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      Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

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      1 , 2 , 46 , 3 , 4 , 46 , 1 , 2 , 4 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 1 , 2 , 13 , 14 , 15 , 16 , 5 , 16 , 17 , 1 , 1 , 18 , 1 , 2 , 2 , 19 , 1 , 2 , 1 , 2 , 20 , 21 , 22 , 23 , 22 , 1 , 2 , 24 , 25 , 1 , 26 , 27 , 28 , 27 , 29 , 18 , 18 , 7 , 9 , 30 , 22 , 5 , 31 , 32 , 5 , 31 , 33 , 11 , 34 , 10 , 11 , 12 , 10 , 11 , 12 , 1 , 2 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 18 , Million Veteran Program, 2 , 42 , 43 , 29 , 44 , 45 , 3 , 4 , 47 , 1 , 2 , 24 , 35 , 47
      medRxiv
      Cold Spring Harbor Laboratory

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          Abstract

          Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

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          Most cited references95

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          A global reference for human genetic variation

          The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
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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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              • Record: found
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              The UK Biobank resource with deep phenotyping and genomic data

              The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.
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                Author and article information

                Journal
                medRxiv
                MEDRXIV
                medRxiv
                Cold Spring Harbor Laboratory
                30 January 2023
                : 2023.01.24.23284960
                Affiliations
                [1 ]Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
                [2 ]Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
                [3 ]Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA
                [4 ]Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
                [5 ]Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
                [6 ]Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
                [7 ]Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
                [8 ]School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
                [9 ]Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
                [10 ]Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark
                [11 ]The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark
                [12 ]Center for Genomics and Personalized Medicine, Aarhus, Denmark
                [13 ]Department of Psychological and Brain Sciences, Washington University in St. Louis, Saint Louis, MO, USA
                [14 ]Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
                [15 ]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
                [16 ]Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
                [17 ]Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
                [18 ]Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA
                [19 ]Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT, USA
                [20 ]Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia
                [21 ]Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
                [22 ]Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
                [23 ]Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia
                [24 ]Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
                [25 ]Department of Genetics, Yale School of Medicine, New Haven, CT, USA
                [26 ]Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
                [27 ]Department of Medicine, Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA
                [28 ]Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
                [29 ]Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
                [30 ]School of Psychology, University of Queensland, Brisbane, QLD, Australia
                [31 ]Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
                [32 ]Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA
                [33 ]Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
                [34 ]Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
                [35 ]Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA
                [36 ]National Center for PTSD, US Department of Veterans Affairs, West Haven, CT, USA
                [37 ]Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA, USA
                [38 ]Department of Medicine, Divisions of Aging and Preventative Medicine, Brigham and Women’s Hospital, Boston, MA, USA
                [39 ]Department of Medicine, Harvard Medical School, Boston, MA, USA
                [40 ]Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
                [41 ]Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
                [42 ]Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
                [43 ]Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, CT, USA
                [44 ]VA San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA
                [45 ]Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA
                [46 ]These authors contributed equally
                [47 ]These authors jointly supervised this work
                Author notes
                [*]

                A list of members and their affiliations appears in the Supplementary Information

                Corresponding Authors: Joel Gelernter, Department of Psychiatry, Yale School of Medicine, Veterans Affairs Connecticut Healthcare System, 116A2, 950 Campbell Ave, West Haven, CT 06516, USA. joel.gelernter@ 123456yale.edu , Hang Zhou, Department of Psychiatry, Yale School of Medicine; Veterans Affairs Connecticut Healthcare System, 43A35, 950 Campbell Ave, West Haven, CT 06516, USA. hang.zhou@ 123456yale.edu
                Article
                10.1101/2023.01.24.23284960
                9901058
                36747741
                9f1ae7b6-86cf-4c97-923d-6bc255c8de54

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.

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