title: Comprehensive Computational Analysis of GWAS Loci Identifies CCR2 as a Candidate Gene for Celiac Disease Pathogenesis.
abstract: Celiac disease (CD) is a gluten intolerance disorder with known genetic contribution. The recent fine mapping and genome-wide association studies (GWAS) have identified up to 57 non-HLA CD susceptibility SNPs, majority of which are non-coding variants lacking any functional annotation. Therefore, we adopted multidimensional computational approach for uncovering the plausible mechanisms through which these GWAS SNPs are connected to CD pathogenesis. At initial phase, we identified that 25 (43.85%) out of 57 CD-SNPs lies in evolutionarily constrained genetic element regions. In follow-up phases, through computational (CADD, GWAVA, and FATHMM algorithms) deleterious intensity measurements, we have discovered that 42 (3.94%) out of 1065 variants (57 CD-lead and 1008-linked SNPs; r2≥ 0.8) are differentially deleterious in nature to CD. Further functional scrutinization of these CD variants by public domain eQTL mapping, gene expression, knockout mouse model, and pathway analyses revealed that deleterious SNPs of CCR2 gene influences its expression levels and may also elicit a cascade of T-cell-mediated immunological events leading to intestinal gluten intolerance in genetically susceptible individuals. This study demonstrates the utility of integrated in silico analysis of annotations, gene expression, and pathways in prioritizing the potential complex disease variants from large-scale open source genomic data. J. Cell. Biochem. 118: 2193-2207, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Babajan
authors.initials: B
authors.lastname: Banaganapalli
authors.affiliation: Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Department of Clinical Biochemistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Omran
authors.initials: O
authors.lastname: Rashidi
authors.affiliation: Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Omar I
authors.initials: OI
authors.lastname: Saadah
authors.affiliation: Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Imran Ali
authors.initials: IA
authors.lastname: Khan
authors.affiliation: Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Jumana Y
authors.initials: JY
authors.lastname: Al-Aama
authors.affiliation: Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Noor Ahmad
authors.initials: NA
authors.lastname: Shaik
authors.affiliation: Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Ramu
authors.initials: R
authors.lastname: Elango
mesh_terms: D000465:Algorithms; D000818:Animals; D002446:Celiac Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019295:Computational Biology / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054390:Receptors, CCR2 / Q000235:genetics*
chemical_list: D054390:Receptors, CCR2
keywords: CCR2; CELIAC DISEASE; COMPUTATIONAL BIOLOGY; GWAS