Genetic variation in catechol-O-methyltransferase: Effects on working memory in schizophrenic patients, their siblings, and healthy controls

Background: Catechol-O-methyltransferase (COMT) val(108/158) met (rs4680) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865, rs165599, and rs2097603. In a large sample, we examined whether these SNPs affect WM. Methods: Schizophrenic probands (n = 325), their nonpsychotic siblings (n = 359), and normal control subjects (n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Results: Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val(108/158) met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val(108/158)met SNPs showed main effects on WM parameters, consistent with inverted U models of doparmine signaling. Conclusions: We extended earlier findings of a val(108/158)met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val(108/158). met effect in a nonlinear manner.