The Importance of Parental Genotypes to Rare-Variant Association Testing with Affected Sib Pairs
Date Issued
2016
Date
2016
Author(s)
Hung, Jui-Hsiang
Abstract
With the advent of next-generation sequencing technologies, genetic epidemiologists now search for rare variants (minor allele frequency (MAF) < 1%) or low-frequency variants (MAF < 5%) that are responsible for susceptibility to complex diseases. Family-based study designs such as recruiting affected sib pairs (ASPs) are promising because rare variants can be enriched in families with multiple affected subjects. Moreover, family-based designs are robust against population substructure. Recently, Epstein et al. developed rare-variant association tests using ASPs. ASPs’ total numbers of rare variants in a gene/region are regressed on their identity by descent (IBD) scores. Despite promising simulation results, including desired type-I error rates and high statistical power, we find their methods are valid only when the IBD scores are unambiguous. Unfortunately, in reality, real IBD scores are usually not known and need to be estimated from genotypes. We here find incorporating parental genotypes is crucial to the validity and power of rare-variant association testing with ASPs. Cautions need to be taken to analyze rare variants of ASPs without their parental genotypes. When parental genotypes are not available, genotypes of other family members (such as unaffected siblings) should be collected to improve the accuracy of IBD estimation.
Subjects
Rare variants
low-frequency variants
affected sib pairs
identity by descent
next-generation sequencing
Type
thesis
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