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      Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s disease

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          Abstract

          Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer’s disease and related dementias.

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          Most cited references84

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          Second-generation PLINK: rising to the challenge of larger and richer datasets

          PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.
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            The Human Genome Browser at UCSC

            As vertebrate genome sequences near completion and research refocuses to their analysis, the issue of effective genome annotation display becomes critical. A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu. This browser displays assembly contigs and gaps, mRNA and expressed sequence tag alignments, multiple gene predictions, cross-species homologies, single nucleotide polymorphisms, sequence-tagged sites, radiation hybrid data, transposon repeats, and more as a stack of coregistered tracks. Text and sequence-based searches provide quick and precise access to any region of specific interest. Secondary links from individual features lead to sequence details and supplementary off-site databases. One-half of the annotation tracks are computed at the University of California, Santa Cruz from publicly available sequence data; collaborators worldwide provide the rest. Users can stably add their own custom tracks to the browser for educational or research purposes. The conceptual and technical framework of the browser, its underlying MYSQL database, and overall use are described. The web site currently serves over 50,000 pages per day to over 3000 different users.
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              Biological Insights From 108 Schizophrenia-Associated Genetic Loci

              Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
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                Author and article information

                Contributors
                leonardhl@nih.gov
                Journal
                Mol Psychiatry
                Mol Psychiatry
                Molecular Psychiatry
                Nature Publishing Group UK (London )
                1359-4184
                1476-5578
                18 May 2023
                18 May 2023
                2023
                : 28
                : 7
                : 3121-3132
                Affiliations
                [1 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Laboratory of Neurogenetics, National Institute on Aging, , National Institutes of Health, ; Bethesda, MD USA
                [2 ]Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, ( https://ror.org/05t99sp05) San Francisco, CA USA
                [3 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Neurology and Weill Institute for Neurosciences, , University of California, San Francisco, ; San Francisco, CA USA
                [4 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Memory and Aging Center, , University of California, San Francisco, ; San Francisco, CA USA
                [5 ]Preventive Neurology Unit, Centre for Prevention Diagnosis and Detection, Wolfson Institute of Population Health, Queen Mary University of London, ( https://ror.org/026zzn846) London, UK
                [6 ]GRID grid.133342.4, ISNI 0000 0004 1936 9676, Neuroscience Research Institute and the department of Molecular, Cellular and Developmental Biology, , University of California, Santa Barbara, ; Santa Barbara, CA USA
                [7 ]Neuroscience Group of Antioquia, University of Antioquia, ( https://ror.org/03bp5hc83) Medellín, Colombia
                [8 ]Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, ( https://ror.org/048b34d51) London, UK
                [9 ]UCL Movement Disorders Centre, University College London, ( https://ror.org/02jx3x895) London, UK
                [10 ]Data Tecnica International LLC, ( https://ror.org/001h41c24) Washington, DC USA
                [11 ]Center for Alzheimer’s and Related Dementias, National Institutes of Health, ( https://ror.org/01cwqze88) Bethesda, MD USA
                [12 ]Alector, Inc. 131 Oyster Point Blvd, Suite 600, ( https://ror.org/03vagve85) South San Francisco, CA 94080 USA
                [13 ]Gwangju Alzheimer’s disease and Related Dementia Cohort Research Center, Chosun University, ( https://ror.org/01zt9a375) Gwangju, 61452 Korea
                [14 ]BK FOUR Department of Integrative Biological Sciences, Chosun University, ( https://ror.org/01zt9a375) Gwangju, 61452 Korea
                [15 ]Department of Biomedical Science, Chosun University, ( https://ror.org/01zt9a375) Gwangju, 61452 Korea
                [16 ]Korea Brain Research Institute, ( https://ror.org/055zd7d59) Daegu, 41062 Korea
                [17 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Longitudinal Studies Section, National Institute on Aging, , National Institutes of Health, ; Baltimore, MD USA
                [18 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Integrative Neurogenomics Unit, , Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, ; Bethesda, MD USA
                [19 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Department of Radiology and Biomedical Imaging, , University of California, San Francisco, ; San Francisco, CA USA
                [20 ]German Center for Neurodegenerative Diseases (DZNE), ( https://ror.org/043j0f473) Tübingen, Germany
                Author information
                http://orcid.org/0000-0001-7049-6281
                http://orcid.org/0000-0001-9978-093X
                http://orcid.org/0000-0002-6953-7733
                http://orcid.org/0000-0001-5218-1737
                http://orcid.org/0000-0003-4144-8162
                http://orcid.org/0000-0002-6273-1613
                http://orcid.org/0000-0001-9358-8111
                http://orcid.org/0000-0001-7274-2634
                http://orcid.org/0000-0003-2390-8110
                Article
                2089
                10.1038/s41380-023-02089-w
                10615750
                37198259
                fdd4ade4-6d35-4f8e-81bd-474f85e8359f
                © The Author(s) 2023

                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
                : 20 October 2022
                : 27 March 2023
                : 31 March 2023
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000049, U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging);
                Award ID: 1ZIA-NS003154, Z01-AG000949-02, ZO1-AG000535 and Z01-ES101986
                Award ID: 1ZIA-NS003154, Z01-AG000949-02, ZO1-AG000535, Z01-ES101986
                Award ID: R01 AG062588, R01 AG057234, P30 AG062422
                Award ID: R01 AG062588, R01 AG057234, P30 AG062422
                Award Recipient :
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
                Funded by: FundRef https://doi.org/10.13039/100000065, U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS);
                Award ID: U54 NS123985
                Award ID: U54 NS123985
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000957, Alzheimer&rsqu;s Association;
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
                Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
                Funded by: Alzheimer&rsqu;s Association
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2023

                Molecular medicine
                neuroscience,genetics,diseases
                Molecular medicine
                neuroscience, genetics, diseases

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