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      Genetic Association of the PERIOD3 (Per3) Clock Gene with Bipolar Disorder

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          Abstract

          Objective

          Circadian rhythms have been linked to psychiatric disorders such as Depression and Bipolar Disorder (BD). Given previous evidences of sleep/circadian disturbances as well as the genetic susceptibility for BD, we decided to investigate the possible link between the PERIOD3 (Per3) circadian gene and BD.

          Methods

          This is a genetic association case (BD) vs. control study of the Per3 gene. We further subdivided our BD sample into “good sleepers” (PSQI ≤5) and “poor sleepers” (PSQI>5) according to the Pittsburgh Sleep Quality Index (PSQI) global score, and then we assessed genetic association of the Per3 gene with sleep quality in the BD group.

          Results

          There were 209 cases and 213 controls in our sample. The GT genotype of the SNP rs707467 significantly associated with BD (χ 2=8.80; p-value=0.01; adjusted residual=±2.6). We also found significant association of the SNP rs10462020 allele T with BD (χ 2=5.81; p-value=0.01) as well as the genotype TT (χ 2= 6.01; p-value=0.04; adjusted residual=±2.4).

          Conclusion

          In this study we demonstrated evidences of genetic association between the Per3 gene and BD. The results of association between the Per3 gene and BD in our sample may bring additional evidence to the former findings of association between the Per3 gene and BD.

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          Most cited references52

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          A rating scale for mania: reliability, validity and sensitivity.

          An eleven item clinician-administered Mania Rating Scale (MRS) is introduced, and its reliability, validity and sensitivity are examined. There was a high correlation between the scores of two independent clinicians on both the total score (0.93) and the individual item scores (0.66 to 0.92). The MRS score correlated highly with an independent global rating, and with scores of two other mania rating scales administered concurrently. The score also correlated with the number of days of subsequent stay in hospital. It was able to differentiate statistically patients before and after two weeks of treatment and to distinguish levels of severity based on the global rating.
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            Molecular components of the mammalian circadian clock.

            Circadian rhythms are approximately 24-h oscillations in behavior and physiology, which are internally generated and function to anticipate the environmental changes associated with the solar day. A conserved transcriptional-translational autoregulatory loop generates molecular oscillations of 'clock genes' at the cellular level. In mammals, the circadian system is organized in a hierarchical manner, in which a master pacemaker in the suprachiasmatic nucleus (SCN) regulates downstream oscillators in peripheral tissues. Recent findings have revealed that the clock is cell-autonomous and self-sustained not only in a central pacemaker, the SCN, but also in peripheral tissues and in dissociated cultured cells. It is becoming evident that specific contribution of each clock component and interactions among the components vary in a tissue-specific manner. Here, we review the general mechanisms of the circadian clockwork, describe recent findings that elucidate tissue-specific expression patterns of the clock genes and address the importance of circadian regulation in peripheral tissues for an organism's overall well-being.
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              System-level identification of transcriptional circuits underlying mammalian circadian clocks.

              Mammalian circadian clocks consist of complexly integrated regulatory loops, making it difficult to elucidate them without both the accurate measurement of system dynamics and the comprehensive identification of network circuits. Toward a system-level understanding of this transcriptional circuitry, we identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of their transcriptional dynamics. Here we report the roles of E/E' boxes, DBP/E4BP4 binding elements and RevErbA/ROR binding elements in nine, seven and six genes, respectively. Our results indicate that circadian transcriptional circuits are governed by two design principles: regulation of E/E' boxes and RevErbA/ROR binding elements follows a repressor-precedes-activator pattern, resulting in delayed transcriptional activity, whereas regulation of DBP/E4BP4 binding elements follows a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Our analysis further suggests that regulation of E/E' boxes is a topological vulnerability in mammalian circadian clocks, a concept that has been functionally verified using in vitro phenotype assay systems.
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                Author and article information

                Journal
                Psychiatry Investig
                Psychiatry Investig
                PI
                Psychiatry Investigation
                Korean Neuropsychiatric Association
                1738-3684
                1976-3026
                September 2017
                11 September 2017
                : 14
                : 5
                : 674-680
                Affiliations
                [1 ]Institute of Biological Sciences, Post-Graduation Program in Neurosciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
                [2 ]Post-Graduation Program in Molecular Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
                [3 ]Mental Health Department, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
                [4 ]Medicine School, UNI-BH (University Center of Belo Horizonte)-Belo Horizonte, Minas Gerais, Brazil.
                Author notes
                Correspondence: Paulo Marcos Brasil Rocha, MD, PhD. Mental Health Department, Faculty of Medicine, Federal University of Minas Gerais-Avenida Professor Alfredo Balena, 190, Belo Horizonte 30130-100, Minas Gerais, Brazil. Tel: +55 0xx 31 34099785, paulombrasil@ 123456gmail.com
                Article
                10.4306/pi.2017.14.5.674
                5639137
                bb2adec3-5a01-44c0-ac0d-ed14ec716711
                Copyright © 2017 Korean Neuropsychiatric Association

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 June 2016
                : 23 September 2016
                : 26 October 2016
                Funding
                Funded by: Instituto Nacional de Ciência e Tecnologia de Medicina Molecular;
                Award ID: 473674/2009-2
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                bipolar disorder,period3,gene,circadian,biological rhythms
                Clinical Psychology & Psychiatry
                bipolar disorder, period3, gene, circadian, biological rhythms

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