Confounding from cryptic relatedness in haplotype-based association studies

Abstract

Cryptic relatedness was suggested to be an important source of confounding in population-based association studies (PBAS). The impact of cryptic relatedness on the performance of haplotype phase inference and haplotype-based association tests is not clear. In this study, we used the Hapmap genetic data to simulate a set of related samples. We evaluated the accuracy of haplotype phase inferred by PHASE 2.1 and calculated the power, type I error rates, accuracy and positive prediction value (PPV) of haplotype frequency-based association tests (HFAT) and haplotype similarity-based association tests (HSAT) under various scenarios, considering relatedness levels, disease models and sample sizes. Cryptic relatedness appeared to slightly increase the accuracy of haplotype phase inference. We observed significant negative effect of cryptic relatedness on the performance of HFAT and HSAT. Ignoring cryptic relatedness may increase spurious association results in haplotype-based PBAS.