The unstable trinucleotide repeat story of major psychosis

New hopes for cloning susceptibility genes for schizophrenia and bipolar af fective disorder followed the discovery of a novel type of DNA mutation, na mely unstable DNA. One class of unstable DNA, trinucleotide repeat expansio n, is the causal mutation in myotonic dystrophy, fragile X mental retardati on, Huntington disease and a number of other rare Mendelian neurological di sorders. This finding has led researchers in psychiatric genetics to search for unstable DNA sites as susceptibility factors for schizophrenia and bip olar affective disorder. Increased severity and decreased age at onset of d isease in successive generations, known as genetic anticipation, was report ed for undifferentiated psychiatric diseases and for myotonic dystrophy ear ly in the twentieth century, but was initially dismissed as the consequence of ascertainment bias. Because unstable DNA was demonstrated to be a molec ular substrate for genetic anticipation in the majority of trinucleotide re peat diseases including myotonic dystrophy, many recent studies looking for genetic anticipation have been performed for schizophrenia and bipolar aff ective disorder with surprisingly consistent positive results. These studie s are reviewed, with particular emphasis placed on relevant sampling and st atistical considerations, and concerns are raised regarding the interpretat ion of such studies. In parallel, molecular genetic investigations looking for evidence of trinucleotide repeat expansion in both schizophrenia and bi polar disorder are reviewed. Initial studies of genome-wide trinucleotide r epeats using the repeat expansion detection technique suggested possible as sociation of large CAG/CTG repeat tracts with schizophrenia and bipolar aff ective disorder. More recently, three loci have been identified that contai n large, unstable CAG/CTG repeats that occur frequently in the population a nd seem to account for the majority of large products identified using the repeat expansion detection method. These repeats localize to an intron in t ranscription factor gene SEF2-1B at 18q21, a site named ERDA1 on 17q21 with no associated coding region, and the 3' end of a gene on 13q21, SCA8, that is believed to be responsible for a form of spinocerebellar ataxia. At pre sent no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder. Preliminary evidence suggests that large repeat alleles at SCA8 that are n on-penetrant for ataxia may be a susceptibility factor for major psychosis. A fourth, but much more infrequently unstable CAG/CTG repeat has been iden tified within the 5' untranslated region of the gene, MAB21L1, on 13q13. A fifth CAG/CTG repeat locus has been identified within the coding region of an ion transporter, KCNN3 (hSKCa3), on 1q21. Although neither large alleles nor instability have been observed at KCNN3, this repeat locus has been ex tensively analyzed in association and family studies of major psychosis, wi th conflicting findings. Studies of polyglutamine containing genes in major psychosis have also shown some intriguing results. These findings, reviewe d here, suggest that, although a major role for unstable trinucleotides in psychosis is unlikely, involvement at a more modest level in a minority of cases cannot be excluded, and warrants further investigation. (C) 2000 Wile y-Liss, Inc.