Genetic Variants from Large Cohorts and Familial Studies Implicate Common Mechanisms in Schizophrenia

Schizophrenia has an estimated population prevalence of 1%, but the etiology of this devastating psychiatric condition remains largely uncharacterized. A pronounced genetic component underlies schizophrenia, with heritability estimates ranging from 60% to 80%. Until now, genome-wide association studies have successfully identified 287 distinct genetic loci associated with schizophrenia, but these primarily involve common variants that have minimal individual risk. The recent advent of exome sequencing and genome sequencing has identified ultra-rare sequence variants associated with schizophrenia in familial cases as well as in large cohorts. These studies have implicated multiple gene variants that individually have a large effect size in contributing to schizophrenia. A comparison indicates that these genes exhibit high expression levels in the central nervous system and their protein products participate in many converging pathways encompassing synaptic transmission, glutamatergic neurotransmission, chromatin modification processes, transcriptional regulation, and ubiquitin–proteasome degradation. Although model systems have been established for some genes, most remain to be further studied to identify how gene dysfunction correlates with disease.