chapter  14
11 Pages

From first contact to the final frontier: A star trek along the DISC1 pathway to schizophrenia

WithDAVID PORTEOUS

First contact It was in the late 1980s that Professor H. John Evans, Director of the MRC Clinical and Population Cytogenetics Unit (now Human Genetics Unit) encouraged psychiatrists David St Clair, Walter Muir and Douglas Blackwood to trawl the registry of cytogenetic records accumulated over the years by the unit for possible cases with psychiatric phenotypes. In the intervening years this simple, but effective, strategy has reaped several notable successes, none more so than through the Scottish family that lead to the discovery of DISC1. In 1990, St Clair, Muir, Blackwood, Evans and colleagues first reported a Scottish family with a high loading of psychiatric illness, which co-segregated with a balanced translocation between chromosomes 1 and 11 (log of the odds, LOD, = 3.4; St Clair et al., 1990). A decade or so later, Blackwood et al. (2001) published a major update, now reporting on 87 family members of who 37 carried the translocation. Of 29 individuals carrying the translocation and for whom a psychiatric assessment was possible, 7 had a diagnosis of schizophrenia (SCZ), 1 had a diagnosis of bipolar disorder (BP) and there were 10 cases of recurrent major depression (MDD). Thus, 18 of 29 (62%) translocation carriers had a diagnosis of major mental illness whereas none of 38 non-translocation carriers had such a diagnosis, compelling statistical evidence for a causal link between the t(1;11) and the psychiatric liability in this unique family. Indeed, the updated LOD score of 3.6 for schizophrenia alone and of 7.1 for the broad diagnosis of major mental illness remains to this day one of the single most striking linkage findings in the psychiatric field. Importantly, the psychiatric presentations were typical with no other distinguishing clinical features. Moreover, Blackwood et al. (2001) also reported that the latency and amplitude of the event related potential (ERP) P300, a measure of the speed and efficiency of information processing, was indistinguishable between unaffected and affected translocation carriers and that as a group the translocation carriers showed the characteristic abnormal ERP P300 associated with SCZ and with BP. The pattern of inheritance in the Scottish t(1;11) family was thus consistent with a simple dominant mode of inheritance for a broad spectrum of major psychiatric illness, with incomplete penetrance, and with altered ERP P300 as a correlated endophenotype. Secondary and independently segregating genetic risk factors, variable environmental exposures

and/or stochastic events may influence the presence or absence of clinical signs and the specific psychiatric diagnosis at the age of ascertainment, but it is clear that in this family the t(1;11) accounts for essentially all of the transmitted genetic risk. At the time, this finding was viewed sceptically by many as it challenged two fervently held precepts-on the clinical side, the aetiological distinction between schizophrenia, bipolar disorder and major depressive disorder, and on the genetic side, the notion that these psychiatric conditions were “always” complex, nonMendelian disorders. While the biological explanation remained uncertain, the evidence for a simple, shared genetic liability for a broad spectrum of mental illness in this particular family was beyond challenge.