Date of Award

Spring 1-1-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology & Neuroscience

First Advisor

Matthew C. Keller

Second Advisor

Angela Bryan

Third Advisor

Marissa Ehringer

Fourth Advisor

Soo Rhee

Fifth Advisor

Michael Stallings

Abstract

The past five years have seen substantial advances in the field of human genetics, both in methodological development and insights into disease etiology. In particular, genome-wide association studies (GWAS) using single-nucleotide polymorphism (SNP) data from tens of thousands of individuals have given scientists access to the vast majority of common genetic variation across the entire genome, enabling unbiased exploration of the genetic etiology of schizophrenia and other complex traits. My research has largely focused on extensions of genome-wide methods beyond traditional association studies, examining how to best utilize already-existing datasets to ask evolutionarily and biologically informed questions about the genetic basis of schizophrenia and other complex traits. For my first study, I attempt an independent replication of Keller et al.’s 2012 study that found a robust association between increased genome-wide autozygosity (a proxy for distant inbreeding) and schizophrenia. We find little evidence for such a relationship in the larger replication dataset, but the combined (original plus replication) dataset does show a significant autozygosity ~ schizophrenia association. My second study focuses on the question of whether “classic” candidate genes for schizophrenia contain lower p-values in the latest GWAS than other genes on average. We find almost no support for the hypothesis that genes historically considered relevant to schizophrenia etiology are in fact enriched for common genetic risk variants above and beyond genes not given such a designation. In my third study, I return to the relationship between autozygosity and complex traits, this time using data from a large biobank to assess the evidence for a relationship between inbreeding and several fitness-related complex traits. We initially find significant relationships between autozygosity and several traits, including height, fluid intelligence, grip strength, and birth weight, but only the relationship with fluid intelligence remains significant after we control for socio-demographic traits (e.g. educational attainment, income) in the model. Overall, our results suggest that only fluid intelligence shows robust evidence of directional dominance, while the relationships between autozygosity and the remaining traits are likely mediated by parental assortative mating on socio-demographic confounders.

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