A CAG repeat polymorphism of KCNN3 predicts SK3 channel function and cognitive performance in schizophrenia.

KCNN3, encoding the small conductance calcium-activated potassium channel SK3, harbours a polymorphic CAG repeat in the amino-terminal coding region with yet unproven function. Hypothesizing that KCNN3 genotypes do not influence susceptibility to schizophrenia but modify its phenotype, we explored their contribution to specific schizophrenic symptoms. Using the Göttingen Research Association for Schizophrenia (GRAS) data collection of schizophrenic patients (n = 1074), we performed a phenotype-based genetic association study (PGAS) of KCNN3. We show that long CAG repeats in the schizophrenic sample are specifically associated with better performance in higher cognitive tasks, comprising the capacity to discriminate, select and execute (p < 0.0001). Long repeats reduce SK3 channel function, as we demonstrate by patch-clamping of transfected HEK293 cells. In contrast, modelling the opposite in mice, i.e. KCNN3 overexpression/channel hyperfunction, leads to selective deficits in higher brain functions comparable to those influenced by SK3 conductance in humans. To conclude, KCNN3 genotypes modify cognitive performance, shown here in a large sample of schizophrenic patients. Reduction of SK3 function may constitute a pharmacological target to improve cognition in schizophrenia and other conditions with cognitive impairment.

Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms.

CONTEXT: Schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown. OBJECTIVE: To prepare the ground for a novel "phenomics" approach, a unique schizophrenia patient database was established by GRAS (Göttingen Research Association for Schizophrenia), designed to allow association of genetic information with quantifiable phenotypes.Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenotype-based genetic association study (PGAS) of GRAS [corrected] DESIGN: Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated. SETTING: Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany. PARTICIPANTS: One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory. RESULTS: Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in Cplx2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells. CONCLUSIONS: The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression.