Likelihood ratio tests for association with multiple disease susceptibility alleles, genotyping errors, or missing parental data

Abstract

Multiple disease susceptibility alleles, genotype errors, or missing genotype data can create problems when testing for association between alleles or genotypes at a genetic marker and a dichotomous phenotype. I used likelihood methods to study the impact of each of these factors on detecting association. In the presence of multiple disease susceptibility alleles, I found that power of the likelihood ratio test (LRT) declines less when based on haplotypes made up of tightly linked single nucleotide polymorphisms (SNPs) than when based on individual SNPs. The result suggests that statistical methods based on haplotypes may be useful to identify and locate complex disease genes. Genotype errors can lead to excess type I error in nuclear family (case-parents) studies when errors resulting in Mendelian inconsistent families are corrected but other errors remain in the data. I developed a LRT for single SNPs or haplotypes that incorporates nuisance parameters for genotype errors and showed that type I error rate can be controlled at little cost to power. For nuclear family data in which missing parents and additional siblings create a diversity of family structures, I developed a unified approach to computing LRT power for a test of association. Comparison of LRT power with power of a family-based association test showed that LRT has greater power.