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      The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia

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          Abstract

          Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence ( P=7.0 × 10 −7) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample ( N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression ( N=1196) and schizophrenia ( N=479) and UK non-psychiatric comparison groups ( N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia ( P=0.034) and recurrent major depression ( P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ∼1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data.

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          Most cited references16

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          SCAN. Schedules for Clinical Assessment in Neuropsychiatry.

          After more than 12 years of development, the ninth edition of the Present State Examination (PSE-9) was published, together with associated instruments and computer algorithm, in 1974. The system has now been expanded, in the framework of the World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration Joint Project on Standardization of Diagnosis and Classification, and is being tested with the aim of developing a comprehensive procedure for clinical examination that is also capable of generating many of the categories of the International Classification of Diseases, 10th edition, and the Diagnostic and Statistical Manual of Mental Disorders, revised third edition. The new system is known as SCAN (Schedules for Clinical Assessment in Neuropsychiatry). It includes the 10th edition of the PSE as one of its core schedules, preliminary tests of which have suggested that reliability is similar to that of PSE-9. SCAN is being field tested in 20 centers in 11 countries. A final version is expected to be available in January 1990.
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            A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system.

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              Genomewide Association for Major Depressive Disorder: A possible role for the presynaptic protein Piccolo

              Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network (GAIN) initiative of the US Foundation for the National Institutes of Health, we conducted a genomewide association study of 435,291 SNPs genotyped in 1,738 MDD cases and 1,802 controls selected to be at low liability for MDD. Eleven of the top 200 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and plays an important role in monoaminergic neurotransmission in the brain) with p-values of 7.7×10−7 for rs2715148 and 1.2×10−6 for rs2522833. We undertook replication of SNPs in this region in 5 independent samples (6,079 MDD independent cases and 5,893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded p=6.4×10−8 for the non-synonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding-domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.
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                Author and article information

                Journal
                Mol Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                October 2010
                21 July 2009
                : 15
                : 10
                : 1016-1022
                Affiliations
                [1 ]simpleDepartment of Psychological Medicine and Neurology, School of Medicine, Cardiff University , Cardiff, UK
                [2 ]simpleDepartment of Psychiatry, National Centre for Mental Health, University of Birmingham , Birmingham, UK
                [3 ]simpleBiostatistics and Bioinformatics Unit, School of Medicine, Cardiff University , Cardiff, UK
                [4 ]simpleSGDP, The Institute of Psychiatry, King's College London, Denmark Hill , London, UK
                Author notes
                [* ]simpleDepartment of Psychological Medicine, School of Medicine, Cardiff University , Heath Park, Cardiff, CF14 4XN, UK. E-mail: craddockn@ 123456cardiff.ac.uk
                [5]

                The members of the Wellcome Trust Case Control Consortium (WTCCC) are listed in Supplementary Online Material.

                Article
                mp200949
                10.1038/mp.2009.49
                3011210
                19621016
                03bd7176-869d-42a2-8a38-2ad7c7fdae8e
                Copyright © 2010 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 15 January 2009
                : 31 March 2009
                : 03 April 2009
                Categories
                Original Article

                Molecular medicine
                schizophrenia,unipolar depression,genetics,nosology,classification,bipolar disorder
                Molecular medicine
                schizophrenia, unipolar depression, genetics, nosology, classification, bipolar disorder

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