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      Widespread sex differences in gene expression and splicing in the adult human brain

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          Abstract

          There is strong evidence to show that men and women differ in terms of neurodevelopment, neurochemistry and susceptibility to neurodegenerative and neuropsychiatric disease. The molecular basis of these differences remains unclear. Progress in this field has been hampered by the lack of genome-wide information on sex differences in gene expression and in particular splicing in the human brain. Here we address this issue by using post-mortem adult human brain and spinal cord samples originating from 137 neuropathologically confirmed control individuals to study whole-genome gene expression and splicing in 12 CNS regions. We show that sex differences in gene expression and splicing are widespread in adult human brain, being detectable in all major brain regions and involving 2.5% of all expressed genes. We give examples of genes where sex-biased expression is both disease-relevant and likely to have functional consequences, and provide evidence suggesting that sex biases in expression may reflect sex-biased gene regulatory structures.

          Abstract

          Men and women differ in terms of their neurochemistry, behaviour and susceptibility to disease. Here the authors show that sex differences in gene expression and splicing are widespread in adult human brain, and that sex-biased expression is likely to have functional consequences.

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          Most cited references 24

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          Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

          Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.
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            Genotype imputation.

            Genotype imputation is now an essential tool in the analysis of genome-wide association scans. This technique allows geneticists to accurately evaluate the evidence for association at genetic markers that are not directly genotyped. Genotype imputation is particularly useful for combining results across studies that rely on different genotyping platforms but also increases the power of individual scans. Here, we review the history and theoretical underpinnings of the technique. To illustrate performance of the approach, we summarize results from several gene mapping studies. Finally, we preview the role of genotype imputation in an era when whole genome resequencing is becoming increasingly common.
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              The epidemiology of autism spectrum disorders.

              Autism spectrum disorders (ASDs) are complex, lifelong, neurodevelopmental conditions of largely unknown cause. They are much more common than previously believed, second in frequency only to mental retardation among the serious developmental disorders. Although a heritable component has been demonstrated in ASD etiology, putative risk genes have yet to be identified. Environmental risk factors may also play a role, perhaps via complex gene-environment interactions, but no specific exposures with significant population effects are known. A number of endogenous biomarkers associated with autism risk have been investigated, and these may help identify significant biologic pathways that, in turn, will aid in the discovery of specific genes and exposures. Future epidemiologic research should focus on expanding population-based descriptive data on ASDs, exploring candidate risk factors in large well-designed studies incorporating both genetic and environmental exposure data and addressing possible etiologic heterogeneity in studies that can stratify case groups and consider alternate endophenotypes.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                22 November 2013
                : 4
                Affiliations
                [1 ]Reta Lilla Weston Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology , Queen Square, London WC1N 3BG, UK
                [2 ]Department of Genetics, King Faisal Specialist Hospital and Research Centre , PO Box 3354, Riyadh 11211, Saudi Arabia
                [3 ]Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital , 8th Floor, Tower Wing, London SE1 9RT, UK
                [4 ]MRC Sudden Death Brain Bank Project, Department of Neuropathology, University of Edinburgh , Wilkie Building, Teviot Place, Edinburgh EH8 9AG, UK
                [5 ]These authors contributed equally to this work
                [6 ]Investigators within the North American Brain Expression Consortium are listed in Supplementary Note 1
                Author notes
                Article
                ncomms3771
                10.1038/ncomms3771
                3868224
                24264146
                Copyright © 2013, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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