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

abstract: ...Introduction 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 b Gene 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] e DAOA rs3916967 (C/T) 32/88/89 50/118/77 177/494/361 0.018 0.018 0.21 0.72 [0.550.93] 0.029 0.026 0.28 0.78 [0.661.0] DAOA rs2391191 (A/C) 28/75/79 39/111/70 179/487/357 0.055 0.039 0.50 0.75 [0.571.0] 0.020 0.019 0.21 0.75 [0.631.0] DAOA rs1935062 (C/A) 26/67/89 35/102/86 146/460/405 0.12 0.12 0.78 0.80 [0.581.0] 0.069 0.066 0.52 0.80 [0.651.0] COMT rs5993883 (T/G) 33/120/53 71/112/57 269/510/223 0.025 0.030 0.27 0.73 [0.560.95] 0.0017 * 1.0E 4 * 0.021 * 0.68 [0.911.4] COMT rs165599 (G/A) 29/94/87 25/93/126 87/443/501 0.093 0.094 0.69 1.27 [1.01.8] 0.014 0.017 0.16 1.34 [1.11.7] 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

... Biosystems, Foster City, CA, USA), in accordance with the manufacturers instructions. Allelic discrimination was performed with the ABI PRISM 7900HT SDS and the SDS 2.2.1 program (Applied Biosystems). In the DAOA gene, fifteen SNPs (rs3916967, rs2391191, rs1935062, rs947267, rs778294, rs778326, rs3916971, rs1642681, rs778293, rs1362886, rs778284, rs3918342, rs1421292, rs778308, rs778321) were studied ( Figure 1a ), and in the COMT gene, four SNPs (rs5993883, rs740601, rs4680, rs165599) were studied. All

... covariates. A 3 SNP window existed only for DAOA . p0.05 was regarded significant in the analyses of haplotype distribution. SNPs with nominal allele frequency associated with cognitive manic symptoms (p<0.05) were further tested for genotype association using logistic regression in dominant, recessive and codominant models. An allele by allele epistasis test was performed between the SNPs rs2391191 in DAOA and rs5993883 in COMT using logistic regression with a multiplicative interaction term, Genotype by genotype epistasis was performed using logistic binary regression with the interaction term rs2391191*rs5993883, where the SNP genotypes were binary categorized according to dominance of the alleles A and T, repectively, using IBM SPSS Statistics version 20.0 (IBM Coporation, USA). All other calculations were performed using PLINK in BC|SNPmax data management and analysis ( http://pngu.mgh.harvard.edu/purcell/plink/ ) [24] . The statistical power to exclude association between CMS and allele

... supported by genotypic association tests in the case-case model, rs3916967 (p dominant =0.016, p trend =0.018), rs 2391191 (p dominant =0.020, p trend =0.055), and rs1935062 (p dominant =0.042, p trend =0.11). In the case-controls model, association was found to rs3916967 (p dominant =0.037, p trend =0.076), rs 2391191 (p dominant =0.028, p trend =0.061), and rs1935062 (p dominant =0.026, p trend =0.11). COMT In the case-case analysis of COMT , SNP rs5993883 minor allele T (OR=0.73, p=0.023) ( Table 2 ) was less common among the cognitive manic symptoms patients and thus allele G (OR=1.37, p=0.025) was positively associated with cognitive manic symptoms. In the case-control analysis, both SNPs rs5993883 minor allele G (OR=1.45, p=0.0017) (OBS: different minor/major alleles from case-case analysis; major allele T: OR=0.68) and rs165599 minor allele A (OR=1.34, p=0.014) were nominally associated with cognitive manic symptoms ( Table 3 ). The COMT haplotype analysis was not analyzed since LD between

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