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      Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates PRKCA

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          Abstract

          Globally, diarrhea remains one of the major causes of pediatric morbidity and mortality. The initial symptoms of diarrhea can often lead to long-term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here, we conducted a genetic study of susceptibility to symptomatic disease associated with Cryptosporidium infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase C alpha ( PRKCA) associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.

          ABSTRACT

          Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and sub-Saharan Africa, where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long-term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, and yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh, namely, the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for length-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 ( P = 3.73 × 10 −8), an intronic SNP and expression quantitative trait locus (eQTL) of protein kinase C alpha ( PRKCA). Each additional risk allele conferred 2.4 times the odds of Cryptosporidium-associated diarrhea in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation.

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          Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

          Genetic association studies have identified 215 risk loci for inflammatory bowel disease 1–8, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization.
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            Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

            We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European-ancestry we identified 244 independent multi-disease signals including 27 novel genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multi-disease signals with expression data sets from human, rat and mouse, and epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases that is genetically identical to another disease, possibly due to diagnostic misclassification, molecular subtypes, or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
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              Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

              Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                mBio
                mBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                Jan-Feb 2020
                4 February 2020
                : 11
                : 1
                : e03343-19
                Affiliations
                [a ]Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California, USA
                [b ]Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
                [c ]Department of Medicine, Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, Virginia, USA
                [d ]Wellcome Trust Sanger Institute, University of Oxford, Oxford, United Kingdom
                [e ]Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom
                [f ]Department of Medicine, University of Cambridge, Cambridge, United Kingdom
                [g ]Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA
                [h ]University of Vermont College of Medicine and Vaccine Testing Center, Burlington, Vermont, USA
                [i ]Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
                [j ]International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh
                Harvard T.H. Chan School of Public Health
                Author notes
                Address correspondence to Priya Duggal, pduggal@ 123456jhu.edu .
                Article
                mBio03343-19
                10.1128/mBio.03343-19
                7002356
                32019797
                b9a890f6-f4de-4829-b674-6ae385658656
                Copyright © 2020 Wojcik et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 22 December 2019
                : 2 January 2020
                Page count
                supplementary-material: 9, Figures: 4, Tables: 1, Equations: 0, References: 58, Pages: 12, Words: 10057
                Funding
                Funded by: Henske Family;
                Award Recipient :
                Funded by: Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases Discovery Program;
                Award Recipient :
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;
                Award ID: AI043596
                Award Recipient :
                Funded by: Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation), https://doi.org/10.13039/100000865;
                Award Recipient :
                Categories
                Research Article
                Host-Microbe Biology
                Custom metadata
                January/February 2020

                Life sciences
                cryptosporidium,genetics,genome analysis
                Life sciences
                cryptosporidium, genetics, genome analysis

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