Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

Abstract

An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) Ͼ120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.1 on 18q21.1. In a set of patients and controls in which we had previously found a significant difference in RED size distribution, the frequency of expansions at the CTG18.1 locus was 13% in bipolar patients (n = 60) and 5% in controls (n = 114) (P Ͻ 0.07) with a significantly different size distribution (P Ͻ 0.03). A second set of patients were ascertained from 14 affective disorder families showing anticipation. Twelve of the families had members with RED products Ͼ120 nt. The RED product distribution was significantly different (P Ͻ 0.0007) between affected (n = 53) and unaffected (n = 123) offspring. Using PCR, a higher frequency (P Ͻ 0.04) of CTG18.1 expansions as well as a different (P Ͻ 0.02) repeat size distribution was seen between affected and unaffected offspring. In addition, a negative correlation between RED product size and the age-of-onset could be seen in affected offspring (r s = −0.3, P = 0.05, n = 43). This effect was due to an earlier onset in individuals with long CTG18.1 expansions. No difference in ERDA1 expansion frequency was seen either between bipolar patients (35%, n = 60) and matched controls (29%, n = 114), or between affected and unaffected offspring in the families. We conclude that expanded alleles at the CTG18.1 locus confers an odds ratio of 2.6-2.8 and may thus act as a vulnerability factor for affective disorder, while the ERDA1 locus seems unrelated to disease.

Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study

“…4 Finally, EO was reported to be involved in anticipation (increase in disease severity and decrease in age at onset in succeeding generations), as suggested in BPDs. [6][7][8][9] EO of MD could be an important variable in identifying some forms of MD that are more genetically homogeneous or may carry some degree of relatively increased genetic loading or phenotypic expression. 5 EO, as a specific phenotype, may be helpful to identify vulnerability genes (ie increase penetrance).…”

Are (CTG)n expansions at the SCA8 locus rare polymorphisms?

“…It is therefore possible that the disease in the large SCA8 kindred 2 might be caused by another mutation in, or closely linked to, the same gene. Indeed, large alleles of other polymorphic trinucleotide loci were found in controls of specific origins [3][4][5][6][7][8][9] .…”

Allelic distribution of CTG18.1 in Caucasian populations: association studies in bipolar disorder, schizophrenia, and ataxia

“…8,9 Further, the repeat expansion detection (RED) method has identified subjects with larger RED products of (CAG) n in bipolar disorder or schizophrenia compared to controls, with the implication that a locus with an enlarged (CAG) repeat is etiologically associated with the illness. [10][11][12][13][14] However, not all studies have found this. 15,16 We recently described a highly polymorphic (observed heterozygozity 84%) and unstable CAG repeat locus (CTG18.1) in the third intron of the SEF2-1 gene.…”

“…18 The CTG18.1 locus was recently studied in 60 bipolar subjects and 114 controls (all Swedish) as well as 14 Swedish bipolar pedigrees. 10 Of 60 bipolar subjects eight had RED products Ͼ120 nucleotides (40 CAGs) while six of 108 control subjects had RED products Ͼ120 nucleotides determined to be at the CTG18.1 locus. They studied 14 BP pedigrees, 12 of whom had subjects with enlarged CTG18.1 alleles.…”