern, Dermot P., Brant, Steven R., Rioux, John D., Kugathasan, Subra, Anderson, Carl A., Itan, Yuval, and Cho, Judy H.

Published
2021
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48. Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease

Author

Marigorta, Urko M, Denson, Lee A, Hyams, Jeffrey S, Mondal, Kajari, Prince, Jarod, Walters, Thomas D, Griffiths, Anne, Noe, Joshua D, Crandall, Wallace V, Rosh, Joel R, Mack, David R, Kellermayer, Richard, Heyman, Melvin B, Baker, Susan S, Stephens, Michael C, Baldassano, Robert N, Markowitz, James F, Kim, Mi-Ok, Dubinsky, Marla C, Cho, Judy, Aronow, Bruce J, Kugathasan, Subra, and Gibson, Greg

Subjects
Biological Sciences, Genetics, Crohn's Disease, Prevention, Human Genome, Autoimmune Disease, Inflammatory Bowel Disease, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Age of Onset, Alleles, Child, Crohn Disease, Datasets as Topic, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Ileum, Inflammatory Bowel Diseases, Models, Genetic, Observational Studies as Topic, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, RNA, Messenger, Risk Assessment, Transcription, Genetic, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest, we hypothesized that summation of risk-allele-associated gene expression, namely a transcriptional risk score (TRS), should provide accurate estimates of disease risk. We integrate summary-level GWAS and expression quantitative trait locus (eQTL) data with RNA-seq data from the RISK study, an inception cohort of pediatric Crohn's disease. We show that TRSs based on genes regulated by variants linked to inflammatory bowel disease (IBD) not only outperform genetic risk scores (GRSs) in distinguishing Crohn's disease from healthy samples, but also serve to identify patients who in time will progress to complicated disease. Our dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion versus protection, thereby linking statistical association to biological mechanism. The TRS approach constitutes a potential strategy for personalized medicine that enhances inference from static genotypic risk assessment.

Published
2017

49. Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

Author

Kugathasan, Subra, Denson, Lee A, Walters, Thomas D, Kim, Mi-Ok, Marigorta, Urko M, Schirmer, Melanie, Mondal, Kajari, Liu, Chunyan, Griffiths, Anne, Noe, Joshua D, Crandall, Wallace V, Snapper, Scott, Rabizadeh, Shervin, Rosh, Joel R, Shapiro, Jason M, Guthery, Stephen, Mack, David R, Kellermayer, Richard, Kappelman, Michael D, Steiner, Steven, Moulton, Dedrick E, Keljo, David, Cohen, Stanley, Oliva-Hemker, Maria, Heyman, Melvin B, Otley, Anthony R, Baker, Susan S, Evans, Jonathan S, Kirschner, Barbara S, Patel, Ashish S, Ziring, David, Trapnell, Bruce C, Sylvester, Francisco A, Stephens, Michael C, Baldassano, Robert N, Markowitz, James F, Cho, Judy, Xavier, Ramnik J, Huttenhower, Curtis, Aronow, Bruce J, Gibson, Greg, Hyams, Jeffrey S, and Dubinsky, Marla C

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Inflammatory Bowel Disease, Prevention, Autoimmune Disease, Clinical Research, Digestive Diseases, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Adalimumab, Adolescent, Anti-Inflammatory Agents, Non-Steroidal, Child, Cohort Studies, Crohn Disease, Disease Progression, Female, Gastrointestinal Microbiome, Humans, Infliximab, Intestinal Obstruction, Male, Prognosis, Propensity Score, Prospective Studies, Risk Assessment, Severity of Illness Index, Tumor Necrosis Factor-alpha, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundStricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown.MethodsWe did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk.FindingsBetween Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%.InterpretationOur findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy.FundingCrohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.

Published
2017

50. Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

Author

Brant, Steven, Okou, David, Simpson, Claire, Cutler, David, Haritunians, Talin, Bradfield, Jonathan, Chopra, Pankaj, Prince, Jarod, Begum, Ferdouse, Kumar, Archana, Huang, Chengrui, Venkateswaran, Suresh, Datta, Lisa, Wei, Zhi, Thomas, Kelly, Herrinton, Lisa, Klapproth, Jan-Micheal, Quiros, Antonio, Seminerio, Jenifer, Liu, Zhenqiu, Alexander, Jonathan, Baldassano, Robert, Dudley-Brown, Sharon, Cross, Raymond, Dassopoulos, Themistocles, Denson, Lee, Dhere, Tanvi, Dryden, Gerald, Hanson, John, Hou, Jason, Hussain, Sunny, Hyams, Jeffrey, Isaacs, Kim, Kader, Howard, Kappelman, Michael, Katz, Jeffry, Kellermayer, Richard, Kirschner, Barbara, Kuemmerle, John, Kwon, John, Lazarev, Mark, Li, Ellen, Mack, David, Mannon, Peter, Moulton, Dedrick, Newberry, Rodney, Osuntokun, Bankole, Patel, Ashish, Saeed, Shehzad, Targan, Stephan, Valentine, John, Wang, Ming-Hsi, Zonca, Martin, Rioux, John, Duerr, Richard, Silverberg, Mark, Cho, Judy, Hakonarson, Hakon, Zwick, Michael, McGovern, Dermot, and Kugathasan, Subra

Subjects
Genetic Analysis, Risk Factor, SNP, Trans-Ethnic, Adenylyl Cyclases, Black or African American, Case-Control Studies, Cell Adhesion Molecules, Neuronal, Colitis, Ulcerative, Crohn Disease, GPI-Linked Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, HLA-DQ alpha-Chains, HLA-DRB1 Chains, Humans, Interleukin-12 Subunit p40, KCNQ2 Potassium Channel, Polymorphism, Single Nucleotide, Receptors, CXCR6, Receptors, Chemokine, Receptors, Interleukin, Receptors, Prostaglandin E, EP4 Subtype, Receptors, Virus, Repressor Proteins, Sorting Nexins, Tenascin, Ubiquitin Thiolesterase, White People
Abstract

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohns disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P

Published
2017

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