Response to Amar J. Klar: The chromosome 1;11 translocation provides the best evidence supporting genetic etiology for schizophrenia and bipolar affective disorders.

MANY common disorders, including schizophrenia ers are affected, however, and the probable mode of disease inheritance is dominant with reduced peneand bipolar affective disorder, are highly heritatrance. That is to say inheritance of the translocation ble, yet do not exhibit simple inheritance patterns. Indiconfers a genetic predisposition to develop psychiatric vidual risk is usually attributed to the coalescence of illness rather than a certainty of becoming ill. One possimultiple, independent, and additive risk factors (modble reason for this is the presence of modifiers with ifiers), both genetic and environmental, or to the effect either a protective or a disease-enhancing influence. of one of a number of genes of major effect and variable Similar rates of penetrance have been observed in penetrance, with secondary genetic modifiers and enviHirschsprung disease (aganglionic megacolon), and a ronmental factors determining the degree of penerecent report demonstrates that the genetic interplay trance. Nowhere is the debate more lively and contenof three different loci, one of major effect, can explain tious than in psychiatric genetics (Weiss and Terwilliger the inheritance pattern of this disorder (Gabriel et al. 2000), but in truth there is a dearth of substantiated, 2002). Given that genetic interplay between one major empirical data. For example, the reported number of and two minor genetic risk factors is sufficient to explain positive linkage and association studies far exceeds the the incomplete penetrance of Hirschsprung disease munumber of replications. This in part reflects the statistitations, it is not unreasonable to propose a similar mechcal challenge of replication and the complexities of anism for the 1;11 translocation and major psychiatric diagnostic criteria and boundaries. Attempts to rationalillness. ize observations through a novel mechanistic proposal In his recent Note to Genetics (Klar 2002), A. J. S. are therefore to be welcomed and merit careful discusKlar favors an alternative theory to explain the observed sion. Klar recently proposed one such novel mechanistic reduced penetrance in translocation carriers. On the interpretation of data published by us on a large multibasis of mating-type switching in Schizosaccharomyces generation Scottish family with a high loading of major pombe, Klar proposes a theory of random chromosome psychiatric illness (Klar 2002). However, several points strand segregation that predicts 50% of translocation of information not considered by Klar allow us to concarriers will be unaffected, while the other 50% will clude that his model is not supported by the available suffer from a major psychiatric illness. In fact, generadata. tions II–V of the family segregating this translocation In this family, a balanced (1;11)(q42;q14) translocaindicate that 62% (18 of 29) of translocation carriers tion cosegregates with major psychiatric illness with a are affected by schizophrenia, bipolar affective disorder, maximum LOD score of 7.1 (St. Clair et al. 1990; or major depression (note that only 29 translocation Blackwood et al. 2001). The odds for the translocation carriers have been subject to full clinical assessment, being linked to the psychiatric disorders in this family although a total of 37 translocation carriers have been are therefore extremely high. Not all translocation carriidentified; Blackwood et al. 2001). Moreover, at the time of ascertainment, many of the translocation carriers in generation V were at, or below, the average age 1Corresponding author: Medical Genetics Section, Department of of onset. It is therefore more appropriate to consider Medical Sciences, The University of Edinburgh, Molecular Medicine only generations II–IV where an adult life history is Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. E-mail: [email protected] available and where 70% (16/23) of translocation carri-