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Disrupted in Schizophrenia 1

This gene was implicated through studies of an extended pedigree in which a balanced chromosomal translocation (1;11)(q42;q14.3) showed strong evidence for linkage to a fairly broad phenotype comprising schizophrenia, bipolar disorder, and recurrent depression.⁴⁴ The translocation was found to disrupt 2 genes on chromosome 1: DISC1 and DISC2. ^44,45 DISC2 contains no open reading frame and may regulate DISC1 expression via antisense RNA.⁴⁵ A small pedigree has recently been reported in which a 4-bp deletion in exon 12 of DISC1 cosegregates with schizophrenia and schizoaffective disorder,⁴⁶ although independent evidence suggests that the deletion is unlikely to be a highly penetrant risk allele for psychosis.⁴⁷ Interestingly, DISC1 and DISC2 are located close to the chromosome 1 markers implicated in 2 Finnish linkage studies of schizophrenia.^48,49 The Edinburgh group which identified DISC1 found no linkage evidence in their own schizophrenia sample but did find suggestive evidence for linkage in bipolar disorder.⁵⁰ More recently, Hamshere and colleagues²⁹ reported genome-wide significant evidence for linkage at this locus in a linkage study of schizoaffective disorder, bipolar type. DISC1 is certainly an interesting candidate gene for mental disorder, but it is important to remember that translocations exert effects on genes other than those directly disrupted. For example, there are several mechanisms by which a translocation can influence the expression of neighboring genes. In order to unequivocally implicate DISC1 and/or DISC2 in the pathogenesis of psychosis, it is necessary to identify mutations or polymorphisms that are associated with psychosis in nondeleted cases and are not in linkage disequilibrium with neighboring genes. Negative studies in schizophrenia samples were initially reported by the Edinburgh group with a small number of markers⁵¹ and by a group who focused on the 5′ end of the gene in a large Japanese sample.⁵² More recently, several groups have reported positive findings,^53–56 although in no case are the results compelling and there is little agreement as to the specific markers or haplotypes showing association. Interestingly, in 3 of these studies, associations were observed with bipolar disorder as well as schizophrenia,^53–55 and in one the strongest association was observed with schizoaffective disorder.⁵⁴

While no consistent pattern of association has yet emerged and no pathogenically relevant variants have been established, the convergence of the linkage data is strongly suggestive that variation in DISC1 or another gene in this region influences susceptibility to mood-psychosis phenotypes that cut across the traditional Kraepelinian divide.

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