Letter to the Editor

Response to Millar et al. Critique of Chromosome 1;11 Translocation Causing Psychosis

Corresponding author: Amar J. S. Klar, National Cancer Institute, P.O. Box B, Ft. Detrick, Bldg. 539, Frederick, MD 21702., klar{at}ncifcrf.gov (E-mail)

MILLAR et al. 2003 raise several points in their correspondence regarding the Note in GENETICS by KLAR 2002 . First, they propose to exclude the Klar hypothesis, as 70% of chromosome 1;11 translocation carriers are affected, and not 50% expected from the random DNA strand segregation of the translocated chromosome predicted by the hypothesis. In this context, it should be pointed out that in their review article, which formed the basis of the Note mentioned above, they stated "Note that half (only) of the translocation and none of the nontranslocation carriers have a major psychiatric diagnosis" (EVANS et al. 2001 ). That feature of 50% penetrance needed to be explained. Millar et al. now point out that it is more appropriate to consider only generations II–IV, where an adult life history is available, in the data of BLACKWOOD et al. 2001 . In doing so, the fraction of affected individuals among translocation carriers in generations II–IV is 70%: six schizophrenia, one bipolar affective disorder, nine recurrent major depression, and seven unaffected. Because of the small numbers, purely on statistical grounds (two-sided binomial test, P > 0.05), the strand-segregation hypothesis cannot be excluded.

Second, they advance the conventional explanations of genetic heterogeneity, genetics modifiers, and incomplete penetrance to support their conclusion of segregation of a dominant gene of major effect with variable penetrance as the most likely model. Multifactorial inheritance does not mean that genetic mechanisms are understood—in fact they are not. Such explanations have become a dogma in the field of psychiatric genetics. Too many variables are posited, and there is no simple way to independently sort out the contribution of each factor to the disease. We should keep in mind that in the recent past other dogmas in the field consisted of family neglect and/or abuse of the child or of chemical imbalance in the brain causing psychosis.

Third, MILLAR et al. 2003 point out the study of EKELUND et al. 2001 showing linkage of schizophrenia to DISC1 on chromosome 1 in a population in Finland. It should be kept in mind that a very large number of other studies failed to implicate the region in question. In fact, the latest multicenter study found no major locus of influence on chromosome 1 (LEVINSON et al. 2002 ). The bipolar disease segregating with chromosome 9;11 translocation in one study is also consistent with the Klar model, as the effect may be through either chromosome 1 or chromosome 11 (KLAR 2002 ).

Fourth, Millar et al. state that the Klar model presumes modifiers to explain variability in disease phenotype, as both schizophrenia and bipolar disorder are manifested in the Scottish family. That is incorrect, as both disorders were proposed to be the same disease with different manifestations, and no modifier was proposed.

The Klar article aimed to point out the best evidence, if any, favoring a genetic etiology, to challenge the field to scrutinize their main assumptions of genetic heterogeneity and incomplete penetrance, and to advance an alternative hypothesis to explain a genetic oddity. That is, how could the rearrangement create a mutation that is dominant to the wild-type allele in some cases and recessive in the remainder? Until the assumptions of genetic heterogeneity and incomplete penetrance are experimentally proven, it is necessary to consider other hypotheses. This is not to say that the genetic heterogeneity model should not be considered; it should be; however, it should not be considered proven until it is experimentally verified. Both models remain to be experimentally tested, as convincing evidence does not exist for either model. Whether or not either of these hypotheses turns out to be correct, the work on this translocation should be accorded more significance, as it provides the best evidence favoring genetic etiology (KLAR 2002 ). The translocation research material will be extremely useful for future research on these devastating human disorders. Discussions such as this one are useful to highlight the importance of this area of research and to point out the strengths and the weaknesses of the evidence for the prevailing views in the field.

LITERATURE CITED

BLACKWOOD, D. H. R., A. FORDYCE, M. T. WALKER, D. M. ST, D. J. CLAIR, and D. J. CLAIRPORTEOUS ET AL., 2001  Schizophrenia and affective disorders—cosegregating with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 finding in a family. Am. J. Hum. Genet. 69:428-433.[Medline]

EKELUND, J., L. HOVATTA, A. PARKER, T. PAUNIO, and T. VARILO et al., 2001  Chromosome 1 loci in Finnish schizophrenia families. Hum. Mol. Genet. 10:1611-1617.[Abstract/Free Full Text]

EVANS, K. L., W. J. MUIR, D. H. R. BLACKWOOD, and D. J. PORTEOUS, 2001  Nuts and bolts of psychiatric genetics: building on the human genome project. Trends Genet. 17:35-40.[Medline]

KLAR, A. J. S., 2002  The chromosome 1;11 translocation provides the best evidence supporting genetic etiology for schizophrenia and bipolar affective disorders. Genetics 160:1745-1747.[Abstract/Free Full Text]

LEVINSON, D. F., P. A. HOLMANS, C. LAURENT, B. RILEY, and A. E. PULVER et al., 2002  No major schizophrenia locus detected on chromosome 1q in a large multicenter sample. Science 296:739-741.[Abstract/Free Full Text]

MILLAR, J. K., P. A. THOMSON, N. R. WRAY, W. J. MUIR, and D. H. R. BLACKWOOD et al., 2003  Response to Amar J. Klar: the chromosome 1;11 translocation provides the best evidence supporting genetic etiology for schizophrenia and bipolar affective disorders. Genetics 163:833-835.[Free Full Text]

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