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      Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 1 , 1 , 10 , 11 , 8 , 12 , 13 , 14 , 15 , 16 , 17 , 8 , 18 , 19 , 17 , 20 , 15 , 21 , 11 , 22 , 7 , 8 , 23 , 8 , 18 , 24 , 25 , 26 , 6 , 7 , 8 , 11 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 3 , 35 , 36 , 36 , 37 , 38 , 28 , 39 , 40 , 10 , 41 , 42 , 43 , 27 , 44 , 45 , 46 , 47 , 48 , 37 , 38 , 49 , 50 , 51 , 27 , 52 , 53 , 54 , 55 , 6 , 7 , 8 , 56 , 11 , 57 , 58 , 8 , 18 , 59 , 60 , 61 , 37 , 38 , 50 , 62 , 37 , 38 , 50 , 63 , 64 , 10 , 8 , 18 , 65 , 66 , 67 , 19 , 19 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 5 , 75 , 76 , 77 , 78 , 3 , 35 , 79 , 75 , 34 , 53 , 28 , 69 , 69 , 80 , 81 , 54 , 2 , 82 , 83 , 10 , 84 , 27 , 28 , 2 , 85 , 10 , 86 , 87 , 88 , 19 , 19 , 88 , 58 , 54 , 1 , 89 , 90 , 27 , 91 , 92 , 90 , 10 , 93 , 27 , 94 , 95 , 28 , 8 , 12 , 13 , 8 , 12 , 13 , 17 , 96 , 22 , 19 , 26 , 97 , 98 , 99 , 100 , 6 , 7 , 8 , 101 , 17 , 27 , 102 , 40 , 3 , 35 , 79 , 103 , 104 , 105 , 70 , 106 , 107 , 108 , 109 , 19 , 110 , 111 , 111 , 112 , 51 , 51 , 113 , 114 , 115 , 8 , 60 , 116 , 117 , 118 , 111 , 44 , 119 , 51 , 5 , 120 , 121 , 122 , 123 , 22 , 1 , 2 , 8 , 60 , 116 , 124 , 8 , 60 , 114 , 10 , 51 , 1 , 125 , 2 , 126 , 1 , eQTLGen Consortium 127 , 23andMe Research Team 44 , 128 , 14 , 114 , 10 , 37 , 50 , 129 , 130 , 128 , 10 , 131 , 54 , 132 , 133 , 3 , 88 , 122 , 134 , 135 , 101 , 44 , 17 , 67 , 136 , 137 , 138 , 139 , 67 , 101 , 22 , 55 , 11 , 36 , 88 , 140 , 8 , 141 , 7 , 8 , 12 , 13 , 15 , 16 , 142 , 8 , 143 , 37 , 38 , 95 , 144 , 22 , 19 , 42 , 145 , 118 , 146 , 26 , 51 , 70 , 51 , 105 , 147 , 148 , 149 , 41 , 42 , 43 , 111 , 150 , 40 , 151 , 152 , 153 , 115 , 84 , 154 , 8 , 60 , 155 , 156 , 157 , 27 , 158 , 159 , 27 , 160 , 6 , 7 , 8 , 22 , 53 , 161
      Nature genetics
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          Abstract

          Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association (GWA) meta-analysis based in 135,458 cases and 344,901 control, We identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression, and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relations of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine and define the basis of major depression and imply a continuous measure of risk underlies the clinical phenotype.

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          Most cited references51

          • Record: found
          • Abstract: found
          • Article: not found

          'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?

          Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
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            • Record: found
            • Abstract: found
            • Article: not found

            Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

            Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found

              GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

              A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                17 February 2018
                26 April 2018
                May 2018
                26 October 2018
                : 50
                : 5
                : 668-681
                Affiliations
                [1 ]Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, AU
                [2 ]Queensland Brain Institute, The University of Queensland, Brisbane, QLD, AU
                [3 ]Medical and Population Genetics, Broad Institute, Cambridge, MA, US
                [4 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, US
                [5 ]Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, DE
                [6 ]Department of Biomedicine, Aarhus University, Aarhus, DK
                [7 ]iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, DK
                [8 ]iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research,, DK
                [9 ]Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SE
                [10 ]Dept of Biological Psychology & EMGO+ Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, NL
                [11 ]Division of Psychiatry, University of Edinburgh, Edinburgh, GB
                [12 ]Centre for Integrated Register-based Research, Aarhus University, Aarhus, DK
                [13 ]National Centre for Register-Based Research, Aarhus University, Aarhus, DK
                [14 ]Discipline of Psychiatry, University of Adelaide, Adelaide, SA, AU
                [15 ]Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, DE
                [16 ]Munich Cluster for Systems Neurology (SyNergy), Munich, DE
                [17 ]Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, US
                [18 ]Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK
                [19 ]Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, NL
                [20 ]Virginia Institute for Psychiatric and Behavior Genetics, Richmond, VA, US
                [21 ]Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, US
                [22 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE
                [23 ]Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, DK
                [24 ]Statistical genomics and systems genetics, European Bioinformatics Institute (EMBL-EBI), Cambridge, GB
                [25 ]Human Genetics, Wellcome Trust Sanger Institute, Cambridge, GB
                [26 ]Department of Psychiatry, University Hospital of Lausanne, Prilly, Vaud, CH
                [27 ]MRC Social Genetic and Developmental Psychiatry Centre, King’s College London, London, GB
                [28 ]Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, QLD, AU
                [29 ]Centre for Advanced Imaging, The University of Queensland, Saint Lucia, QLD, AU
                [30 ]Queensland Brain Institute, The University of Queensland, Saint Lucia, QLD, AU
                [31 ]Psychological Medicine, Cardiff University, Cardiff, GB
                [32 ]Center for Genomic and Computational Biology, Duke University, Durham, NC, US
                [33 ]Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, US
                [34 ]Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, US
                [35 ]Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
                [36 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, GB
                [37 ]Institute of Human Genetics, University of Bonn, Bonn, DE
                [38 ]Life&Brain Center, Department of Genomics, University of Bonn, Bonn, DE
                [39 ]Psychiatry, Dokuz Eylul University School of Medicine, Izmir, TR
                [40 ]Epidemiology, Erasmus MC, Rotterdam, Zuid-Holland, NL
                [41 ]Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, US
                [42 ]Department of Psychiatry, Massachusetts General Hospital, Boston, MA, US
                [43 ]Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, US
                [44 ]Research, 23andMe, Inc., Mountain View, CA, US
                [45 ]Neuroscience and Mental Health, Cardiff University, Cardiff, GB
                [46 ]Bioinformatics, University of British Columbia, Vancouver, BC, CA
                [47 ]Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, US
                [48 ]Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, US
                [49 ]Department of Psychiatry (UPK), University of Basel, Basel, CH
                [50 ]Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, CH
                [51 ]Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, DE
                [52 ]Department of Psychiatry, Trinity College Dublin, Dublin, IE
                [53 ]Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, US
                [54 ]Psychiatry & Behavioral Sciences, Johns Hopkins University, Baltimore, MD, US
                [55 ]Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, AU
                [56 ]Bioinformatics Research Centre, Aarhus University, Aarhus, DK
                [57 ]Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, GB
                [58 ]University of Exeter Medical School, Exeter, UK
                [59 ]Danish Headache Centre, Department of Neurology, Rigshospitalet, Glostrup, DK
                [60 ]Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Copenhagen, DK
                [61 ]iPSYCH, The Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, DK
                [62 ]Brain and Mind Centre, University of Sydney, Sydney, NSW, AU
                [63 ]Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Mecklenburg-Vorpommern, DE
                [64 ]Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, CH
                [65 ]Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, US
                [66 ]Statistics, Pfizer Global Research and Development, Groton, CT, US
                [67 ]Max Planck Institute of Psychiatry, Munich, DE
                [68 ]Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, US
                [69 ]Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, US
                [70 ]Division of Research, Kaiser Permanente Northern California, Oakland, CA, US
                [71 ]Psychiatry & The Behavioral Sciences, University of Southern California, Los Angeles, CA, US
                [72 ]Informatics Program, Boston Children’s Hospital, Boston, MA, US
                [73 ]Department of Medicine, Brigham and Women’s Hospital, Boston, MA, US
                [74 ]Department of Biomedical Informatics, Harvard Medical School, Boston, MA, US
                [75 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, GB
                [76 ]Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, DK
                [77 ]Swiss Institute of Bioinformatics, Lausanne, VD, CH
                [78 ]Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne, Lausanne, VD, CH
                [79 ]Dept of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
                [80 ]Mental Health, NHS 24, Glasgow, GB
                [81 ]Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, GB
                [82 ]Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, DE
                [83 ]Statistics, University of Oxford, Oxford, GB
