Trinucleotide repeat expansions: do they contribute to bipolar disorder?

It has long been known that bipolar disorder has a true but complex genetic background. Reports on genetic anticipation in bipolar disorder opened the way to a new approach for genetic studies. Indeed, anticipation, a decreasing age at onset, and/or increasing disease severity in successive generations, were recently explained by an expansion of trinucleotide repeats in monogenic diseases like Huntington's disease and Fragile X syndrome. The involvement of trinucleotide repeat expansions in bipolar disorder received even more support when studies reported association of large CAG/CTG repeats with bipolar disorder. Even though a large number of studies have been conducted, this association is still unexplained. Here, we review the studies investigating the trinucleotide repeat expansion hypothesis in bipolar disorder. Studies on anticipation, on association of anonymous large CAG/CTG repeats and on specific trinucleotide repeats are critically analysed and discussed, showing a field with precipitate conclusions or inconclusive results. The analysis suggests that there are indications, though disputable, supporting the trinucleotide repeat expansion hypothesis in bipolar disorder, but no conclusive evidence has been hitherto provided.