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

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. 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. 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. Citation: Hukic DS, Frisén L, Backlund L, Lavebratt C, Landén M, et al. (2013) Cognitive Manic Symptoms in Bipolar Disorder Associated with Polymorphisms in the DAOA and COMT Genes. PLoS ONE 8(7): e67450. doi:10.1371/journal.pone.0067450 Editor: Chunyu Liu, University of Illinois at Chicago, United States of America Received February 13, 2013; Accepted May 17, 2013; Published July 5, 2013 Copyright: 2013 Hukic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This project was supported by grants from Karolinska Institutet, the Swedish Research Council, the Söderström-Königska Foundation, and Psychiatry Southwest, Stockholm. Financial support was also provided through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have read the journal’s policy and have the following conflicts: LB has received consultancy fees from Bristol-Myers Squibb and has been reimbursed by Eli Lilly and Bristol-Myers Squibb for attending conferences and presenting lectures. UÖ has received grant/research support from Bristol-Myers Squibb and Janssen-Cilag and has been a consultant for or received fees for speaking and attending conferences from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Pfizer. GE has been a consultant for AstraZeneca and Janssen-Cilag and his wife is a shareholder of AstraZeneca. ML has been reimbursed by Eli Lilly, AstraZeneca and Wyeth for lectures, serves on advisory boards for AstraZeneca and Lundbeck, and has received research grants from AstraZeneca. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: [email protected]