Anticipation and CAG•CTG repeat expansion in schizophrenia and bipolar affective disorder

Abstract

The genetic contribution to the etiologies of schizophrenia and bipolar affective disorder (BPAD) has been considered for many decades, with twin, family, and adoption studies indicating consistently that the familial clustering of affected individuals is accounted for mainly by genetic factors. Despite the strong evidence for a genetic component, very little is understood about the underlying genetic and molecular mechanisms for schizophrenia and BPAD. In the early 1990s, after the discovery of "dynamic mutation" or "unstable DNA" as a molecular basis for the genetic anticipation observed in Huntington's disease, myotonic dystrophy, and many others, and the recently rediscovered, albeit still controversial, evidence for genetic anticipation in major psychoses, the genetic epidemiology of schizophrenia and BPAD was re-evaluated to demonstrate strong endorsement for the unstable DNA model. Many of the non-Mendelian genetic features of schizophrenia and BPAD could be explained by the behaviour of unstable DNA, and several molecular genetic approaches became available for testing the unstable DNA hypothesis. However, despite promising findings in the mid-1990s, no trinucleotide repeat expansion has yet been identified as a cause of idiopathic schizophrenia or BPAD.

Anticipation in families with Hodgkin's and non-Hodgkin's lymphoma in their pedigree

“…Similar genetic mutations have been discovered in other inherited diseases: CAG, CTG and GCT tri-nucleotide repeats have been found in the genes responsible for myotonic dystrophy [12,13], cerebellar ataxia [14] and Huntington disease [15]. Anticipation and CAG*CTG repeat expansion were found in schizophrenia and bipolar disorder [16,17]. Various other diseases, such as type 2 diabetes [18], hereditary non-polyposis colorectal cancer [19], multiple sclerosis [20], Graves disease [21], Parkinsonism [22], rheumatoid arthritis [23] or Crohn's disease [24] have recently been shown to demonstrate anticipation.…”

“…Anticipation has been described in familial disorders, most commonly in chronic lymphocytic leukemia [6,7], but also in plasma cell disorders [2], Hodgkin's disease [3], non-Hodgkin's lymphoma [4] and in benign disorders such as myotonic dystrophy [12], cerebellar ataxia [14], Huntington disease [15], schizophrenia and bipolar disorder [16,17], type 2 diabetes [18], hereditary nonpolyposis colorectal cancer [19], multiple sclerosis [20], Graves disease [21], Parkinsonism [22], Rheumatoid Arthritis [23] or Crohn's disease [24].…”

Paternal age effect on age of onset in bipolar I disorder is mediated by sex and family history

“…Expansion of DNA trinucleotide repeats is controversial in BPI disorder, but it was observed in certain genomic regions [Mendlewicz et al, 1997; Margolis et al, 1999; Del‐Favero et al, 2002]. Several studies on BPI disorder and schizophrenia reported that the DNA expansion (trinucleotide repeats) differs by offspring sex, with larger expansions in females than in males [O'Donovan et al, 1995; Mendlewicz et al, 1997; Del‐Favero et al, 2002; Fortune et al, 2003]. Trinucleotide repeat expansion is known to be associated with younger AO in several diseases [Hall, 1990].…”