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      Genetics and genomics of psychiatric disease.

      1 , 2

      Science (New York, N.Y.)

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Large-scale genomic investigations have just begun to illuminate the molecular genetic contributions to major psychiatric illnesses, ranging from small-effect-size common variants to larger-effect-size rare mutations. The findings provide causal anchors from which to understand their neurobiological basis. Although these studies represent enormous success, they highlight major challenges reflected in the heterogeneity and polygenicity of all of these conditions and the difficulty of connecting multiple levels of molecular, cellular, and circuit functions to complex human behavior. Nevertheless, these advances place us on the threshold of a new frontier in the pathophysiological understanding, diagnosis, and treatment of psychiatric disease.

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          Most cited references 109

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          An Integrated Encyclopedia of DNA Elements in the Human Genome

          Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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            Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.

            Little is known about lifetime prevalence or age of onset of DSM-IV disorders. To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication. Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview. Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older. Lifetime DSM-IV anxiety, mood, impulse-control, and substance use disorders. Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups. About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.
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              Biological Insights From 108 Schizophrenia-Associated Genetic Loci

              Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
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                Author and article information

                Journal
                Science
                Science (New York, N.Y.)
                1095-9203
                0036-8075
                Sep 25 2015
                : 349
                : 6255
                Affiliations
                [1 ] Departments of Neurology, Psychiatry, and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. dhg@mednet.ucla jf@well.ox.ac.uk.
                [2 ] Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK. dhg@mednet.ucla jf@well.ox.ac.uk.
                Article
                349/6255/1489 NIHMS746099
                10.1126/science.aaa8954
                4694563
                26404826
                Copyright © 2015, American Association for the Advancement of Science.

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