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      Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

      research-article
      1 , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 10 , 11 , 12 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 16 , 27 , 35 , 36 , 37 , 38 , 39 ,   40 , 22 , 25 , 41 , 38 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 1 , 51 , 52 , 53 , 18 , 53 , 54 , 55 , 56 , 55 , 57 , 58 , 59 , 35 , 60 , 61 , 62 , 63 , 64 , 22 , 65 , 29 , 30 , 66 , 67 , 6 , 22 , 68 , 3 , 69 , 10 , 12 , 70 , 20 , 60 , 2 , 1 , 71 , 22 , 1 , 67 , 72 , 73 , 1 , 51 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 60 , 82 , 83 , 84 , 85 , 73 , 86 , 87 , 88 , 89 , 90 , 91 , 44 , 45 , 67 , 28 , 29 , 92 , 74 , 13 , 93 , 22 , 93 , 94 , 95 , 96 , 97 , 15 , 98 , 16 , 99 , 100 , 13 , 101 , 102 , 1 , 51 , 29 , 30 , 36 , 103 , 104 , 1 , 51 , 74 , 5 , 91 , 33 , 34 , 1 , 37 , 43 , 85 , 1 , 51 , 75 , 61 , 105 , 106 , 107 , 108 , 109 , 110 , 27 , 43 , 15 , 93 , 18 , 53 , 111 , 112 , 76 , 77 , 113 , 114 , 2 , 115 , 116 , 85 , 34 , 117 , 118 , 1 , 35 , 119 , 120 , 2 , 121 , 6 , 1 , 22 , 1 , 122 , 2 , 123 , 1 , 85 , 86 , 124 , 84 , 125 , 126 , 60 , 83 , 1 , 1 , 51 , 91 , 127 , 76 , 128 , 2 , 2 , 123 , 3 , 1 , , for the 16p11.2 European Consortium, for the ENIGMA-CNV working group
      Molecular Psychiatry
      Nature Publishing Group UK
      Psychiatric disorders, Neuroscience

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          Abstract

          Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes ( β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum ( β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV ( P = 0.0032, 8.9 × 10 −6, 1.7 × 10 9, 3.5 × 10 −12 and 1.0 × 10 −4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

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          Rethinking schizophrenia.

          How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects about one per cent of the world's population. After a century of studying schizophrenia, the cause of the disorder remains unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is little evidence that these treatments have substantially improved outcomes for most people with schizophrenia. These current unsatisfactory outcomes may change as we approach schizophrenia as a neurodevelopmental disorder with psychosis as a late, potentially preventable stage of the illness. This 'rethinking' of schizophrenia as a neurodevelopmental disorder, which is profoundly different from the way we have seen this illness for the past century, yields new hope for prevention and cure over the next two decades.
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            Association between microdeletion and microduplication at 16p11.2 and autism.

            Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society.
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              Recurrent 16p11.2 microdeletions in autism.

              Autism is a childhood neurodevelopmental disorder with a strong genetic component, yet the identification of autism susceptibility loci remains elusive. We investigated 180 autism probands and 372 control subjects by array comparative genomic hybridization (aCGH) using a 19K whole-genome tiling path bacterial artificial chromosome microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in two probands with autism and none in controls. The deletion spans approximately 500-kb and is flanked by approximately 147-kb segmental duplications (SDs) that are >99% identical, a common characteristic of genomic disorders. We assessed the frequency of this new autism genomic disorder by screening an additional 532 probands and 465 controls by quantitative PCR and identified two more patients but no controls with the microdeletion, indicating a combined frequency of 0.6% (4/712 autism versus 0/837 controls; Fisher exact test P = 0.044). We confirmed all 16p11.2 deletions using fluorescence in situ hybridization, microsatellite analyses and aCGH, and mapped the approximate deletion breakpoints to the edges of the flanking SDs using a custom-designed high-density oligonucleotide microarray. Bioinformatic analysis localized 12 of the 25 genes within the microdeletion to nodes in one interaction network. We performed phenotype analyses and found no striking features that distinguish patients with the 16p11.2 microdeletion as a distinct autism subtype. Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.
