Testing for disease association with rare compound heterozygous and recessive mutations in case-parent sequencing studies. A. Allen1,2, Y. Jiang1, J. McCarthy1 1) Biostatistics & Bioinformatics, DukeUniversity, Durham, NC; 2) Center for Human Genome Variation, Duke University School of Medicine, Durham, NC.

   Compound heterozygous mutations occur on different copies of genes and may completely knock-out gene function. Compound heterozygous mutations have been implicated in a large number of diseases, but there has been very little work developing statistical methods for testing for their role in disease. A major barrier is that phase information is required to determine that both gene copies are affected and phasing rare variants is difficult. Here, we propose a method to test compound heterozygous and recessive disease models in case-parent trios. We propose a simple algorithm for phasing and show via simulations that tests based on phased trios have almost the same power as tests using true phase information. A further complication is that only families where both parents carrying mutations are informative. Thus, the informative sample size will be quite small even when the overall sample size is not, making asymptotic approximations of the null distribution of the statistic inappropriate. In order to deal with this issue we develop an exact test that will give accurate p-values regardless of sample size. Using the simulation, we show that our method is robust to sequencing errors, population stratification, and significantly outperforms other methods when the causal model is recessive.

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