                [84 ]Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, US
                [85 ]School of Psychology and Counseling, Queensland University of Technology, Brisbane, QLD, AU
                [86 ]Child and Youth Mental Health Service, Children’s Health Queensland Hospital and Health Service, South Brisbane, QLD, AU
                [87 ]Child Health Research Centre, University of Queensland, Brisbane, QLD, AU
                [88 ]Estonian Genome Center, University of Tartu, Tartu, EE
                [89 ]Medical Genetics, University of British Columbia, Vancouver, BC, CA
                [90 ]Statistics, University of British Columbia, Vancouver, BC, CA
                [91 ]DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, DE
                [92 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, DE
                [93 ]Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, AU
                [94 ]Humus, Reykjavik, IS
                [95 ]MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, GB
                [96 ]Virginia Institute for Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, US
                [97 ]Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, NL
                [98 ]Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, NL
                [99 ]Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, US
                [100 ]Solid Biosciences, Boston, MA, US
                [101 ]Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, MO, US
                [102 ]Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, ES
                [103 ]Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, NL
                [104 ]Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, Campus Innenstadt, Munich, DE
                [105 ]Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Campus Innenstadt, Munich, DE
                [106 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, US
                [107 ]Behavioral Health Services, Kaiser Permanente Washington, Seattle, WA, US
                [108 ]Faculty of Medicine, Department of Psychiatry, University of Iceland, Reykjavik, IS
                [109 ]School of Medicine and Dentistry, James Cook University, Townsville, QLD, AU
                [110 ]Institute of Health and Wellbeing, University of Glasgow, Glasgow, GB
                [111 ]deCODE Genetics / Amgen, Reykjavik, IS
                [112 ]Psychiatry & Human Behavior, University of Mississippi Medical Center, Jackson, MS, US
                [113 ]College of Biomedical and Life Sciences, Cardiff University, Cardiff, GB
                [114 ]Institute of Epidemiology and Social Medicine, University of Münster, Münster, Nordrhein-Westfalen, DE
                [115 ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, DE
                [116 ]KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NO
                [117 ]Department of Psychiatry, University of California, San Diego, San Diego, CA, US
                [118 ]Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, GB
                [119 ]Clinical Neurosciences, University of Cambridge, Cambridge, GB
                [120 ]Internal Medicine, Erasmus MC, Rotterdam, Zuid-Holland, NL
                [121 ]Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, CH
                [122 ]Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, DE
                [123 ]Department of Psychiatry, Leiden University Medical Center, Leiden, NL
                [124 ]Virginia Institute of Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, US
                [125 ]Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, US
                [126 ]Institute for Molecular Bioscience; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, AU
                [127 ]Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, NL
                [128 ]Department of Psychiatry, University of Münster, Münster, Nordrhein-Westfalen, DE
                [129 ]Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, DE
                [130 ]Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, CH
                [131 ]Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Amsterdam, NL
                [132 ]Centre for Integrative Biology, Università degli Studi di Trento, Trento, Trentino-Alto Adige, IT
                [133 ]Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Rheinland-Pfalz, DE
                [134 ]Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, US
                [135 ]Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, GB
                [136 ]Centre for Addiction and Mental Health, Toronto, ON, CA
                [137 ]Department of Psychiatry, University of Toronto, Toronto, ON, CA
                [138 ]Division of Psychiatry, University College London, London, GB
                [139 ]Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, US
                [140 ]Institute of Molecular and Cell Biology, University of Tartu, Tartu, EE
                [141 ]Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, DK
                [142 ]University of Liverpool, Liverpool, GB
                [143 ]Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, DK
                [144 ]Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, US
                [145 ]Psychiatry, Harvard Medical School, Boston, MA, US
                [146 ]Psychiatry, University of Iowa, Iowa City, IA, US
                [147 ]Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, US
                [148 ]Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, US
                [149 ]Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Niedersachsen, DE
                [150 ]Faculty of Medicine, University of Iceland, Reykjavik, IS
                [151 ]Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Zuid-Holland, NL
                [152 ]Psychiatry, Erasmus MC, Rotterdam, Zuid-Holland, NL
                [153 ]Psychiatry, Dalhousie University, Halifax, NS, CA
                [154 ]Division of Epidemiology, New York State Psychiatric Institute, New York, NY, US
                [155 ]Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK
                [156 ]Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, MA, US
                [157 ]Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, US
                [158 ]Department of Medical & Molecular Genetics, King’s College London, London, GB
                [159 ]Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, US
                [160 ]NIHR BRC for Mental Health, King’s College London, London, GB
                [161 ]Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, US
                Author notes
                Correspond with: PF Sullivan ( pfsulliv@ 123456med.unc.edu ), Department of Genetics, CB#7264, University of North Carolina, Chapel Hill, NC, 27599-7264, USA. Voice, +919-966-3358. NR Wray ( naomi.wray@ 123456uq.edu.au ), Institute for Molecular Bioscience, Queensland Brain Institute, Brisbane, Australia. Voice, +61 7 334 66374
                [†]

                Equal contributions.

                [*]

                Co-last authors.

                Article
                NIHMS943355
                10.1038/s41588-018-0090-3
                5934326
                29700475
                f5343316-aa8b-4a76-9063-f118126f85d1

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