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                Author and article information

                Contributors
                andreassen@medisin.uio.no
                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group UK (London )
                1359-4184
                1476-5578
                3 October 2018
                3 October 2018
                2020
                : 25
                : 3
                : 584-602
                Affiliations
                [1 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, , Oslo University Hospital, ; Oslo, Norway
                [2 ]deCODE Genetics/Amgen, Reykjavik, Iceland
                [3 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, , Keck School of Medicine of the University of Southern California, ; Marina del Rey, USA
                [4 ]ISNI 0000 0004 0389 4927, GRID grid.497530.c, Janssen Research and Development, ; La Jolla, CA USA
                [5 ]ISNI 0000 0001 0423 4662, GRID grid.8515.9, Service of Medical Genetics, , Centre Hospitalier Universitaire Vaudois and University of Lausanne, ; Rue du Bugnon 46, 1011 Lausanne, Switzerland
                [6 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Biological Psychology, , Vrije Universiteit Amsterdam, ; van Boechorststraat 1, 1081 BT Amsterdam, The Netherlands
                [7 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Psychiatry, , Academic Medical Center, ; Amsterdam, The Netherlands
                [8 ]ISNI 0000 0004 0382 5980, GRID grid.429568.4, National Ageing Research Institute, ; Melbourne, Australia
                [9 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Academic Unit for Psychiatry of Old Age, , University of Melbourne, ; Melbourne, Australia
                [10 ]ISNI 0000 0001 2297 375X, GRID grid.8385.6, Institute of Neuroscience and Medicine (INM-1), , Research Centre Juelich, ; Wilhelm-Johnen-Str., 52425 Juelich, Germany
                [11 ]ISNI 0000 0001 2176 9917, GRID grid.411327.2, C. and O. Vogt Institute for Brain Research, Medical Faculty, , University of Dusseldorf, ; Merowingerplatz 1A, 40225 Dusseldorf, Germany
                [12 ]GRID grid.494742.8, JARA-BRAIN, Juelich-Aachen Research Alliance, ; Wilhelm-Johnen-Str., 52425 Juelich, Germany
                [13 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Umeå Center for Functional Brain Imaging (UFBI), , Umeå University, ; 90187 Umeå, Sweden
                [14 ]ISNI 0000 0004 0436 6763, GRID grid.1025.6, Mathematics and Statistics, , Murdoch University, ; Perth, Australia
                [15 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, The Hospital for Sick Children, , University of Toronto, ; Toronto, M5G 1X8 Canada
                [16 ]South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, One West University Blvd., 78520 Brownsville, TX USA
                [17 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Netherlands Twin Register, , Vrije Universiteit, ; van der Boechorststraat 1, 1081BT Amsterdam, Netherlands
                [18 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Human Genetics, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [19 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Department of Clinical Science, , University of Bergen, ; Bergen, Norway
                [20 ]ISNI 0000 0000 9753 1393, GRID grid.412008.f, Center for Medical Genetics and Molecular Medicine, , Haukeland University Hospital, ; Bergen, Norway
                [21 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Centre for Healthy Brain Ageing and Dementia Collaborative Research Centre, , UNSW, ; Sydney, Australia
                [22 ]ISNI 0000000090126352, GRID grid.7692.a, Department of Psychiatry, Brain Center Rudolf Magnus, , University Medical Center Utrecht, ; Utrecht, The Netherlands
                [23 ]GRID grid.5603.0, Department of Diagnostic Radiology and Neuroradiology, , University Medicine Greifswald, ; Greifswald, Germany
                [24 ]The Mind Research Network, The University of New Mexico, Albuquerque, NM Mexico
                [25 ]ISNI 0000 0004 0488 7120, GRID grid.4912.e, The Royal College of Surgeons in Ireland, ; 123 St Stephen’s Green, Dublin 2, Ireland
                [26 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Radiology, , University of California San Diego, ; La Jolla, USA
                [27 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Center for Multimodal Imaging and Genetics, , University of California San Diego, ; La Jolla, USA
