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      Weighted Burden Analysis of Exome-Sequenced Case-Control Sample Implicates Synaptic Genes in Schizophrenia Aetiology

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          Abstract

          A previous study of exome-sequenced schizophrenia cases and controls reported an excess of singleton, gene-disruptive variants among cases, concentrated in particular gene sets. The dataset included a number of subjects with a substantial Finnish contribution to ancestry. We have reanalysed the same dataset after removal of these subjects and we have also included non-singleton variants of all types using a weighted burden test which assigns higher weights to variants predicted to have a greater effect on protein function. We investigated the same 31 gene sets as previously and also 1454 GO gene sets. The reduced dataset consisted of 4225 cases and 5834 controls. No individual variants or genes were significantly enriched in cases but 13 out of the 31 gene sets were significant after Bonferroni correction and the “FMRP targets” set produced a signed log p value (SLP) of 7.1. The gene within this set with the highest SLP, equal to 3.4, was FYN, which codes for a tyrosine kinase which phosphorylates glutamate metabotropic receptors and ionotropic NMDA receptors, thus modulating their trafficking, subcellular distribution and function. In the most recent GWAS of schizophrenia it was identified as a “prioritized candidate gene”. Two of the subunits of the NMDA receptor which are substrates of FYN are coded for by GRIN1 (SLP = 1.7) and GRIN2B (SLP = 2.1). Of note, for some sets there was a substantial enrichment of non-singleton variants. Of 1454 GO gene sets, three were significant after Bonferroni correction. Identifying specific genes and variants will depend on genotyping them in larger samples and/or demonstrating that they cosegregate with illness within pedigrees.

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          The online version of this article (10.1007/s10519-018-9893-3) contains supplementary material, which is available to authorized users.

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          Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings.

          It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants. To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants. We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population. Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register. In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden. Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status. Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; P < 10-10). This reduction was consistently greater among men than women, suggesting that male fitness was particularly sensitive. Although sisters of patients with schizophrenia and bipolar disorder had increased fecundity (FR range, 1.02-1.03; P < .01), this was too small on its own to counterbalance the reduced fitness of affected patients. Brothers of patients with schizophrenia and autism showed reduced fecundity (FR range, 0.94-0.97; P < .001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; P < 10-10). In the case of depression, this more than compensated for the lower fecundity of affected individuals. Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.
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            NMDA receptor regulation by Src kinase signalling in excitatory synaptic transmission and plasticity.

            Regulation of postsynaptic glutamate receptors is one of the main mechanisms for altering synaptic efficacy in the central nervous system. Recent studies have given insight into the upregulation of the NMDA receptor by Src family tyrosine kinases, which bind to scaffolding proteins in the NMDA receptor complex. Src acts as a common step in signalling cascades that link G-protein-coupled receptors with protein kinase C via the intermediary cell-adhesion kinase beta. This signalling to NMDA receptors is required for long-term potentiation in the CA1 region of the hippocampus.
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              Truncating mutations in RBM12 are associated with psychosis

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                Author and article information

                Contributors
                d.curtis@ucl.ac.uk
                Journal
                Behav Genet
                Behav. Genet
                Behavior Genetics
                Springer US (New York )
                0001-8244
                1573-3297
                21 March 2018
                21 March 2018
                2018
                : 48
                : 3
                : 198-208
                Affiliations
                [1 ]ISNI 0000000121901201, GRID grid.83440.3b, UCL Genetics Institute, , University College London, ; Darwin Building, Gower Street, London, WC1E 6BT UK
                [2 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Centre for Psychiatry, , Barts and the London School of Medicine and Dentistry, ; London, UK
                [3 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Neurodegenerative Disease, UCL Institute of Neurology, , University College London, ; London, UK
                Author information
                http://orcid.org/0000-0002-4089-9183
                Article
                9893
                10.1007/s10519-018-9893-3
                5934462
                29564678
                22673e47-46d8-493a-bc73-df8f11885aa4
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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.

                History
                : 22 November 2017
                : 13 March 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: 516702
                Award Recipient :
                Categories
                Original Research
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Genetics
                schizophrenia,exome,gene,weighted burden test,fyn, fmrp target
                Genetics
                schizophrenia, exome, gene, weighted burden test, fyn, fmrp target

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