Abstract
There is strong evidence that genetic factors make substantial contributions to the etiology of autism, schizophrenia and bipolar disorders, with heritability estimates being at least 80% for each. These illnesses have complex inheritance, with multiple genetic and environmental factors influencing disease risk; however, in psychiatry, complex genetics is further compounded by phenotypic complexity. Autism, schizophrenia and bipolar disorder are effectively syndromic constellations of symptoms that define groups of patients with broadly similar outcomes and responses to treatment. As such the diagnostic categories are likely to be heterogeneous and the boundaries between them somewhat arbitrary. Recent applications of whole-genome technologies have discovered rare copy number variants and common single-nucleotide polymorphisms that are associated with risk of developing these disorders. Furthermore, these studies have shown an overlap between the genetic loci and even alleles that predispose to the different phenotypes. The findings have several implications. First, they show that copy number variations are likely to be important risk factors for autism and schizophrenia, whereas common single-nucleotide polymorphism alleles have a role in all disorders. Second, they imply that there are specific genetic loci and alleles that increase an individual's risk of developing any of these disorders. Finally, the findings suggest that some of the specific genetic loci implicated so far encode proteins, such as neurexins and neuroligins, that function in synaptic development and plasticity, and therefore may represent a common biological pathway for these disorders.
Highlights
Studies of CNVs and other rare alleles have found overlap between autism and schizophrenia, whereas those of common single-nucleotide polymorphisms (SNPs) variants have shown overlap between schizophrenia and bipolar disorder. These findings suggest that schizophrenia, autism and other neurodevelopmental http://genomemedicine.com/content/1/10/102
The findings support the view that schizophrenia has a stronger neurodevelopmental compo nent than bipolar disorder and suggest that it lies on a gradient of decreasing neurodevelopmental impairment between syndromes such as mental retardation and autism, on one hand, and bipolar disorder on the other [74]
We have argued on the basis of recent genetic data that these findings point to common pathophysiological mechanisms, and this is an important area for future research
Summary
It has long been recognized that psychiatric disorders and symptoms aggregate in families and the evidence for a substantial role for genetic factors is incontrovertible [1]. Several loci have been implicated at genome-wide levels of statistical significance for schizo phrenia [11,13,14,53], including ZNF804A (encoding a protein with zinc finger and nucleic acid binding domains) [11] and the major histocompatibility complex (MHC) region [13,14,53] These studies have provided strong evidence for genetic overlap between schizophrenia and bipolar disorder [13,58]. Deletions of α-Neurexin result in increased lethality, normal synapse number and gross anatomy but severely impaired synaptic functioning, a pattern strikingly similar to neuroligin gene knockouts [16,66,67] Such biological roles fit with hypotheses of the etiology of autism and schizophrenia in which a neurodevelopmental insult and adult imbalance in excitatory and inhibitory neurotrans mission occur in the absence of overt macro-pathology. Further work on the biology of neurexins, neuroligins and related proteins is certainly required and it seems likely that the pathogenic roles of these proteins will be illuminated by further human genetic studies
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