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      Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ethnic meta-analysis

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      1 , 2 , 44 , 3 , 4 , 5 , 6 , 44 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 13 , 14 , 1 , 17 , 18 , 13 , 19 , 13 , 14 , 1 , 20 , 16 , 21 , 7 , 16 , 22 , 23 , 24 , 16 , 25 , 26 , 27 , 28 , 29 , 30 , 30 , 31 , 32 , 31 , 32 , 31 , 32 , 33 , 33 , 2 , 17 , 17 , 2 , 34 , 35 , 7 , 36 , 16 , 25 , 13 , 14 , 16 , 25 , 34 , 37 , 23 , 26 , 38 , 11 , 39 , 34 , 40 , 4 , 41 , 2 , 17 , 1 , 20 , 16 , 25 , 26 , 13 , 14 , The HPAP Consortium, Regeneron Genetics Center, VA Million Veteran Program, 1 , 2 , 44 , 1 , 17 , 18 , 44 , * , 29 , 42 , 43 , 44 , *
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          Abstract

          We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ethnic meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program, DIAMANTE, Biobank Japan, and other studies. We report 568 associations, including 286 autosomal, 7 X chromosomal, and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D-associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD), and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease, CKD, PAD, and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

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          Most cited references63

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          Is Open Access

          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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            An Integrated Encyclopedia of DNA Elements in the Human Genome

            Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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              LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

              Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                30 April 2020
                15 June 2020
                July 2020
                15 December 2020
                : 52
                : 7
                : 680-691
                Affiliations
                [1 ]Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
                [2 ]Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
                [3 ]Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System, Nashville, TN, USA.
                [4 ]Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
                [5 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
                [6 ]Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
                [7 ]VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
                [8 ]College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA.
                [9 ]Edith Nourse Rogers Memorial VA Hospital, Bedford, MA, USA.
                [10 ]Center for Population Health, University of Massachusetts, Lowell, MA, USA.
                [11 ]Phoenix VA Health Care System, Phoenix, AZ, USA.
                [12 ]Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA.
                [13 ]VA Palo Alto Health Care System, Palo Alto, CA, USA.
                [14 ]Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
                [15 ]Department of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
                [16 ]VA Boston Healthcare System, Boston, MA, USA,
                [17 ]Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
                [18 ]Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
                [19 ]Department of Statistics, Stanford University, Stanford, CA, USA.
                [20 ]Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
                [21 ]Department of Global Health, Peking University School of Public Health, Beijing, Beijing, China.
                [22 ]Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
                [23 ]Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
                [24 ]Division of Vascular Surgery and Endovascular Therapy, University of Florida School of Medicine, Gainesville, FL, USA.
                [25 ]Department of Medicine, Brigham Women’s Hospital, Boston, MA, USA.
                [26 ]Department of Medicine, Harvard Medical School, Boston, MA, USA.
                [27 ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
                [28 ]Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
                [29 ]Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
                [30 ]Punjab Institute of Cardiology, Lahore, Punjab, Pakistan.
                [31 ]Department of Medicine, King Edward Medical University, Lahore, Punjab, Pakistan.
                [32 ]Mayo Hospital, Lahore, Punjab, Pakistan.
                [33 ]Department of Cardiology, Faisalabad Institute of Cardiology, Faisalabad, Punjab, Pakistan.
                [34 ]Atlanta VA Medical Center, Decatur, GA, USA.
                [35 ]Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
                [36 ]Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
                [37 ]Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
                [38 ]Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.
                [39 ]College of Medicine, University of Arizona, Phoenix, AZ, USA.
                [40 ]Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA.
                [41 ]Nashville VA Medical Center, Nashville, TN, USA.
                [42 ]Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
                [43 ]Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
                [44 ]These authors contributed equally to this work.
                Author notes

                Author Contributions

                M.V., J.M.K., K.-M.C., D.S., B.F.V., P.S.T., and C.J.O. were responsible for the concept and design. The acquisition, analysis or interpretation of data were performed by M.V., J.M.K., K.-M.C., D.S., B.F.V., P.S.T., R.L.J., C.T., T.L.A., J.E.H., J.Z., J.H., K.L., X.Z., J.A.L., A.T.H., K.M.L, D.K., S.P., J.D., O.M., A.R., N.H.M., S.H., I.H.Q., M.N.A., U.M., A.J., S.A., X.S., L.G., K.H.K., K.S., Y.V.S., S.L.D., K.C., J.S.L., J.M.G., L.S.P., D.R.M., J.B.M., P.D.R., P.W.W., T.L.E., D.J.R., S.M.D., and C.J.O. The authors M.V. and D.S. drafted the manuscript. The critical revision of the manuscript for important intellectual content was carried out by M.V., J.M.K., K.-M.C., D.S., B.F.V., J.A.L., P.S.T., C.T., J.Z., J.H., X.Z., D.K., X.S., L.G., K.H.K., K.S., L.S.P., J.B.M., P.D.R., T.L.E., S.M.D., and C.J.O. Finally, K.-M.C., D.S., and B.F.V. provided administrative, technical, or material support

                Article
                NIHMS1589535
                10.1038/s41588-020-0637-y
                7343592
                32541925
                8d62ed89-3148-4aa7-a8ee-b64c5583a09c

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