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Motivation Genetic heterogeneity is the phenomenon that distinct genetic variants may give rise to the same phenotype. The recently introduced algorithm Fast Automatic Interval Search (FAIS) enables the genome-wide search of candidate regions for genetic heterogeneity in the form of any contiguous sequence of variants, and achieves high computational efficiency and statistical power. Although FAIS can test all possible genomic regions for association with a phenotype, a key limitation is its inability to correct for confounders such as gender or population structure, which may lead to numerous false-positive associations. Results We propose FastCMH, a method that overcomes this problem by properly accounting for categorical confounders, while still retaining statistical power and computational efficiency. Experiments comparing FastCMH with FAIS and multiple kinds of burden tests on simulated data, as well as on human and Arabidopsis samples, demonstrate that FastCMH can drastically reduce genomic inflation and discover associations that are missed by standard burden tests. Availability and Implementation An R package fastcmh is available on CRAN and the source code can be found at: https://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/fastcmh.html Supplementary information Supplementary data are available at Bioinformatics online.
