Identification of novel rare coding variants contributing to schizophrenia and antipsychotic treatment response

Abstract

Schizophrenia is a severe psychiatric disorder characterized by hallucination, cognitive impairment and social dysfunction, affecting approximately 1% of the population worldwide. It is a highly heritable disorder in which genetic variations contribute to more than 80% of population variance in disease liability, but the known genetic risk factors associated with schizophrenia only explain less than 30% of the disease risk.

In addition, there is currently no cure for the disorder and most of the patients require life-long antipsychotic medication. However, the various limitations associated with these treatments, including high relapse rate, adverse drug reactions, and poor drug response rates, impose a huge economic burden on the society. Moreover, response to antipsychotic treatment is influenced by both genetic and environmental factors, resulting in extremely heterogeneous responses to antipsychotics among patients. Unfortunately, no putative genetic risk factor has been discovered to be consistently associated with antipsychotic treatment response.

In this thesis, I aimed to identify novel rare coding variants contributing to i) schizophrenia liability and ii) antipsychotic treatment response, using exome sequencing studies (139 cases/153 controls for the study of schizophrenia liability, and 156 responders/160 non-responders for the study of antipsychotic treatment response). Using both hypothesis-free and hypothesis-driven strategies, I successfully replicated the findings of previous studies, including the disruption of calcium ion channel genes in schizophrenia. Moreover, I discovered that schizophrenia patients showed significant enrichment for rare non-synonymous coding variants involved in the SKP1 protein-protein interaction network as well as positive regulation of chemotaxis (GO: 0050921), both of which may implicate immunity in schizophrenia. These findings add to a growing body of evidence linking immunity and schizophrenia. Also, I found that rare coding variants in genes involved in the glutamate receptor and transmission are more frequent in schizophrenia with poor response to antipsychotics treatment. My findings are consistent with the hypothesis that glutamatergic dysfunction is implicated in schizophrenia. In addition, our study provides support for the potential role of glutamate in subgroups of patients who do not respond to the available dopaminergic blockage based antipsychotics. The results from both studies are consistent with our existing knowledge that schizophrenia as a polygenic trait which involves multiple genes and biological systems. Taken together, my study suggests that exome sequencing is a powerful tool for discovering yet-unknown (rare coding) genetic variants for neuropsychiatric diseases and their associated clinical characteristics.