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Schweiger, R.* ; Fisher, E.* ; Weissbrod, O.* ; Rahmani, E.* ; Müller-Nurasyid, M. ; Kunze, S. ; Gieger, C. ; Waldenberger, M. ; Rosset, S.* ; Halperin, E.*

Detecting heritable phenotypes without a model using fast permutation testing for heritability and set-tests.

Nat. Commun. 9:4919 (2018)

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Testing for association between a set of genetic markers and a phenotype is a fundamental task in genetic studies. Standard approaches for heritability and set testing strongly rely on parametric models that make specific assumptions regarding phenotypic variability. Here, we show that resulting p-values may be inflated by up to 15 orders of magnitude, in a heritability study of methylation measurements, and in a heritability and expression quantitative trait loci analysis of gene expression profiles. We propose FEATHER, a method for fast permutation-based testing of marker sets and of heritability, which properly controls for false-positive results. FEATHER eliminated 47% of methylation sites found to be heritable by the parametric test, suggesting a substantial inflation of false-positive findings by alternative methods. Our approach can rapidly identify heritable phenotypes out of millions of phenotypes acquired via high-throughput technologies, does not suffer from model misspecification and is highly efficient.

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