title: An Efficient Multiple-Testing Adjustment for eQTL Studies that Accounts for Linkage Disequilibrium between Variants.
abstract: Methods for multiple-testing correction in local expression quantitative trait locus (cis-eQTL) studies are a trade-off between statistical power and computational efficiency. Bonferroni correction, though computationally trivial, is overly conservative and fails to account for linkage disequilibrium between variants. Permutation-based methods are more powerful, though computationally far more intensive. We present an alternative correction method called eigenMT, which runs over 500 times faster than permutations and has adjusted p values that closely approximate empirical ones. To achieve this speed while also maintaining the accuracy of permutation-based methods, we estimate the effective number of independent variants tested for association with a particular gene, termed Meff, by using the eigenvalue decomposition of the genotype correlation matrix. We employ a regularized estimator of the correlation matrix to ensure Meff is robust and yields adjusted p values that closely approximate p values from permutations. Finally, using a common genotype matrix, we show that eigenMT can be applied with even greater efficiency to studies across tissues or conditions. Our method provides a simpler, more efficient approach to multiple-testing correction than existing methods and fits within existing pipelines for eQTL discovery.
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Joe R
authors.initials: JR
authors.lastname: Davis
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Fresard
authors.affiliation: Department of Computer Science, Stanford University, Stanford 94305, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Knowles
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pala
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Battle
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address: smontgom@stanford.edu.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
mesh_terms: D006801:Humans; D015810:Linkage Disequilibrium; D040641:Quantitative Trait Loci