Bipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function.
Focusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes.
Clinical characteristics of the Bipolar 1 patient sample.
having all three symptoms: talkativeness, distractibility, and tought disorder.
The finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model.
Allelic association in bipolar 1 patients with cognitive manic symptoms (CMS) patients compared to non-CMS and to ABD controls in the DAOA and COMT genes.
SNP (minor allele(a)/major allele(b)).
gender and rs1718119 as covariate.
point-wise p-value from 10,000 pemutations with no covarite (EMP1).
corrected empirical p-value by max (T) permutation.
odds ratio (OR), the proportion of minor versus major allele affected (cognitive manic symptoms factor)/proportion of minor versus major allele unaffected (non-cognitive manic symptoms factor or ABD controls).
significant after correction for multiple testing by max (T) permutation.
Haplotype association of haplotype group 1 in bipolar 1 patients with cognitive manic symptoms (CMS) compared with non-CMS patients or ABD controls in the DAOA gene.
frequency (F) in sample.
gender and rs1718119 as covariates.
odds ratios (OR) for each haplotype.
Identifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population.