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Abstract

Variants can affect traits differently depending on whether they are inherited from the mother or the father, but genome wide association studies (GWAS) treat maternal and paternal alleles as equivalent. In addition, the variants identified by GWAS do not account for a significant portion of the heritability for the corresponding trait and the "missing heritability" could be due to underlying biological mechanisms that are not yet well understood. My thesis addresses these limitations by disentangling the effects of maternal and paternal alleles on gene expression as well as on disease-associated phenotypes in the Hutterites, a founder population of European descent. With phased genotype data we can ask questions about parent-of-origin effects in this population. First, we tested for maternal and paternal genetic associations on cardiovascular disease and asthma associated traits and developed a novel method to detect variants that have opposite effects on the trait of interest depending on the parent of origin of the variant. We identified variants that have maternal-only or paternal-only effects, as well as variants that have opposite effects on traits, which would not be detected in a standard GWAS. This is the largest family based study of parent-of-origin effects on quantitative traits and the first to look for opposite parental effects. In the second chapter, we map RNA-seq rads from lymphoblastoid cell lines (LCLs) to parental haplotypes in 306 Hutterites and detect known imprinted genes and two novel imprinted genes (PXDC1 and PWAR6). These imprinted gene patterns are validated using parent-of-origin expression from peripheral blood leukocytes (PBL) from 99 different Hutterites; imprinting control regions near the novel genes were validated using PBL methylation in the same 99 Hutterites. Finally, we explore searching for parent-of-origin effects on gene expression or parent-of-origin eQTLs, first for opposite effects and then for maternal and paternal specific effects.

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