                [28 ]ISNI 0000 0001 2297 375X, GRID grid.8385.6, Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, , Genomic Imaging, Research Centre Juelich, ; Leo-Brandt-Strasse 5, 52425 Jülich, Germany
                [29 ]ISNI 0000 0004 1937 0642, GRID grid.6612.3, Human Genomics Research Group, Department of Biomedicine, , University of Basel, ; Hebelstrasse 20, 4031 Basel, Switzerland
                [30 ]GRID grid.410567.1, Institute of Medical Genetics and Pathology, , University Hospital Basel, ; Schönbeinstrasse 40, 4031 Basel, Switzerland
                [31 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Psychosis Studies, Insitute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; 16 De Crespingy Park, SE5 8AF London, United Kingdom
                [32 ]ISNI 0000 0004 1936 9705, GRID grid.8217.c, Neuropsychiatric Genetics Research Group, Discipline of Psychiatry, School of Medicine, , Trinity College Dublin, ; Dublin 2, Ireland
                [33 ]ISNI 0000 0004 1770 272X, GRID grid.7821.c, Department of Medicine and Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, , University of Cantabria-IDIVAL, ; 39008 Santander, Spain
                [34 ]CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Santander, 39011 Spain
                [35 ]Department of Psychiatry and Mental Health, Anzio Road, 7925 Cape Town, South Africa
                [36 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; De Crespigny Park, SE5 8AF London, United Kingdom
                [37 ]ISNI 0000 0001 2116 3923, GRID grid.451056.3, National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, ; London, United Kingdom
                [38 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Biological Psychology, Behavioral and Movement Sciences, , Vrije Universiteit, ; van der Boechorststraat 1, 1081 BT Amsterdam, Netherlands
                [39 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Amsterdam Neuroscience, , VU University medical center, ; van der Boechorststraat 1, 1081 BT Amsterdam, NH Netherlands
                [40 ]ISNI 0000000089150953, GRID grid.1024.7, Faculty of Health and Institute of Health and Biomedical Innovation, , Queensland University of Technology, ; Brisbane, Queensland Australia
                [41 ]ISNI 0000 0000 9752 8549, GRID grid.413079.8, Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience, , University of California at Davis, ; 4860 Y Street, Suite 3700, Sacramento, California 95817 USA
                [42 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Alzheimer Center and Department of Neurology, , VU University Medical Center, ; De Boelelaan 1105, 1081HV Amsterdam, Netherlands
                [43 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Medical Research Council – Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, , King’s College London, ; London, United Kingdom
                [44 ]ISNI 0000 0004 0488 0789, GRID grid.6142.1, Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition & Genomics Centre (NICOG) & NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, , National University of Ireland Galway, ; H91 TK33 Galway, Ireland
                [45 ]ISNI 0000 0004 1936 9705, GRID grid.8217.c, Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Psychiatry, , Trinity College Dublin, ; Dublin 8, Ireland
                [46 ]ISNI 0000 0001 0423 4662, GRID grid.8515.9, LREN - Département des neurosciences cliniques, , Centre Hospitalier Universitaire Vaudois and University of Lausanne, ; Lausanne, Switzerland
                [47 ]ISNI 0000 0001 0041 5028, GRID grid.419524.f, Max-Planck-Institute for Human Cognitive and Brain Sciences, ; Leipzig, Germany
                [48 ]ISNI 0000 0001 2111 7257, GRID grid.4488.0, Division of Psychological and Social Medicine and Developmental Neurosciences, , Faculty of Medicine, TU Dresden, ; 01307 Dresden, Germany
                [49 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Psychiatry, , Massachusetts General Hospital, Boston, ; Massachusetts, 02114 USA
                [50 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Martinos Center for Biomedical Imaging, , Massachusetts General Hospital, ; Charlestown, Massachusetts 02129 USA
                [51 ]ISNI 0000 0004 1936 8921, GRID grid.5510.1, Department of Psychology, , University of Oslo, ; Oslo, Norway
