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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.    Methodology  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.   10.1371/journal.pone.0067450.t001  Table 1   Clinical characteristics of the Bipolar 1 patient sample.Bipolar disorder type 1 [n]  488    Men [n (%)]  209 (43)    Talkativeness [n (%)]  373 (76)    Distracibility [n (%)]  269 (55)    Thought disorder [n (%)]  372 (76)    Cognitive manic symptoms *  [n (%)]  215 (44)    Men [n (%)]  81 (39)    Non-Cognitive manic symptoms [n (%)]  248 (51)    Men [n (%)]  117 (56)    Unknown [n (%)]  25 (5)    Men [n (%)]  11 (44)    Anonymous blood donors (ABD)  1044    Men [n (%)]  616 (59)*  having all three symptoms: talkativeness, distractibility, and tought disorder.Results  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.   10.1371/journal.pone.0067450.t002  Table 2   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.BP1 CMS  BP1 non-CMS  ABD  BP1 CMS vs. non-CMS b    BP1 CMS vs. ABD controls bGene  SNP a    aa/ab/bb  aa/ab/bb  aa/ab/bb  p  EMP1 c    EMP2 d    OR [95% CI]  e    p  EMP1 c    EMP2 d    OR [95% CI]  eDAOA    rs3916967 (C/T)  32/88/89  50/118/77  177/494/361  0.018  0.018  0.21  0.72 [0.55–0.93]  0.029  0.026  0.28  0.78 [0.66–1.0]DAOA    rs2391191 (A/C)  28/75/79  39/111/70  179/487/357  0.055  0.039  0.50  0.75 [0.57–1.0]  0.020  0.019  0.21  0.75 [0.63–1.0]DAOA    rs1935062 (C/A)  26/67/89  35/102/86  146/460/405  0.12  0.12  0.78  0.80 [0.58–1.0]  0.069  0.066  0.52  0.80 [0.65–1.0]COMT    rs5993883 (T/G)  33/120/53  71/112/57  269/510/223  0.025  0.030  0.27  0.73 [0.56–0.95]  0.0017 *    1.0E −4   *    0.021 *    0.68 [0.91–1.4]COMT    rs165599 (G/A)  29/94/87  25/93/126  87/443/501  0.093  0.094  0.69  1.27 [1.0–1.8]  0.014  0.017  0.16  1.34 [1.1–1.7]a  SNP (minor allele(a)/major allele(b)).    b  gender and rs1718119 as covariate.    c  point-wise p-value from 10,000 pemutations with no covarite (EMP1).    d  corrected empirical p-value by max (T) permutation.    e  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.10.1371/journal.pone.0067450.t003  Table 3   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.CMS vs non-CMS b    CMS vs ABD bDAOA    rs3916967  rs2391191  rs1935062  F a    p  OR [95% CI] c    F a    p  OR [95% CI] cHaplotype 1  C  A  C  0.32  0.25  0.83 [0.66–1.1]  0.33  0.14  0.83 [0.71–1.1]    Haplotype 2  T  G  C  0.032  0.34  0.64 [0.32–1.1]  0.037  0.19  0.58 [0.37–1.1]    Haplotype 3  C  A  A  0.074  0.077  0.58 [0.39–0.89]  0.075  0.10  0.65 [0.47–1.0]    Haplotype 4  T  G  A  0.57  0.029  1.38 [1.17–1.8]  0.56  0.0057  1.41 [1.1–1.6]a  frequency (F) in sample.    b  gender and rs1718119 as covariates.    c  odds ratios (OR) for each haplotype.Conclusion  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.

Cognitive Manic Symptoms in Bipolar Disorder Associated with Polymorphisms in the DAOA and COMT Genes