A population-driven family-based genetic study of schizophrenia

Two landmark genetic studies of schizophrenia (SCZ), the severe and highly heritable psychotic illness, recently established that some SCZ cases are caused by a rare protein-truncating variant (PTV) in one of 12 genes (i.e., the “12 known causal SCZ genes”). GRIA3, a gene on the X chromosome that codes for an AMPA glutamate receptor component, is one of the 12 known causal SCZ genes. Presented here is a process developed to identify individuals in an urban community affected by rare PTVs in the 12 known causal SCZ genes, followed by a case series focused on four individuals from the same extended family affected by a rare PTV in GRIA3. Carriers of rare PTVs in the 12 known causal SCZ genes were identified by mining whole-exome sequencing data from the diverse population of New York City (N = 30,813). Identified carriers were re-contacted to undergo comprehensive neuropsychiatric assessments and biospecimen collection. Among the identified carriers was an African-American female with a rare PTV in GRIA3 (i.e., “the index carrier”). Follow-up studies of the index carrier and the index carrier's extended family identified an X-linked pattern of inheritance between the rare PTV and severe neuropsychiatric diseases. Five affected family members have been confirmed as carriers of the rare PTV and three additional living affected family members have yet to be genotyped. No affected non-carriers have been identified. The primary psychiatric diagnoses for affected family members were SCZ (N=3), developmental delay (N=1), and mild to severe intellectual disability (N=4; one with psychosis). Affected males in the family exhibited more severe and debilitating forms of illness than affected females in the family, but having two X chromosomes was not entirely protective. Future studies of neural cells from affected carriers will attempt to determine how the rare PTV causes disease and why there is clinical variability between family members with the same causal variant. Population-driven family-based genetic studies such as the one presented here are a new way to investigate the mechanisms of disease in individual patients.