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      Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

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          Abstract

          By analyzing the exomes of 12,332 unrelated Swedish individuals – including 4,877 affected with schizophrenia – in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant in schizophrenia cases than controls ( P = 1.3 × 10 −10). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this genetic signal arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.

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          Most cited references 24

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          Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites

          mirSVR is a new machine learning method for ranking microRNA target sites by a down-regulation score. The algorithm trains a regression model on sequence and contextual features extracted from miRanda-predicted target sites. In a large-scale evaluation, miRanda-mirSVR is competitive with other target prediction methods in identifying target genes and predicting the extent of their downregulation at the mRNA or protein levels. Importantly, the method identifies a significant number of experimentally determined non-canonical and non-conserved sites.
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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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              Structural variation of chromosomes in autism spectrum disorder.

              Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                9 September 2016
                03 October 2016
                November 2016
                03 April 2017
                : 19
                : 11
                : 1433-1441
                Affiliations
                [1 ]Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [2 ]Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
                [3 ]Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
                [4 ]Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
                [5 ]Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
                [6 ]Department of Psychiatry and Neurochemistry, Institute of Neuroscience a Physiology at Sahlgrenska Academy at University of Gothenburg, 413 45 Göteborg, Sweden
                [7 ]Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA
                [8 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden
                Author notes
                Correspondence should be addressed to S.A.M. ( mccarroll@ 123456genetics.med.harvard.edu )
                Article
                NIHMS815183
                10.1038/nn.4402
                5104192
                27694994

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