The Polygenetic Basis of Mutations in the Development of Schizophrenia
Schizophrenia is a mental disorder often presented in patients by abnormal thought processes, impaired emotional responses, and negative symptoms. As a chronic disorder that affects ~1% of all people, schizophrenia can be have debilitating effects on patients, especially on their social lives. Due to the lack of knowledge on its pathophysiology and also the heterogeneity of the symptoms, it has been increasingly important to understand the genetics of schizophrenia.
Due to the marked reduction in fecundity seen in schizophrenic patients, the high heritability of the disorder pointed to the possibility that genetic alleles that were risk factors might occur as de novo mutations. Previous exome sequencing studies showed no promising results, but the inconclusive results were likely due to small sample size and a narrow focus on target genes. Two recent studies, the largest of their kind, gathered data from nearly 7000 people (nearly 3500 patients) from Sweden and Bulgaria, and showed that genetic effects on schizophrenia seemed to be very complex. Specifically, both papers published in Nature reflected on the implication of genetic mutations in clusters of specific proteins that governed signaling networks dealing with learning and memory. The studies identified the presence of de novo mutations, often nonsense mutations, notably in genes related to the PSD (post-synaptic density of dendrites), the calcium channels, the postsynaptic ARC complex, and the NMDA receptors.
In addition, the studies identified de novo mutations that linked schizophrenia to known gene targets of autism spectrum disorder (ASD) and intellectual disability. However, direct evidence for an overlap at the individual gene level for these three disorders was not observed. Regardless, in a broad sense, their results suggested that any overlap in genetic targets (such as FMRP or PSD targets) are far from complete, and more studies will be needed to elucidate which genes and pathways are shared and which are specific to a disease.
Overall, the findings from the two recent studies suggest that the risk for schizophrenia arises from combined effects of many genes or polygenicity. They also seem to suggest that many of the affected genes show de novo mutations in clusters that work in networks of functionally-related genes. The heterogeneity of schizophrenia, and of many other mental disorders, has often been explained by the differences in the clinical and symptomatic presentations of patients. But now, these studies also suggest that rather than being caused by a single gene dysfunction, the heterogeneity if schizophrenia can be explained by a large number of genetic mutations that contribute to an overall risk for the disorder. There is hope that the results of these studies will help in the development of a more personalized treatment for patients rather than the use of an outlined over-arching treatment that is currently employed.
1. Fromer, M., et al. De novo mutations in schizophrenia implicate synaptic networks. Nature Articles (2014)
2. Purcell, S.M., et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature Articles (2014)