Defense Date


Document Type


Degree Name

Doctor of Philosophy


Clinical and Translational Sciences

First Advisor

Kenneth Kendler


Major Depression (MD) and Generalized Anxiety Disorder (GAD) are psychiatric disorders that arise from dysfunction of the core human capacities for emotion. Sapience is inextricably bound up with the potential for feelings of regret, worry and concern. When these emotions lead to clinically significant impairment or distress, they may result in one or both of the disorders of MD and GAD. The occurrence of MD and GAD in the same person, known as comorbidity, is remarkably high; substantially higher than would be expected by chance.

MD and GAD have been studied since the mid-20th century, resulting in a substantial body of literature. The personality trait of neuroticism is also known to correlate highly with these disorders. This project was designed to compare the etiological structure of MD and GAD using a range of psychosocial and genetic methods in three datasets, while also assessing the correlated trait of neuroticism. Results are used to inform theoretical formulation of an approximate model of comorbidity for the two disorders.

Psychosocial findings suggest that MD and GAD have similar relationships with most risk factors, and that neuroticism displays results consistent with it composing a portion of the liability to MD and GAD.

Efforts to detect specific genetic loci involved in the etiology of MD and GAD are modestly successful. Two genome-wide significant variants were found for MD (one already identified in the literature); two for GAD, and one for neuroticism. There were also a number of significant genomic regions for each outcome.

The use of aggregate genetic methods to estimate heritability based on genotypes was less successful. Estimation was only successful in one sample of the three, and produced modest estimates of heritability (0.2-0.25) for MD and comorbid MD+GAD. Genetic correlation was estimated to be very high between neuroticism and MD.

Models of comorbidity are evaluated in light of these results, and a model comprising multiple liability distributions, one shared entirely by MD and GAD, and two additional correlated ones for the two disorders, with reciprocal phenotypic causation, is deemed most consistent with observed evidence.


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