DESCRIPTION (provided by applicant): Recent advances in inexpensive whole exome and whole genome sequencing have opened up the prospect of identifying rare variants influencing common, complex diseases. Though only carried in a few individuals each, highly penetrant rare variants may collectively explain a large portion of disease risk. Such variants might be private to a single family, making them difficult to identify even in large case/control samples. However, the study of rare variants in extreme families has the potential to provide groundbreaking insights into the biology underlying common disease. For example, families with rare forms of hypercholesterolemia taught us much about the biology of heart disease. Schizophrenia (SCZ) is a heritable mental illness associated with substantial morbidity and mortality. Identifying genes that contribute to risk of psychosis, a defining feature of SCZ, shoul provide critical information regarding SCZ pathophysiology. We have identified a large extended family that has all the hallmarks of a potentially Mendelian, monogenic form of psychosis due to a highly penetrant founder mutation. There are at least 36 individuals with psychosis (verified by in person diagnostic interviews) in this family who are grandchildren or great grandchildren of a single couple. Additionally, the family comes from an isolated population in a remote location in Costa Rica and there is known consanguinity in the pedigree. Interestingly, there are also indications of immune system involvement in affected members of the family. The goal of this study is to utilize exome sequencing to identify the mutation responsible for psychosis in this family and characterize its effects, including penetrance, variable expressivity in the neurocognitive and neurological domains, and potential immune system involvement. We will also assess the prevalence of the mutation in individuals with SCZ in Costa Rica and test whether other mutations in this gene may influence SCZ risk in a sample of US Caucasian, Hispanic, and African American cases and controls.

This project is centered around studying a large family with many individuals who have psychosis, a key feature of schizophrenia. The pattern of illness in the family suggests that there is a single gene of large effect responsible for their psychosis. We will identify this gene, study how it works, and investigate whether it also affects schizophrenia risk in the general population. This will advance our understanding of the basic biological processes underlying schizophrenia, has the potential to aid in diagnosis and prevention, and may suggest new avenues of treatment.