ProGeM: a framework for the prioritization of candidate causal genes at molecular quantitative trait loci

Nucleic Acids Research
David StaceyDirk S Paul

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 ...Continue Reading

Citations

Apr 15, 2020·Annual Review of Genomics and Human Genetics·Natalie Niepoth, Andres Bendesky
May 12, 2020·Frontiers in Endocrinology·Lu LiuLei Zhang
Sep 23, 2020·Nature Metabolism·Vanessa LinkeJoshua J Coon
Dec 1, 2020·International Journal of Cancer. Journal International Du Cancer·Eleanor L WattsRuth C Travis
Dec 8, 2020·Human Molecular Genetics·Beatriz Calvo-SerraMariona Bustamante
Sep 12, 2020·Cell Systems·Niek VerweijPim van der Harst
Apr 9, 2021·Nature·Joseph NasserJesse M Engreitz
May 13, 2021·Nucleic Acids Research·Jeffrey MolendijkBenjamin L Parker

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Methods Mentioned

BETA
genotyping
deamination

Software Mentioned

PhenoScanner
Windows 7
R
Single Nucleotide Polymorphisms Annotator ( SNiPA )
ProGeM
Ensembl
PolySearch
Functional Mapping and Annotation of GWAS tool ( FUMA )
ToppGene Suite
VEP

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