A model for family-based case-control studies of genetic imprinting and epistasis

Abstract

Genetic imprinting, or called the parent-of-origin effect, has been recognized to play an important role in the formation and pathogenesis of human diseases. Although the epigenetic mechanisms that establish genetic imprinting have been a focus of many genetic studies, our knowledge about the number of imprinting genes and their chromosomal locations and interactions with other genes is still scarce, limiting precise inference of the genetic architecture of complex diseases. In this article, we present a statistical model for testing and estimating the effects of genetic imprinting on complex diseases using a commonly used case-control design with family structure. For each subject sampled from a case and control population, we not only genotype its own single nucleotide polymorphisms (SNPs) but also collect its parents' genotypes. By tracing the transmission pattern of SNP alleles from parental to offspring generation, the model allows the characterization of genetic imprinting effects based on Pearson tests of a 2 × 2 contingency table. The model is expanded to test the interactions between imprinting effects and additive, dominant and epistatic effects in a complex web of genetic interactions. Statistical properties of the model are investigated, and its practical usefulness is validated by a real data analysis. The model will provide a useful tool for genome-wide association studies aimed to elucidate the picture of genetic control over complex human diseases.

Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

“…To test this hypothesis we used our recently developed model[27] that has been demonstrated to be genetically meaningful in our previous studies on IBD susceptibility genes[30,35,36]. …”

“…Using this model we have previously studied epistatic interaction between SNPs within the DLG5 gene and between IBD genes DLG5 , OCTN1 , IL23R and NOD2 [28,35,36], and found that epistatic interaction is an important component in IBD pathogenesis. In this study, we used the same method to study gene-gene interaction in IL-10 signaling transduction pathway.…”

Mapping complex traits as a dynamic system

“…Basically, these designs include outcrossed families [29,74], sex-specific linkage analysis [19,25], reciprocal crosses [90,148,149,192], multigenerational pedigrees [92], open-pollinated populations [138] and case-control studies [87]. From these designs, significant imprinted QTLs were detected for body composition and body weight in pigs, chickens, sheep and canine, endosperm traits in maize, and stem growth in hickory tree.…”

Two Powerful Tests for Parent-of-Origin Effects at Quantitative Trait Loci on the X Chromosome

“…Hanson et al [19] extended a variance-components approach to test for parent-of-origin effects by sampling siblings. Li et al [20] proposed a multi-locus likelihood method for investigating parent-of-origin effects on the basis of case-control mother-child pairs. However, these methods are proposed for detecting the effects on autosomal alleles instead of alleles on the X chromosome.…”