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Studies of Individual Genes

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Linkage studies can provide at best indirect evidence for shared genetic effects. More direct evidence has come from reports implicating variation in the same genes as influencing susceptibility to both schizophrenia and bipolar disorder. In most cases, the gene was first implicated in studies of schizophrenia, and the evidence in most cases is strongest for this phenotype. This could reflect the true contribution to the phenotype or may simply reflect the fact that substantially greater resources and samples have been used to date on studies of schizophrenia. We will consider the evidence for each gene in turn.

NRG1

NRG1 was first implicated in schizophrenia in the Icelandic population after a systematic study of 8p21-22 revealed association between schizophrenia and a multimarker haplotype at the 5′ end of NRG1. 31 Strong evidence for association with the same haplotype, known as HAPICE, was subsequently found in a large sample from Scotland,32 with further support coming from our own UK sample.33 These and subsequent studies of NRG1 in schizophrenia have been reviewed recently.34 Overall, there is strong evidence from several studies that genetic variation in NRG1 confers risk to schizophrenia, but not all studies have found the same haplotype to be associated and, as yet, specific susceptibility and protective variants have not been identified. NRG1 has not yet been extensively studied in bipolar disorder. However, in the only published study to date, we found significant evidence for association of HAPICE with susceptibility to bipolar disorder of a similar magnitude to that seen by us in schizophrenia (OR = 1.3).35 In the bipolar cases with predominantly mood-incongruent psychotic features, the effect was greater (OR = 1.7), as was the case in the subset of schizophrenia patients who had experienced mania (OR = 1.6). Pending replication, these findings should be treated with caution, but they suggest that NRG1 plays a role in influencing susceptibility to both bipolar disorder and schizophrenia and that it may exert a specific effect in the subset of functional psychoses characterized by both manic and mood-incongruent psychotic features.

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