Large CAG/CTG repeats are associated with childhood-onset schizophrenia

Abstract

Recent studies have shown an association between trinucleotide repeat expansions (TREs) and adult-onset schizophrenia (AOS). Childhood-onset schizophrenia (COS) is a severe variant of schizophrenia with onset of symptoms before age 12 years. We have used the repeat expansion detection (RED) method to investigate the occurrence of repeat expansions in a group of well-characterized COS patients as well as a set of clinically related childhood-onset psychosis cases labeled 'multidimensionally impaired' (MDI). The difference observed in the CAG/CTG RED product distribution between normal (n = 44) and COS (n = 36) samples was only marginally significant (P = 0.036). However, male COS samples (n = 20) had a significantly different RED product distribution compared to male controls (n = 25, P = 0.002) with longer RED products in COS. No such difference was seen in females (n cont = 19; n COS = 16; P = 0.236). The difference remained significant between male COS (n = 12) and male controls (n = 24) when only Caucasian samples were used (P = 0.003). Similarly, the RED product distribution in male MDI samples (n = 18) was significantly different compared to male controls (P = 0.018). Some of the detected TREs in all three populations (COS, MDI and control) correlated with expanded alleles found at the CTG18.1 locus on chromosome 18. In conclusion, we have found an association between TREs and COS. This association is specifically significant in the male population. Thus, the occurrence of an expanded trinucleotide repeat may contribute to the genetic risk of COS, possibly in combination with other factors.

Linkage and associated studies of schizophrenia

“…Such studies have shown increased sizes of ligation products in schizophrenics, but there is large overlap between the product sizes in schizophrenics and normals, and the differences are not specific to schizophrenia [Morris et al, 1995;O'Donovan et al, 1996;Bowen et al, 1996;Gaitonde et al, 1997;Speight et al, 1997;Vincent et al, 1998;Burgess et al, 1998;Laurent et al, 1998;Li et al, 1998a;Martorell et al, 1999]. Studies of trinucleotide repeats in known genes have been disappointing.…”

Analysis of genome-wide CAG/CTG repeats, and at SEF2-1B and ERDA1 in schizophrenia and bipolar affective disorder

“…The samples were split and analysed for both genders separately using M-W to determine whether a sex effect was present, as has been reported in several previous studies. 9,29 No significant differences in distribution were seen between male affecteds and matched controls, female affecteds and matched controls, male vs female affecteds or male vs female controls (P Ͼ 0.05). No significant correlations were observed with age or age-of-onset.…”

“…Given the high frequencies of large alleles at SEF2-1B and ERDA1 in our affected and control populations as well as others, [23][24][25]27 such high frequencies are likely the case in other studies which have reported significant increases in CAG/CTG repeat distribution amongst affected individuals. [6][7][8][9]11,29 A recently published study has reported weak evidence of association of large repeats at SEF2-1B (but not ERDA1) with BPAD. 30 Our findings in this study contradict this.…”

Trinucleotide Repeat Expansion and Neuropsychiatric Disease

“…Of 8 studies examining bipolar disorder, 4 reported an association between bipolar disorder and longer CAG repeats, [194][195][196][197] while another 4 did not find a significant association. [198][199][200][201] In schizophrenia, an association with long CAG repeats was found in 3 studies 194,202,203 but not in 7 others. [198][199][200][204][205][206][207] Two CAG expansions that occur frequently in the normal population, located in an intron of the SEF2-1 gene on chromosome 18 181 and in the ERDA1/Dir1 locus on chromosome 17,208,209 are now known to account for most of the long CAG repeats detected by RED.…”