                [52 ]ISNI 0000 0004 0501 3839, GRID grid.419550.c, Language and Genetics Department, , Max Planck Institute for Psycholinguistics, ; Wundtlaan 1, 6525 XD Nijmegen, Netherlands
                [53 ]ISNI 0000000122931605, GRID grid.5590.9, Donders Institute for Brain, , Cognition and Behaviour, Radboud University, ; Nijmegen, Netherlands
                [54 ]ISNI 0000 0004 0444 9382, GRID grid.10417.33, Department of Psychiatry, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [55 ]ISNI 0000 0004 4910 6535, GRID grid.460789.4, NeuroSpin, CEA, , Université Paris-Saclay, ; F-91191 Gif-sur-Yvette, France
                [56 ]ISNI 0000 0001 2272 1771, GRID grid.467811.d, Division of Cerebral Integration, , National Institute for Physiological Sciences, ; Aichi, Japan
                [57 ]ISNI 0000000419368710, GRID grid.47100.32, Yale University School of Medicine, ; 40 Temple Street, Suite 6E, 6511 New Haven, Vaud USA
                [58 ]ISNI 0000 0001 0626 2712, GRID grid.277313.3, Olin Neuropsychiatric Research Center, Institute of Living, , Hartford Hospital, ; 300 George Street, 6106 Hartford, CT USA
                [59 ]GRID grid.5603.0, Department of Psychiatry und Psychotherapy, , University Medicine Greifswald, ; Greifswald, Germany
                [60 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, K.G. Jebsen Centre for Neuropsychiatric Disorders, , University of Bergen, ; Bergen, Norway
                [61 ]ISNI 0000 0001 1516 2393, GRID grid.5947.f, Department of Neuroscience, Faculty of Medicine, , Norwegian University of Science and Technology, ; Trondheim, Norway
                [62 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, , Osaka University, ; Suita, Osaka Japan
                [63 ]GRID grid.487647.e, Princess Máxima Center for Pediatric Oncology, ; Lundlaan 6, 3584 EA Utrecht, The Netherlands
                [64 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Dept. of Psychiatry and Psychotherapie, , Charite, Humboldt University, ; Chariteplatz 1, 10017 Berlin, Germany
                [65 ]ISNI 000000040459992X, GRID grid.5645.2, Child and adolescent Psychiatry / Psychology, , Erasmus medical center-Sophia’s Childerens hospitaal, ; Rotterdam, Wytemaweg 8, 3000 CB Rotterdam, The Netherlands
                [66 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Institute of Human Genetics, , University of Bonn, ; Sigmund-Freud-Str. 25, 53127 Bonn, Germany
                [67 ]ISNI 0000 0004 0488 0789, GRID grid.6142.1, The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, , National University of Ireland Galway, ; Galway, Ireland
                [68 ]ISNI 0000 0004 1761 798X, GRID grid.256115.4, Department of Psychiatry, , Fujita Health University School of Medicine, ; Toyoake, Japan
                [69 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Center for Human Development, , University of California San Diego, ; San Diego, CA USA
                [70 ]ISNI 0000 0001 0728 696X, GRID grid.1957.a, Department of Psychiatry, Psychotherapy and Psychosomatics, , RWTH Aachen University, Medical Faculty, ; Pauwelsstraße 30, 52074 Aachen, Germany
                [71 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, , Karolinska University Hospital Solna, ; R5:00, SE-17176 Stockholm, Sweden
                [72 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Genome Informatics, Graduate School of Medicine, , Osaka University, ; 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
                [73 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Psychiatry, , Yale University, ; 40 Temple Street, 6515 New Haven, CT USA
                [74 ]ISNI 0000 0004 0612 1014, GRID grid.416731.6, Sunnaas Rehabilitation Hospital HT, ; Nesodden, Norway
                [75 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Brain and Mind Centre, , University of Sydney, ; Sydney, Australia
                [76 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, NORMENT - KG Jebsen Centre, Department of Clinical Science, , University of Bergen, ; Jonas Lies veg 87, 5021 Bergen, Norway
                [77 ]ISNI 0000 0000 9753 1393, GRID grid.412008.f, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, , Haukeland University Hospital, ; Jonas Lies veg 87, 5021 Bergen, Norway
                [78 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Genomic Medicine Institute, Lerner Research Institute, , Cleveland Clinic, ; Cleveland, OH USA
                [79 ]ISNI 0000000121901201, GRID grid.83440.3b, Institute of Neurology, , University College London, ; London, United Kingdom
