Following the discovery of trinucleotide repeat expansion mutations as the cause of Huntington’s disease, myotonic dystrophy, Friederich’s ataxia and a number of spinocerebellar ataxias in the early 1990s, it was noted that this newly discovered disease mechanism was the likely mechanism of anticipation in families affected by these diseases. Anticipation is the observed phenomenon of increased severity and decreased age of onset in successive generations. Anticipation has also been reported in psychiatric disorders such as schizophrenia and bipolar disorder for well over a century (Morel, 1857; Mott, 1911). Despite reservations concerning numerous biases in the observation of anticipation (e.g. Penrose, 1948), a number of groups researching the genetics of these disorders embarked on studies to  establish whether trinucleotide repeat expansion could potentially be a disease mechanism. Initial studies seemed to support this, but our own research cast doubt on these findings. Generally, the accepted view is that large trinucleotide repeat expansions are not a major cause or risk factor in schizophrenia or bipolar disorder. However, technical limitations of the research prevent us from dismissing all forms of unstable repeats, and smaller repeats, from playing a role.  Next generation sequencing may soon see a revisiting of these issues.

During this period of research, my work and that of several other groups, identified three loci in the human genome that contain large unstable CAG/CTG repeat stretches present in pyschosis patients and in healthy individuals. These are: SEF2-1B, ERDA1 and SCA8. SEF2-1B is located on 18q21.2 in intron 3 of the gene TCF4 (NM_001243226). ERDA1 is located on 17q21.33, in intron 4 of the carbonic anhydrase gene CA10 (NM_001082533). Thirdly, a large CAG/CTG repeat was identified by us in patient with bipolar disorder. This repeat was subsequently reported as SCA8- where expansion was associated with spinocerebellar ataxia (Koob et al, 1999).  The repeat is located upstream of a gene called KLHL1 on 13q21.33, and appears to be in a non-coding antisense RNA, now termed ATXN8OS. However, our work showed clearly that expanded repeats at this locus are present in non-ataxia individuals (Vincent et al, 2000:Vincent_2000_SCA8). The SCA8 findings are still controversial, and even today it is still not understood why there is a dichotomy, in that some expanded alleles appear to cause ataxia and others don’t.

I published a review/discussion of trinucleotide repeats in psychiatric disease: “Unstable repeat expansion in major psychiatric disorders: two decades on, is dynamic DNA back on the menu?” in Psychiatric Genetics (Aug 2016).Unstable DNA_PG_2016. In addition to a historic overview, I have suggested that new technologies such as single molecule real-time (SMRT) sequencing may be applied to assessing known unstable repeats and uncovering new repeats in psychiatric populations, and may yet reveal true association of expanded repeats with psychiatric disorders.