ProGeM: a framework for the prioritization of candidate causal genes at molecular quantitative trait loci.
Nucleic Acids Res
; 47(1): e3, 2019 01 10.
Article
em En
| MEDLINE
| ID: mdl-30239796
ABSTRACT
Quantitative trait locus (QTL) mapping of molecular phenotypes such as metabolites, lipids and proteins through genome-wide association studies represents a powerful means of highlighting molecular mechanisms relevant to human diseases. However, a major challenge of this approach is to identify the causal gene(s) at the observed QTLs. Here, we present a framework for the 'Prioritization of candidate causal Genes at Molecular QTLs' (ProGeM), which incorporates biological domain-specific annotation data alongside genome annotation data from multiple repositories. We assessed the performance of ProGeM using a reference set of 227 previously reported and extensively curated metabolite QTLs. For 98% of these loci, the expert-curated gene was one of the candidate causal genes prioritized by ProGeM. Benchmarking analyses revealed that 69% of the causal candidates were nearest to the sentinel variant at the investigated molecular QTLs, indicating that genomic proximity is the most reliable indicator of 'true positive' causal genes. In contrast, cis-gene expression QTL data led to three false positive candidate causal gene assignments for every one true positive assignment. We provide evidence that these conclusions also apply to other molecular phenotypes, suggesting that ProGeM is a powerful and versatile tool for annotating molecular QTLs. ProGeM is freely available via GitHub.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Locos de Características Quantitativas
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Estudo de Associação Genômica Ampla
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Estudos de Associação Genética
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Anotação de Sequência Molecular
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article