                [80 ]ISNI 0000 0004 0409 4614, GRID grid.280503.c, The Mind Research Network, ; 1101 Yale Blvd., 87106 Albuquerque, CT USA
                [81 ]ISNI 0000 0001 2188 8502, GRID grid.266832.b, Dept. of Electrical and Computer Engineering, , University of New Mexico, ; 87131 Albuquerque, New Mexico USA
                [82 ]Department of Biological and Medical Psychology, Jonas Lies vei 91, N-5009 Bergen, Norway
                [83 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Department of Biomedicine, , University of Bergen, ; 5009 Bergen, Norway
                [84 ]ISNI 0000 0001 2294 1395, GRID grid.1049.c, QIMR Berghofer Medical Research Institute, ; Brisbane, Queensland Australia
                [85 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Centre for Healthy Brain Ageing, School of Psychiatry, , University of New South Wales, ; Sydney, New South Wales 2052 Australia
                [86 ]ISNI 0000 0004 0488 7120, GRID grid.4912.e, Molecular and Cellular Therapeutics, , Royal College of Surgeons in Ireland, ; 123 St. Stephens Green, D02 YN77 Dublin, Ireland
                [87 ]ISNI 0000000090126352, GRID grid.7692.a, Centre for Molecular Medicine, , University Medical Center Utrecht, ; Heidelberglaan 100, 3584 CX Utrecht, Netherlands
                [88 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Centre for Advanced Imaging, , University of Queensland, ; Brisbane, Queensland Australia
                [89 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Program in Complex Trait Genomics, Institute for Molecular Bioscience, , University of Queensland, ; St Lucia, Queensland Australia
                [90 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, , VU University Medical Center/GGZ inGeest, ; Amsterdam, The Netherlands, Oldenaller 1, 1081 HJ Amsterdam, The Netherlands
                [91 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, CHU Sainte-Justine Research Center, , Université de Montréal, ; Montréal, QC Canada
                [92 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Departments of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, , King’s College London, ; London, United Kingdom
                [93 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Center for Neurobehavioral Genetics, , University of California, Los Angeles, ; California, 90095 USA
                [94 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Rotman Research Institute, , University of Toronto, ; Toronto, M6A 2E1 Canada
                [95 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Psychiatry, , University of Toronto, ; Toronto, M5S 1A1 Canada
                [96 ]GRID grid.428122.f, Center for Developing Brain, , Child Mind Institute, ; New York, NY 10022 USA
                [97 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Psychology, , University of Toronto, ; Toronto, M5S 1A1 Canada
                [98 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, , VU University Medical, ; Amsterdam, Netherlands
                [99 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Departments of Radiology & Clinical Neuroscience, , University of Calgary, ; Calgary, T2N 1N4 Canada
                [100 ]ISNI 0000 0001 2180 1817, GRID grid.11762.33, Bioinformatics Service, Nucleus, , University of Salamanca (USAL), ; 37007 Salamanca, Spain
                [101 ]Department of Integrative Medical Biology, Linnéus väg 9, 901 87 Umeå, Sweden
                [102 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Centre for Population Neuroscience and Stratified Medicine, Social, Genetic and Development Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; 16 De Crespigny Park, SE5 8AF London, UK
                [103 ]ISNI 0000 0001 0705 4923, GRID grid.413629.b, Psychiatry Imaging Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, , Hammersmith Hospital, ; Du Cane Road, W12 0NN London, UK
                [104 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Center for Integrative Genomics, , University of Lausanne, ; Genopode building, CH-1015 Lausanne, Switzerland
                [105 ]ISNI 0000 0004 0627 3560, GRID grid.52522.32, Department of Neurology, , University Hospital of Trondheim, ; Edvard Griegs gate 8, N-7006 Trondheim, Norway
                [106 ]Orygen, The National Centre of Excellence in Youth Mental Health, 35 Poplar Road, 3502 Parkville, New Mexico Australia
