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      Comparative genetic architectures of schizophrenia in East Asian and European populations

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 4 , 5 , 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 4 , 6 , 9 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 20 , 21 , 29 , 30 , 23 , 31 , 32 , 20 , 21 , 33 , 34 , 35 , Schizophrenia Working Group of the Psychiatric Genomics Consortium, Indonesia Schizophrenia Consortium, Genetic REsearch on schizophreniA neTwork-China and Netherland (GREAT-CN), 27 , 28 , 37 , 38 , 39 , 9 , 40 , 41 , 6 , 42 , 27 , 28 , 37 , 6 , 43 , 4 , 5 , 6 , 44 , 45 , 20 , 21 , 20 , 21 , 29 , 30 , 46 , 47 , 11 , 48 , 49 , 50 , 51 , 4 , 6 , 52 , 47 , 4 , 5 , 6 , 53 , 9 , 54 , 55 , 13 , 56 , 57 , 19 , 20 , 58 , * , 59 , * , 2 , 60 , * , 34 , 35 , 61 , * , 62 , 63 , * , 8 , 9 , 64 , * , 4 , 5 , 6 , *
      Nature genetics
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          Abstract

          Schizophrenia is a debilitating psychiatric disorder with approximately 1% lifetime risk globally. Large-scale schizophrenia genetic studies have reported primarily on European ancestry samples, potentially missing important biological insights. Here, we report the largest study to date of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant associations in 19 genetic loci. Common genetic variants that confer risk for schizophrenia have highly similar effects between East Asian and European ancestries ( r g = 0.98 ± 0.03), indicating that the genetic basis of schizophrenia and its biology are broadly shared across populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries identified 208 significant associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping reduced the sets of candidate causal variants in 44 loci. Polygenic risk scores had reduced performance when transferred across ancestries, highlighting the importance of including sufficient samples of major ancestral groups to ensure their generalizability across populations.

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          Most cited references38

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          Clinical use of current polygenic risk scores may exacerbate health disparities

          Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation of PRS is that those available today are several times more accurate in individuals of European ancestry than other ancestries. This disparity is an inescapable consequence of Eurocentric biases in genome-wide association studies, thus highlighting that-unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations-clinical uses of PRS today would systematically afford greater improvement for European-descent populations. Early diversifying efforts show promise in leveling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, greater diversity must be prioritized in genetic studies, and summary statistics must be publically disseminated to ensure that health disparities are not increased for those individuals already most underserved.
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            Fine-mapping inflammatory bowel disease loci to single variant resolution

            Summary The inflammatory bowel diseases (IBD) are chronic gastrointestinal inflammatory disorders that affect millions worldwide. Genome-wide association studies have identified 200 IBD-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 IBD loci using high-density genotyping in 67,852 individuals. We pinpointed 18 associations to a single causal variant with >95% certainty, and an additional 27 associations to a single variant with >50% certainty. These 45 variants are significantly enriched for protein-coding changes (n=13), direct disruption of transcription factor binding sites (n=3) and tissue specific epigenetic marks (n=10), with the latter category showing enrichment in specific immune cells among associations stronger in CD and in gut mucosa among associations stronger in UC. The results of this study suggest that high-resolution fine-mapping in large samples can convert many GWAS discoveries into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.
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              Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.

              Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                9216904
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                11 September 2019
                18 November 2019
                December 2019
                18 May 2020
                : 51
                : 12
                : 1670-1678
                Affiliations
                [1 ]Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China & Research Division, Institute of Mental Health, Singapore, Singapore
                [2 ]Human Genetics, Genome Institute of Singapore, Singapore, Singapore
                [3 ]Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA
                [4 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
                [5 ]Department of Medicine, Harvard Medical School, Boston, MA, USA
                [6 ]Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
                [7 ]Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
                [8 ]The Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio-X Institutes & the Affiliated Hospital of Qingdao University, Qingdao, China
                [9 ]Bio-X Institute, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China
                [10 ]Department of Medical Epidemiology and Biostatistics (MEB), C8, Karolinska Instituet, Stockholm, Sweden
                [11 ]Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
                [12 ]Social Genetic & Developmental Psychiatry, King's College, London, London, UK
                [13 ]Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
                [14 ]Australian Centre for Precision Health, School of Health Sciences, University of South Australia Cancer Research Institute, Adelaide, South Australia, Australia
                [15 ]Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
                [16 ]South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
                [17 ]Data Science Institute, Columbia University, New York, NY, USA
                [18 ]New York Genome Center, New York, NY, USA
                [19 ]Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
                [20 ]Peking University Sixth Hospital & Institute of Mental Health, Beijing, China
                [21 ]National Health Commission Key Laboratory of Mental Health & National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
                [22 ]Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, the University of Tokyo, Minato-ku, Tokyo, Japan
                [23 ]Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
                [24 ]Department of Psychiatry, Chonnam National University Medical School, Gwangju, South Korea
                [25 ]RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
                [26 ]Psychiatry Department, University of Indonesia - Cipto Mangunkusumo National General Hospital, Jakarta Pusat, DKI Jakarta, Indonesia
                [27 ]Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
                [28 ]Department of Psychiatry, National Taiwan University College of Medicine, Taipei, Taiwan
                [29 ]Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
                [30 ]Queensland Center for Mental Health Research, The University of Queensland, Wacol, Queensland, Australia
                [31 ]Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
                [32 ]Department of Psychiatry, University Medical Center Utrecht, Utrecht, Utrecht, Netherlands
                [33 ]Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
                [34 ]Department of Psychiatry, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
                [35 ]Center for Brain Science, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
                [37 ]Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
                [38 ]The State University of New York, Syracuse, NY, USA
                [39 ]Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA
                [40 ]Shanghai Center for Women and Children's Health, Shanghai, China
                [41 ]Baoan Maternal and Child Health Hospital, Jinan University, Shenzhen, China
                [42 ]Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
                [43 ]Department of Genetics, Harvard Medical School, Boston, MA, USA
                [44 ]Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
                [45 ]University of Western Australia, Perth, Western Australia, Australia
                [46 ]Institute of Mental Health, Singapore, Singapore
                [47 ]MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
                [48 ]School of Life Science and Technology, ShanghaiTech University, Shanghai, China
                [49 ]Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
                [50 ]Collaborative Innovation Center of Genetics and Development, Shanghai, China
                [51 ]Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
                [52 ]Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany
                [53 ]Institute for Molecular Medicine, Finland (FIMM), Helsinki, Finland
                [54 ]Collaborative Innovation Center, Jining Medical University, Jining, Shandong, China
                [55 ]State Key Laboratory of Brain and Cognitive Sciences, Centre for Genomic Sciences and Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hongkong, HK China
                [56 ]Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
                [57 ]Molecular Horizons and School of Chemistry & Molecular Bioscience, University of Wollongong, and Illawarra Health & Medical Research Institute, Wollongong, New South Wales, Australia
                [58 ]IDG/McGovern Institute for Brain Research at Peking University, Beijing, China
                [59 ]Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
                [60 ]Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
                [61 ]Clinical Research Center for Mental Disease of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
                [62 ]Department of Psychiatry and Behavioral Health System, Icahn School of Medicine at Mount Sinai, New York, NY, USA
                [63 ]Department of Psychiatry, Brain Center Rudolf Magnus, UMC Utrecht, Utrecht, Netherlands
                [64 ]Department of Psychiatry, the First Teaching Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
                Author notes
                [36]

                A list of members and affiliations appears in the Supplementary Note.

                [66]

                These authors jointly supervised the work.

                Article
                EMS84348
                10.1038/s41588-019-0512-x
                6885121
                31740837
                5b535733-c2d0-4c69-ba39-76738401b878

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