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      Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders

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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.

          Highlights

          • Voltage-gated calcium channel classification—genes and proteins.

          • Genetic analysis of neuropsychiatric syndromes.

          • Calcium channel genes identified from GWA studies of psychiatric disorders.

          • Rare mutations in calcium channel genes in psychiatric disorders.

          • Pathophysiological sequelae of CACNA1C mutations and polymorphisms.

          • Monogenic disorders resulting from harmful mutations in other voltage-gated calcium channel genes.

          • Changes in calcium channel gene expression in disease.

          • Involvement of voltage-gated calcium channels in early brain development.

          Abstract

          This review summarises genetic studies in which calcium channel genes have been connected to the spectrum of neuropsychiatric syndromes, from bipolar disorder and schizophrenia to autism spectrum disorders and intellectual impairment. Among many other genes, striking numbers of the calcium channel gene superfamily have been implicated in the aetiology of these diseases by various DNA analysis techniques. We will discuss how these relate to the known monogenic disorders associated with point mutations in calcium channels. We will then examine the functional evidence for a causative link between these mutations or single nucleotide polymorphisms and the disease processes. A major challenge for the future will be to translate the expanding psychiatric genetic findings into altered physiological function, involvement in the wider pathology of the diseases, and what potential that provides for personalised and stratified treatment options for patients.

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          Most cited references270

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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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            De novo gene disruptions in children on the autistic spectrum.

            Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. Copyright © 2012 Elsevier Inc. All rights reserved.
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              The contribution of de novo coding mutations to autism spectrum disorder.

              Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
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                Author and article information

                Contributors
                Journal
                Prog Neurobiol
                Prog. Neurobiol
                Progress in Neurobiology
                Pergamon Press
                0301-0082
                1873-5118
                1 November 2015
                November 2015
                : 134
                : 36-54
                Affiliations
                [a ]Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK
                [b ]Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
                Author notes
                [* ]Corresponding author. a.dolphin@ 123456ucl.ac.uk
                [1]

                Equal contribution.

                Article
                S0301-0082(15)30045-9
                10.1016/j.pneurobio.2015.09.002
                4658333
                26386135
                e4da00fe-43f2-47bf-bdea-3f5902b28bcd
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 July 2015
                : 8 September 2015
                : 8 September 2015
                Categories
                Article

                Neurosciences
                calcium channel,neuropsychiatric disorder,polygenic disorder,mutation,single nucleotide polymorphism,disc1, disrupted in schizophrenia 1,fmri, functional magnetic resonance imaging,fmrp, fragile x mental retardation protein,gwas, genome wide association study,snp, single nucleotide polymorphism

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