These results support our hypothesis that the deletion allele affords protection against bipolar disorder through increased KA1 protein abundance in neuronal cells.
This gene is disrupted by a translocation breakpoint in a patient with schizophrenia, and case control studies show significant association of GRIK4 with both schizophrenia and bipolar disorder.
This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802).
GluK4 knockout mice also showed marked hyperactivity and impaired pre-pulse inhibition, thereby mirroring two of the hallmark endophenotypes of patients with schizophrenia and bipolar disorder.