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Genet Epidemiol. 2018 Oct;42(7):673-683. doi: 10.1002/gepi.22134. Epub 2018 Jun 22.

A subregion-based burden test for simultaneous identification of susceptibility loci and subregions within.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland.
2
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
3
Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Abstract

In rare variant association studies, aggregating rare and/or low frequency variants, may increase statistical power for detection of the underlying susceptibility gene or region. However, it is unclear which variants, or class of them, in a gene contribute most to the association. We proposed a subregion-based burden test (REBET) to simultaneously select susceptibility genes and identify important underlying subregions. The subregions are predefined by shared common biologic characteristics, such as the protein domain or functional impact. Based on a subset-based approach considering local correlations between combinations of test statistics of subregions, REBET is able to properly control the type I error rate while adjusting for multiple comparisons in a computationally efficient manner. Simulation studies show that REBET can achieve power competitive to alternative methods when rare variants cluster within subregions. In two case studies, REBET is able to identify known disease susceptibility genes, and more importantly pinpoint the unreported most susceptible subregions, which represent protein domains essential for gene function. R package REBET is available at https://dceg.cancer.gov/tools/analysis/rebet.

KEYWORDS:

burden test; disease susceptibility genes; rare variant association studies; subset-based approach

PMID:
29931698
PMCID:
PMC6185783
DOI:
10.1002/gepi.22134
[Indexed for MEDLINE]
Free PMC Article

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