Analysis of parent-of-origin effects for secondary phenotypes using case-control mother-child pair data

The detection of parent-of-origin effects (POEs) has become a research focus in genetic association studies since POEs play an important role in explaining the heritability of many complex human disorders. Genetic association studies are commonly conducted based on case-control designs. Case-control genetic association studies often collect additional information on secondary phenotypes other than the case-control status. Various statistical methods have been proposed to analyze the secondary phenotypes, but no methods are specifically tailored for identifying POEs of offspring genes on the secondary phenotypes. The parental origin information may not be determined unambiguously using the genotypes of the test locus for some families, and ignoring such families would lose considerable information. In this article, we focus on case-control mother-child pair design that has been widely used for studying human early life growth and development, and propose a robust and efficient retrospective likelihood method to detect POEs for the secondary phenotypes using multilocus genotypes. The proposed method fully utilizes the information from multilocus genotypes, Hardy-Weinberg equilibrium (HWE), Mendelian inheritance law, and conditional independence between child genotype and maternal covariate given maternal genotype. Large sample properties, including consistency and asymptotic normality, are established for our proposed statistical method. The finite sample performance of our method are demonstrated through extensive simulation studies and application to the Danish National Birth Cohort data.