A Test of Imprinting for Quantitative Traits Using Haplotypes

Imprinting is an epigenetic phenomenon where the same alleles have unequal transcriptions and thus contribute differently to a trait depending on their parent of origin. This mechanism has been found to affect a variety of human disorders. Although various methods for testing imprinting have been proposed in linkage analysis settings, only a few are available for association analysis and they are usually restricted to small families and particular study designs. In this talk, I introduce our recently proposed maximum likelihood test to test association between imprinted SNPs and quantitative phenotypes in general family studies. Our method incorporates haplotype distribution to take advantage of inter-marker LD information in genome-wide association studies (GWAS). Our method also accommodates missing genotypes that often occur in genetic studies. Our simulation studies with various minor allele frequencies, LD structures, family sizes, and missing schemes have uniformly shown that using the new method significantly improves the power of detecting imprinted genes compared with the method using the SNP at the testing locus only. Our simulations suggest that the most efficient strategy to investigate imprinting effects is to recruit one parent and as many offspring as possible under practical constraints. We applied our method to a dataset from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to scan imprinted SNPs for diabetes-related phenotypes, and found that several SNPs in the MTP gene show significant imprinting effects on insulin and glucose levels.