A gene-based association method for mapping traits using reference transcriptome data.

Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, Eyler AE, Denny JC, GTEx Consortium, Nicolae DL, Cox NJ, Im HK
Nat Genet. 2015 47 (9): 1091-8

PMID: 26258848 · PMCID: PMC4552594 · DOI:10.1038/ng.3367

Genome-wide association studies (GWAS) have identified thousands of variants robustly associated with complex traits. However, the biological mechanisms underlying these associations are, in general, not well understood. We propose a gene-based association method called PrediXcan that directly tests the molecular mechanisms through which genetic variation affects phenotype. The approach estimates the component of gene expression determined by an individual's genetic profile and correlates 'imputed' gene expression with the phenotype under investigation to identify genes involved in the etiology of the phenotype. Genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome data sets. PrediXcan enjoys the benefits of gene-based approaches such as reduced multiple-testing burden and a principled approach to the design of follow-up experiments. Our results demonstrate that PrediXcan can detect known and new genes associated with disease traits and provide insights into the mechanism of these associations.

MeSH Terms (7)

Chromosome Mapping Gene Expression Profiling Genetic Predisposition to Disease Genome-Wide Association Study Humans Phenotype Polymorphism, Single Nucleotide

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