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      Genomewide Association Scan of Suicidal Thoughts and Behaviour in Major Depression

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          Abstract

          Background

          Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT.

          Methodology/Principal Findings

          A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality.

          Conclusions/Significance

          This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further.

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          SCAN. Schedules for Clinical Assessment in Neuropsychiatry.

          J. Wing, T F Babor, T. Brugha … (1990)
          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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            Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.

            Yogesh Dwivedi, Hooriyah S. Rizavi, Robert Conley … (2003)
            Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions. These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase-polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas. Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain. Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.
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              Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.

              Elisabeth B Binder, Daria Salyakina, Peter Lichtner … (2004)
              The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2011
                Publication date (Electronic): 5 July 2011
                Volume: 6
                Issue: 7
                Electronic Location Identifier: e20690
                Affiliations
                [1 ]MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom
                [2 ]Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria
                [3 ]Department of Psychiatry, University of Hong Kong, Hong Kong, Special Administrative Region, China
                [4 ]Max Planck Institute of Psychiatry, Munich, Germany
                [5 ]Department of Psychiatry, University of Geneva, Geneva, Switzerland
                [6 ]MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
                [7 ]Barts and The London Medical School, Queen Mary University of London, London, United Kingdom
                [8 ]Department of Psychiatry, Neuropharmacology and Neurobiology Section, University of Birmingham, Birmingham, United Kingdom
                [9 ]Department of Psychiatry, Trinity Centre for Health Science, Dublin, Ireland
                [10 ]Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
                [11 ]Department of Psychiatry, University of Bonn, Bonn, Germany
                [12 ]Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark
                [13 ]Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
                [14 ]University Hospital Center and University of Lausanne, Lausanne, Switzerland
                [15 ]GlaxoSmithKline Research & Development, Stockley Park, United Kingdom
                [16 ]GlaxoSmithKline Research & Development, Verona, Italy
                [17 ]Department of Psychiatry, University of Toronto, Toronto, Canada
                [18 ]NeuroSearch A/S, Ballerup, Denmark
                [19 ]NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King's College London, London, United Kingdom
                University of Muenster, Germany
                Author notes

                Conceived and designed the experiments: P. McGuffin CML AEF IWC GB. Performed the experiments: SC-W. Analyzed the data: CML AWB MYN NP RU AS BM-M MI. Contributed reagents/materials/analysis tools: NC MJO AK LJ IJ MG JPR WM OM MR MP JP FT P. Muglia KJA EBB SL. Wrote the paper: AS CML NP RU IWC P. McGuffin AEF GB.

                Article
                Publisher ID: PONE-D-11-02073
                DOI: 10.1371/journal.pone.0020690
                PMC ID: 3130038
                PubMed ID: 21750702
                SO-VID: b50bda72-adb2-41af-a3ac-bbe94586cfb7
                Copyright © Schosser 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.
                History
                Date received : 27 January 2011
                Date accepted : 7 May 2011
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Genome-Wide Association Studies
                Subject: Medicine
                Subject: Mental Health
                Subject: Psychiatry
                Subject: Mood Disorders

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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