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A Subregion-based Burden Test for Simultaneous Identification of Susceptibility Loci and Subregions in Rare-variant Association Studies

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’s 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 based on shared common biologic characteristics, such as the protein domain or possible functional impact.  Based on a subset-based approach considering local correlations between combinations of test statistics of sub-regions, 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.

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Zhu B, Mirabello L, Chatterjee N. A subregion-based burden test for simultaneous identification of susceptibility loci and subregions in rare-varient association studies. Genet Epidemiol 2018. 


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