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      Investigating the genetic architecture of general and specific psychopathology in adolescence

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          Abstract

          Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology. We examine how genetic risk for schizophrenia relates to adolescent psychosis-related and internalizing psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of the developmental pathways at this age. PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine the relationships of these PRSs with psychopathology factors modelled within (i) a correlated factors structure and (ii) a bifactor structure. The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression and anxiety, but, when modelling a general psychopathology factor based on these measures, specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology. Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples.

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          Most cited references27

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          Identification of 15 genetic loci associated with risk of major depression in individuals of European descent

          Despite strong evidence supporting the heritability of Major Depressive Disorder, previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-reported data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 reporting no history of depression through 23andMe, and meta-analyzed these results with published MDD GWAS results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with pval<1.0×10−5 in the meta-analysis were further analyzed in a replication dataset (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint-analysis over all three datasets. Some of these loci were also implicated in GWAS of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to traditional means of ascertainment for neuropsychiatric disease genomics.
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            Developing constructs for psychopathology research: research domain criteria.

            There exists a divide between findings from integrative neuroscience and clinical research focused on mechanisms of psychopathology. Specifically, a clear correspondence does not emerge between clusters of complex clinical symptoms and dysregulated neurobiological systems, with many apparent redundancies. For instance, many mental disorders involve multiple disruptions in putative mechanistic factors (e.g., excessive fear, deficient impulse control), and different disrupted mechanisms appear to play major roles in many disorders. The Research Domain Criteria (RDoC) framework is a heuristic to facilitate the incorporation of behavioral neuroscience in the study of psychopathology. Such integration might be achieved by shifting the central research focus of the field away from clinical description to more squarely examine aberrant mechanisms. RDoC first aims to identify reliable and valid psychological and biological mechanisms and their disruptions, with an eventual goal of understanding how anomalies in these mechanisms drive psychiatric symptoms. This approach will require new methods to ascertain samples, relying on hypothesized psychopathological mechanisms to define experimental groups instead of traditional diagnostic categories. RDoC, by design, uncouples research efforts from clinically familiar categories to focus directly on fundamental mechanisms of psychopathology. RDoC proposes a matrix of domains and levels of analyses and invites the field to test and refine the framework. If RDoC is successful, the domains will ultimately relate to familiar psychopathologies in ways that promote new knowledge regarding etiology and more efficient development of new preventive and treatment interventions. PsycINFO Database Record (c) 2010 APA, all rights reserved
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              Validity and reliability of the CAPE: a self-report instrument for the measurement of psychotic experiences in the general population.

              General population longitudinal cohort studies have demonstrated the prognostic validity of self-reported psychotic experiences, but data on reliability and cross-validation with interview-based measures of these experiences are sparse. This study tested the reliability and validity of the Community Assessment of Psychic Experiences (CAPE42). At baseline, the CAPE42 was used to measure the subclinical psychosis phenotype in a general population sample (n = 765). At follow-up (mean interval: 7.7 months), the Structured Interview for Schizotypy, Revised (SIS-R), the Brief Psychiatric Rating Scale (BPRS), and the CAPE42 were administered (n = 510). Baseline self-reported dimensions of psychosis were specifically and independently associated with their equivalent interview-based dimension at follow-up (standardized effect sizes of 0.4-0.5) and with their equivalent self-reported measure (standardized effect sizes of 0.6-0.8). The results indicate that self-reported dimensions of psychotic experiences in general population samples appear to be stable, reliable and valid.
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                Author and article information

                Contributors
                +44(0)117 3310160 , hannah.jones@bristol.ac.uk
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                8 August 2018
                8 August 2018
                2018
                : 8
                : 145
                Affiliations
                [1 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Centre for Academic Mental Health, Population Health Sciences, Bristol Medical School, , University of Bristol, ; Bristol, UK
                [2 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), , University of Bristol, ; Bristol, UK
                [3 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, NIHR Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust, , University of Bristol, ; Bristol, UK
                [4 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Psychiatry, , University of Cambridge, ; Cambridge, UK
                [5 ]ISNI 0000 0004 0488 7120, GRID grid.4912.e, Department of Psychiatry, , Royal College of Surgeons in Ireland, ; Dublin, Ireland
                [6 ]ISNI 0000 0001 0807 5670, GRID grid.5600.3, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, , Cardiff University, ; Cardiff, UK
                [7 ]ISNI 0000000121901201, GRID grid.83440.3b, Division of Psychiatry, , University College London, ; London, UK
                [8 ]GRID grid.420283.f, 23andMe, Inc., ; Mountain View, CA USA
                Author information
                http://orcid.org/0000-0002-5883-9605
                http://orcid.org/0000-0002-0387-880X
                http://orcid.org/0000-0001-5205-8245
                http://orcid.org/0000-0001-7073-2379
                http://orcid.org/0000-0003-4798-0862
                Article
                204
                10.1038/s41398-018-0204-9
                6082910
                30089819
                9803d590-a441-419f-8bbf-a1e153883094
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 14 December 2017
                : 12 June 2018
                : 15 June 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000265, Medical Research Council (MRC);
                Award ID: G0701503, MR/M006727/1 and MR/K004360/1
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2018

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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