Prioritization of risk genes in multiple sclerosis by a refined Bayesian framework followed by tissue-specificity and cell type feature assessment.
BMC Genomics
; 23(Suppl 4): 362, 2022 May 11.
Article
em En
| MEDLINE
| ID: mdl-35545758
ABSTRACT
BACKGROUND:
Multiple sclerosis (MS) is a debilitating immune-mediated disease of the central nervous system that affects over 2 million people worldwide, resulting in a heavy burden to families and entire communities. Understanding the genetic basis underlying MS could help decipher the pathogenesis and shed light on MS treatment. We refined a recently developed Bayesian framework, Integrative Risk Gene Selector (iRIGS), to prioritize risk genes associated with MS by integrating the summary statistics from the largest GWAS to date (n = 115,803), various genomic features, and gene-gene closeness.RESULTS:
We identified 163 MS-associated prioritized risk genes (MS-PRGenes) through the Bayesian framework. We replicated 35 MS-PRGenes through two-sample Mendelian randomization (2SMR) approach by integrating data from GWAS and Genotype-Tissue Expression (GTEx) expression quantitative trait loci (eQTL) of 19 tissues. We demonstrated that MS-PRGenes had more substantial deleterious effects and disease risk. Moreover, single-cell enrichment analysis indicated MS-PRGenes were more enriched in activated macrophages and microglia macrophages than non-activated ones in control samples. Biological and drug enrichment analyses highlighted inflammatory signaling pathways.CONCLUSIONS:
In summary, we predicted and validated a high-confidence MS risk gene set from diverse genomic, epigenomic, eQTL, single-cell, and drug data. The MS-PRGenes could further serve as a benchmark of MS GWAS risk genes for future validation or genetic studies.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estudo de Associação Genômica Ampla
/
Esclerose Múltipla
Tipo de estudo:
Clinical_trials
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Etiology_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
BMC Genomics
Assunto da revista:
GENETICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos