IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
| Jazyk: | angličtina |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
Adult Multifactorial Inheritance QUANTITATIVE TRAIT LOCUS SEQUENCING DATA Genotype Quantitative Trait Loci SUSCEPTIBILITY Cohort Studies CODING VARIANTS 80 and over Humans Genetic Predisposition to Disease GENOME-WIDE ASSOCIATION Polymorphism Genetic Association Studies Aged Inflammatory Bowel Diseases/genetics Crohn Disease/genetics COMPLEX TRAITS Gene Expression Profiling DNA Single Nucleotide Middle Aged CROHNS-DISEASE RARE VARIANTS LOW-FREQUENCY Female Sequence Analysis INFLAMMATORY-BOWEL-DISEASE |
| Zdroj: | Nature Communications. 9 |
| ISSN: | 2041-1723 |
| Popis: | GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by similar to 9720 regulatory modules, of which similar to 3000 operate in multiple tissues and similar to 970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that >= 10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach. |
| Databáze: | OpenAIRE |
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