An integrative systems-based analysis of substance use: eQTL-informed gene-based tests, gene networks, and biological mechanisms.
Am J Med Genet B Neuropsychiatr Genet
; 186(3): 162-172, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33369091
ABSTRACT
Genome-wide association studies have identified multiple genetic risk factors underlying susceptibility to substance use, however, the functional genes and biological mechanisms remain poorly understood. The discovery and characterization of risk genes can be facilitated by the integration of genome-wide association data and gene expression data across biologically relevant tissues and/or cell types to identify genes whose expression is altered by DNA sequence variation (expression quantitative trait loci; eQTLs). The integration of gene expression data can be extended to the study of genetic co-expression, under the biologically valid assumption that genes form co-expression networks to influence the manifestation of a disease or trait. Here, we integrate genome-wide association data with gene expression data from 13 brain tissues to identify candidate risk genes for 8 substance use phenotypes. We then test for the enrichment of candidate risk genes within tissue-specific gene co-expression networks to identify modules (or groups) of functionally related genes whose dysregulation is associated with variation in substance use. We identified eight gene modules in brain that were enriched with gene-based association signals for substance use phenotypes. For example, a single module of 40 co-expressed genes was enriched with gene-based associations for drinks per week and biological pathways involved in GABA synthesis, release, reuptake and degradation. Our study demonstrates the utility of eQTL and gene co-expression analysis to uncover novel biological mechanisms for substance use traits.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transtornos Relacionados ao Uso de Substâncias
/
Predisposição Genética para Doença
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Polimorfismo de Nucleotídeo Único
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Locos de Características Quantitativas
/
Redes Reguladoras de Genes
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Am J Med Genet B Neuropsychiatr Genet
Assunto da revista:
GENETICA MEDICA
/
NEUROLOGIA
/
PSIQUIATRIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Austrália