Genes, animal models and the current understanding of psychiatric disease

Abstract

specifically diagnostic of schizophrenia; and the few treatments available are only partially effective, and only in a subset of patients. Corvin looks to a future in which diagnosis will be guided by molecular etiology, and patients may be treated with drugs known to be effective for the particular genetic subtype of disease. One of the most striking findings of the genetic studies is that individual rare mutations of large effect often confer susceptibility to more than one disorder, for example both schizophrenia and autism. Overlap in susceptibility is also seen in the GWAS that have to date identified 10 common variants with small effects on disease risk, though here the major overlap is seen with bipolar disorder. These findings are consistent with epidemiological studies that indicate shared risk for different disorders, and families in which a spectrum of disorders is observed. The strong association of different disorders with the same mutation suggests they can be distinct phenotypic endpoints that can arise from a common genetic origin, rather than a polygenic effect, a possibility that can be explored using the modeling approach outlined by Mitchell and colleagues. Corvin concludes from this accumulating evidence that schizophrenia will not continue to be viewed as a single disease. In one respect there is a notable difference in the stance taken by the two articles. Mitchell and coauthors espouse the proposition, gaining ground of late [3, 4], that the disease-associated rare variants reported so far (mostly short deletions or duplications) represent only the tip of the iceberg, and that as sequencing studies uncover more functionally relevant mutations, most cases of neuropsychiatric disease will be found to be attributable, in large part, to single rare mutations of large effect. Corvin on the other hand takes the view that with only 5% of cases so far explained by rare mutations, it is too early to judge to what extent they account for the heritability of the disease, and that the combined effect of common alleles, together with environmental factors, may still explain a considerable fraction of cases [5]. These two different outlooks reflect a lively and ongoing debate on