                [107 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Centre for Youth Mental Health, , The University of Melbourne, ; 35 Poplar Road, 3502 Parkville, Victoria Australia
                [108 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Psychiatry, , VU University Medical Center, ; 1007 MB Amsterdam, The Netherlands
                [109 ]ISNI 0000 0000 8900 8842, GRID grid.250407.4, Neuroscience Research Australia, ; Randwick, Australia
                [110 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, School of Medical Sciences, , University of New South Wales, ; Sydney, Australia
                [111 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Clinical and Experimental Epilepsy, , UCL Institute of Neurology, ; London, UK
                [112 ]Chalfont Centre for Epilepsy, London, UK
                [113 ]ISNI 0000 0004 0635 1506, GRID grid.413335.3, Dept of Psychiatry, , University of Cape Town, Groote Schuur Hospital, ; Anzio Rd, 7925 Cape Town, South Africa
                [114 ]MRC Unit on Risk & Resilience in Mental Disorders, Stellenbosch, South Africa
                [115 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Queensland Brain Institute, , University of Queensland, ; St Lucia, Queensland Australia
                [116 ]GRID grid.5603.0, Institute for Community Medicine, , University Medicine Greifswald, ; Greifswald, Germany
                [117 ]GRID grid.484299.a, Neuroimaging Unit, , Technological Facilities. Valdecilla Biomedical Research Institute IDIVAL, ; Santander, Cantabria 39011 Spain
                [118 ]ISNI 0000 0004 1936 7400, GRID grid.256304.6, Department of Psychology, , Georgia State University, ; Atlanta, GA USA
                [119 ]ISNI 0000 0001 2214 904X, GRID grid.11956.3a, Department of Psychiatry, , Stellenbosch University, ; TBH Francie van Zijl Avenue, 7500 Cape Town, South Africa
                [120 ]ISNI 0000 0004 1936 7689, GRID grid.59062.38, Department of Psychiatry, ; 1 South Prospect Street, 5401 Burlington, Vermont USA
                [121 ]ISNI 0000 0004 0640 0021, GRID grid.14013.37, Faculty of Electrical and Computer Engineering, , University of Iceland, ; Reykjavik, Iceland
                [122 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, , King’s College London, ; 16 De Crespigny Park, SE5 8AF London, UK
                [123 ]ISNI 0000 0004 0640 0021, GRID grid.14013.37, Faculty of Medicine, , University of Iceland, ; Reykjavik, Iceland
                [124 ]ISNI 0000 0004 0438 0426, GRID grid.424247.3, German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, ; Greifswald, Germany
                [125 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Centre for Advanced Imaging, , University of Queensland, ; St Lucia, Queensland Australia
                [126 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Department of Psychiatry, , Osaka University Graduate School of Medicine, ; Suita, Osaka Japan
                [127 ]ISNI 0000 0001 2292 3357, GRID grid.14848.31, Department of Pediatrics, , University of Montreal, ; Montreal, H3C 3J7 Canada
                [128 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Department of Medical Genetics, , Oslo University Hospital, ; Kirkeveien 166, 424 Oslo, Norway
                Author information
                http://orcid.org/0000-0001-8644-956X
                http://orcid.org/0000-0002-4461-3568
                Article
                118
                10.1038/s41380-018-0118-1
                7042770
                30283035
                c97e4d71-2261-4324-9483-84aeea15d2a2
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 12 February 2018
                : 2 May 2018
                : 25 May 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100005416, Norges Forskningsråd (Research Council of Norway);
                Award ID: 223273
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation);
                Award ID: 32003B_159780
                Award ID: 31003A_160203
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000893, Simons Foundation;
                Award ID: SFARI274424
                Award Recipient :
                Categories
                Article
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                © Springer Nature Limited 2020

                Molecular medicine
                psychiatric disorders,neuroscience
                Molecular medicine
                psychiatric disorders, neuroscience

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