There is nothing common about the debilitating disorder schizophrenia. In the absence of a single disease-associated gene, researchers believed that the effects of several common alleles combined to cause schizophrenia. Researchers recently found increased rates of rare mutations (affecting only a few people each) in people with autism. Now Walsh et al. report increased rates of rare genetic deletions or duplications in people with schizophrenia in a recent article in Science.
Researchers previously identified several genes associated with schizophrenia, including DISC1, PDE4B and NPAS3, by karyotyping, physically examining chromosomes. However, the detection limit for this technique is approximately 1 Mb, which may obscure small genetic deletions and duplications. The authors used microarrays to look for 100 kb to 15 Mb structural variations in 150 adults with schizophrenia and 268 controls.
People with schizophrenia were 3 times as likely as controls to have rare structural variants. Childhood-onset schizophrenia (COS) is rare and usually more severe than the typical adult-onset form. In a second cohort, people with COS were 4 times as likely as controls to have rare structural mutations. In contrast, rates of mutation in noncoding genetic regions were similar in people with schizophrenia and controls, suggesting that rare mutations that associate with schizophrenia specifically affect genes.
In the original cohort of adults with schizophrenia, nearly all of the rare mutations were different. However, some impacted the same genes. In people with schizophrenia, disrupted genes were over-represented in pathways involved in brain development and signaling, including neuronal differentiation and growth, axon guidance, long-term potentiation and glutamate receptor and kinase signaling. In contrast, genes disrupted in controls were not over-represented in common pathways.
Previous genome-wide association studies identified neuregulin 1, which is important in neuronal differentiation and synapse formation, as a schizophrenia susceptibility gene. In the current study, the authors identified rare mutations in the neuregulin receptor ERBB4 in people with schizophrenia.
In the COS cohort, the authors identified structural mutations in several genes or genetic regions previously associated with autism, including neurexin 1 and 16p11.2, suggesting that disruption of genes important in neuronal development may contribute to different disease states. Although some of the newly identified structural mutations were de novo, many were inherited from unaffected parents. It is unclear why these mutations associate with disease in some people but not others. These data may suggest that multiple rare variants contribute to COS and other severe forms of psychiatric diseases.