The recent identification of mutations that confer substantial risk for schizophrenia has generated much excitement within the field. However, there is much more to be learned. Very few of the individual rare variants have been definitively identified. In addition, the relative contributions of rare variants of large effect and common alleles with modest effects are not known. It is clear, however, that the role of rare variants is not limited to a small percentage of patients. Further studies on a much larger scale are needed to uncover the rare genetic variants that underlie schizophrenia.
Statistical power to detect the association of rare variants in a gene depends not only on sample size, but also on the sensitivity of a method to detect mutations. To understand the contribution of rare variants to schizophrenia, it is first necessary to ascertain the full spectrum of structural variants as well as other classes of variation including point mutations and indels. This could best be achieved through whole-genome sequencing. As the power and cost of genome-wide screening technologies improves, we anticipate that many more critical genes will be identified. These discoveries may include loci that are hotspots, with mutation rates of one in 10,000, as well as many other genes and genomic regions with lower mutation rates (e.g. one in 100,000) and lower overall frequencies. Although the cost of whole-genome sequencing in a large patient sample is substantial, a significant investment could be justified given the power of the data derived from these methods to transform the field of psychiatric genetics.
The discovery of rare schizophrenia-associated CNVs and other mutations that confer substantial risk of disease would, for the first time, identify single mutations that have reasonable predictive value, with potential to improve the clinical diagnosis of patients. First, the clinical relevance of the individual mutations must be definitively established and the penetrance for a variety of clinical phenotypes must be understood. This can be achieved by intensive clinical studies of patients and their families who share a disease mutation.
The ultimate goal of psychiatric genetic research is to identify and characterize neurobiological pathways and processes that are disrupted in individuals with mental disorders. Although schizophrenia might arise from a multitude of different causes, it is likely that these will influence a more limited number of key brain systems or pathways. A thorough characterization of these critical pathways will make a substantial contribution to our understanding of pathophysiology and provide important targets for treatment.