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      Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease

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      1 , 2 , 3 , 1 , 2 , 4 , 1 , 2 , 1 , 2 , 5 , 6 , 1 , 2 , 1 , 2 , 7 , 8 , 9 , 10 , 6 , 6 , 6 , 5 , 5 , 5 , 1 , 11 , 5 , 5 , 12 , 13 , 14 , 15 , 16 , 17 , 6 , 7 , 8 , 18 , 19 , 20 , 9 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 30 , 25 , International Genetics of Parkinson Disease Progression (IGPP) Consortium, 1 , 2 , 5 , 11 , *
      Nature genetics

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          Abstract

          A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia (PDD), a major determinant for quality of life, we performed a genome-wide survival study (GWSS) of 11.2 million variants in 3,821 PD patients over 31,053 longitudinal visits. We discover and replicate RIMS2 as a progression locus ( P = 2.78 × 10 −11; hazard ratio (HR) = 4.77), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10 −8) and WWOX (HR = 2.12, P = 2.37 × 10 −8), and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.

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          Most cited references84

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          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
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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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              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
                25 June 2021
                06 May 2021
                June 2021
                06 November 2021
                : 53
                : 6
                : 787-793
                Affiliations
                [1 ]Center for Advanced Parkinson Research, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
                [2 ]Precision Neurology Program of Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
                [3 ]School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, China
                [4 ]School of Computer Science, Northwestern Polytechnical University, Xi’an, Shaanxi, China
                [5 ]Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
                [6 ]Sorbonne Université, Institut National de la Santé et de la Recherche Médicale and Centre d’Investigation Clinique 1422, Centre National de la Recherche Scientifique, Institut du Cerveau – Paris Brain Institute - ICM, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, France
                [7 ]The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway
                [8 ]Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway
                [9 ]Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, MO, USA
                [10 ]Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, “Exposome and heredity” team, CESP, Villejuif, France
                [11 ]Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
                [12 ]Praxis Precision Medicines, Cambridge, MA, USA
                [13 ]Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, NY, USA
                [14 ]Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
                [15 ]Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Perth, WA, Australia
                [16 ]Perron Institute for Neurological and Translational Science, Nedlands, Perth, WA, Australia
                [17 ]Banner Sun Health Research Institute, Sun City, AZ, USA
                [18 ]Department of Neurology, Stavanger University Hospital, Stavanger, Norway
                [19 ]Department of Neurology, Haukeland University Hospital, Bergen, Norway
                [20 ]Department of Clinical Medicine, University of Bergen, Bergen, Norway
                [21 ]Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
                [22 ]Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA
                [23 ]German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany
                [24 ]Translational Genomics Core of Partners HealthCare Personalized Medicine, Cambridge, MA, USA
                [25 ]Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
                [26 ]Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany, and Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
                [27 ]Department of Neurology, University Medical Center Göttingen, Göttingen, Germany and Paracelsus-Elena-Klinik, Kassel, Germany
                [28 ]Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany and Paracelsus-Elena-Klinik, Kassel, Germany
                [29 ]Institute of Neurogenetics, University of Lübeck, University Hospital of Schleswig-Holstein, Lübeck, Germany
                [30 ]John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
                [31 ]Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
                Author notes
                [#]

                A list of consortium authors appears at the end of the paper.

                Author contributions

                C.R.S. conceived and designed the study. G.L. contributed to design, and with J.P., J.J.L., and C.R.S. carried out the statistical and bioinformatics analyses. X.D. contributed to the analysis. Z.L. and S.S.A. performed genotyping. Patient samples and phenotypic data were collected by J.-C.C., F.Z., J.M.-G., M.C.C., A.E., S.L., A.B., G.M., J.H.G., A.Y.H., M.A.S., M.T.H., A.-M.W., T.M.H., B.R., I.S., S.K., P.T., T.G.B., F.C.-D., G.A., O.-B.T., J.S.P., P.H., J.J.v.H., R.A.B., C.H.W.-G., J.M., M.K., C.K., C.T., B.M., and C.R.S. All authors are members of the International Genetics of Parkinson’s Disease Progression (IGPP) Consortium. C.R.S. and G.L. drafted the manuscript. All authors reviewed, edited, approved the manuscript prior to submission.

                Article
                NIHMS1684407
                10.1038/s41588-021-00847-6
                8459648
                33958783
                d300d4dc-4545-44ed-842c-6602179fe9c6

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