Testing the Effect of Rare Compound‐Heterozygous and Recessive Mutations in Case–Parent Sequencing Studies

Compound heterozygous mutations are mutations that 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 are few statistical methods for analyzing their role in disease, especially when such mutations are rare. A major barrier is that phase information is required to determine whether 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 in the study of compound heterozygous mutations is that only families where both parents carry 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 test statistic inappropriate. To address this, we develop an exact test that will give appropriate P ‐values regardless of sample size. Using simulation, we show that our method is robust to population stratification and significantly outperforms other methods when the causal model is recessive.