Further support for an association between a polymorphic CAG repeat in the hKCa3 gene and schizophrenia

Abstract

A recent study has suggested that a polymorphism in the hKCa3 potassium channel may be associated with raised susceptibility to schizophrenia. 1 Despite its modest statistical significance, the study 1 is intriguing for two reasons. First, hKCa3 contains a polymorphic CAG repeat in its coding sequence, with large repeats more common in schizophrenics compared with controls. 1 This is interesting in view of several repeat expansion detection (RED) studies 2 that have reported an excess of large CAG repeats in psychotic probands. 3-7 Second, the hKCa3 gene is a functional candidate gene because studies of antipsychotic and psychotogenic compounds suggest that glutamatergic systems modulated by SKCa channels may be important in schizophrenia pathogenesis. 1 In the light of the above, we have tested the hypothesis of an association between schizophrenia and the hKCa3 CAG repeat polymorphism using a case control study design. Under the same model of analysis as the earlier study, schizophrenic probands had a higher frequency of alleles with greater than 19 repeats than controls ( 2 = 2.820, P = 0.047, 1-tail). Our data therefore provide modest support for the hypothesis that polymorphism in the hKCa3 gene may contribute to susceptibility to schizophrenia.

Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study

“…It is noteworthy that the hSKCa3 gene has also been implicated in schizophrenia and bipolar disorders. 6,[14][15][16][17] Although the phenotype of AN and the major psychoses vary considerably, our results may support the hypothesis of common susceptibility genes shared by several psychiatric disorders. Thus, drugs active at the hSKCa3 channel could be considered in the pharmacotherapy of some neuropsychiatric disorders.…”

“…24 The distribution of the alleles in our control population was similar to that previously found in other populations. 6,[15][16][17][18] Comparison of the AN to the control alleles revealed a broad overlap with differences in only one or two CAG repeats in average and modal length. This overlap is not surprising for a common, heterogeneous and probably multifactorial disorder, such as AN.…”

hKCa3/KCNN3 potassium channel gene: association of longer CAG repeats with schizophrenia in Israeli Ashkenazi Jews, expression in human tissues and localization to chromosome 1q21

“…The modal repeat length for both patient and control groups is 19 CAG repeats, as reported in European and North American Caucasians. 8,9 A slight bimodal character is evident in these distributions, with a smaller peak present at 12-14 repeats, as has also been reported in two previous studies. 8,9 The two longest alleles (23 and 24 repeats) are uniquely represented among patients.…”

“…The second polyglutamine repeat is highly polymorphic in Caucasian European and North American populations, ranging from 10-28 repeats in length, with a modal value of 19 repeats. 8,9 Case-control studies have recently shown a significant over-representation of longer hKCa3/KCNN3 CAG-repeat alleles in Caucasian schizophrenia patients compared with ethnically matched controls, although there is considerable overlap in allele sizes, and the modal allele has 19 repeats for all these populations. 8,9 In this report we firstly confirm the previously described association between the presence of longer CAG repeats in the hKCa3/KCNN3 gene and schizophrenia in Israeli Ashkenazi Jews.…”

“…8,9 Case-control studies have recently shown a significant over-representation of longer hKCa3/KCNN3 CAG-repeat alleles in Caucasian schizophrenia patients compared with ethnically matched controls, although there is considerable overlap in allele sizes, and the modal allele has 19 repeats for all these populations. 8,9 In this report we firstly confirm the previously described association between the presence of longer CAG repeats in the hKCa3/KCNN3 gene and schizophrenia in Israeli Ashkenazi Jews. Second, we reveal the presence of hKCa3/KCNN3 transcripts in specific regions of the human brain that have previously been implicated in schizophrenia, using Northern blot analyses and in situ hybridization.…”