Prioritizing Crohn's disease genes by integrating association signals with gene expression implicates monocyte subsets.
Genes Immun
; 20(7): 577-588, 2019 09.
Article
en En
| MEDLINE
| ID: mdl-30692607
ABSTRACT
Genome-wide association studies have identified ~170 loci associated with Crohn's disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying 40 genome-wide significant genes. Co-expression network analysis identified a single gene module, which was substantially enriched for CD locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared with non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Monocitos
/
Enfermedad de Crohn
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Análisis de Secuencia de ADN
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Adolescent
/
Child
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Child, preschool
/
Female
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Humans
/
Male
Idioma:
En
Revista:
Genes Immun
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
BIOLOGIA MOLECULAR
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos