Exome sequencing of Finnish isolates enhances rare-variant association power View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-07-31

AUTHORS

Adam E. Locke, Karyn Meltz Steinberg, Charleston W. K. Chiang, Susan K. Service, Aki S. Havulinna, Laurel Stell, Matti Pirinen, Haley J. Abel, Colby C. Chiang, Robert S. Fulton, Anne U. Jackson, Chul Joo Kang, Krishna L. Kanchi, Daniel C. Koboldt, David E. Larson, Joanne Nelson, Thomas J. Nicholas, Arto Pietilä, Vasily Ramensky, Debashree Ray, Laura J. Scott, Heather M. Stringham, Jagadish Vangipurapu, Ryan Welch, Pranav Yajnik, Xianyong Yin, Johan G. Eriksson, Mika Ala-Korpela, Marjo-Riitta Järvelin, Minna Männikkö, Hannele Laivuori, Susan K. Dutcher, Nathan O. Stitziel, Richard K. Wilson, Ira M. Hall, Chiara Sabatti, Aarno Palotie, Veikko Salomaa, Markku Laakso, Samuli Ripatti, Michael Boehnke, Nelson B. Freimer

ABSTRACT

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power. More... »

PAGES

323-328

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  • Journal

    TITLE

    Nature

    ISSUE

    7769

    VOLUME

    572

    Author Affiliations

  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA
  • Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
  • Quantitative and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
  • Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA
  • National Institute for Health and Welfare, Helsinki, Finland
  • Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
  • Helsinki Institute for Information Technology HIIT and Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland
  • Department of Genetics, Washington University School of Medicine, St Louis, MO, USA
  • McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA
  • Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
  • USTAR Center for Genetic Discovery and Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
  • Federal State Institution “National Medical Research Center for Preventive Medicine” of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
  • Departments of Epidemiology and Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
  • Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
  • Department of General Practice and Primary Health Care, University of Helsinki, Helsinki and Helsinki University Hospital, Helsinki, Finland
  • Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia
  • Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
  • Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland
  • Department of Obstetrics and Gynecology, Tampere University Hospital and University of Tampere, Faculty of Medicine and Health Technology, Tampere, Finland
  • Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
  • Department of Statistics, Stanford University, Stanford, CA, USA
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA
  • