Examination of Common and Rare Variant Genetic Architecture of Psychiatric Disorders

Psychiatric disorders are often heterogenous in their manifestation and genome-wide association studies have identified many common risk variants involved in their polygenic architectures with varying degrees of pleiotropy. In recent years, large-scale biobanks have also begun sequencing the genome of their participants to elucidate the role of rare risk variation in the genetic architecture of complex phenotypes, including psychiatric traits. This dissertation sought to better understand the role of both common and rare risk variation in the genetic architecture of psychiatric disorders with a particular focus on schizophrenia and alcohol problems. In the first three analyses, we focused on characterizing the common risk variant architecture of multiplex schizophrenia families in terms of family history, cross-disorder risk, as well as symptom severity. In the fourth analysis, we compared and contrasted the polygenic architecture of schizophrenia with multiple sclerosis, an autoimmune, neurodegenerative disorder that also shows co-occurring neuropsychiatric symptoms, beyond genetic correlation. In the fifth analysis, we used the 200k exome release of the UK Biobank to investigate the rare variant genetic architecture of alcohol problems by combining machine learning phenotype prediction and empirical information to improve rare variant discovery. Together, these studies contribute to our understanding of the genetic architecture of schizophrenia and its pleiotropic relationship with other psychiatric and neurological disorders and provides new avenues for future studies of this disease in both family and sporadic samples. Additionally, we proposed a novel framework for rare variant analysis of complex disorders that improves discovery of rare variants in biobank datasets