Using Novel Genetic Methods to Better Understand the Associations of Behavior and Brain with Psychiatric Phenotypes

Abstract

Psychiatric disorders comprise a heterogeneous group of conditions that profoundly affect long-term health, cognitive functioning, and overall well-being. Large-scale genome-wide association studies (GWAS) have demonstrated that these disorders have a highly polygenic genetic architecture. At the same time, increasingly powerful GWAS and whole-exome sequencing studies of related phenotypes, including lifestyle factors and brain morphology, provide new opportunities to elucidate the biological pathways linking genetics, brain structure, behavior, and psychopathology. This dissertation leverages advances in GWAS and exome sequencing to investigate the genetic architecture underlying psychiatric symptoms and their correlates across behavioral and neuroanatomical domains, with the aim of clarifying mechanistic links and identifying potential therapeutic targets. In Chapter 1, we evaluated genetic confounding (i.e., genetic factors acting as a common cause) in the associations of sleep duration and physical activity with internalizing problems in adolescents. Using well-powered GWAS and genetically informed methods, the analysis distinguished direct behavioral effects from shared polygenic influences. The findings indicated substantial shared genetic influences between sleep duration and internalizing problems, which may in part reflect reporting-related measurement error arising from shared method variance rather than direct causal effects. In contrast, the associations between physical activity and internalizing problems were not genetically confounded, suggesting a more direct influence of this modifiable behavior after accounting for shared genetic liability. In Chapter 2, we explored if genetic loci shared between major psychiatric disorders and brain morphology show regional or global effects. By integrating GWAS of 180 regions of cortical structures and six major psychiatric disorders, we identified substantial pairwise genetic overlaps of overall cortical surface area or thickness with psychiatric disorders, but no clear directional pattern. Most genomic loci shared across all six disorders, showed opposing directional effects in different regions across the cortex while one locus showed a regional specific effect on reduced primary visual and posterior cingulate surface area. The directional heterogeneity showed the complex link between brain morphology and psychiatric disorders. In Chapter 3, we investigated whole exome-wide associations of comprehensively characterized sleep phenotypes. These phenotypes include self-reported questionnaires, diagnoses and medication prescription extracted from electronic health records, and accelerometer-based measures. These rare-variant associations highlighted potential distinct biological pathways linked to different types of sleep phenotypes and suggested novel therapeutic avenues. Collectively, studies integrate GWAS, exome sequencing, and deep phenotyping to explore how genetic variation contributes to psychiatric disorders. By examining the genetic underpinnings of behavior, brain structure, and psychopathology, this dissertation seeks to elucidate shared and distinct mechanisms across psychiatric conditions. By jointly leveraging causal inference, cross-disorder analyses, and deep phenotyping approaches, this work informs strategies for prevention and intervention in precision psychiatry.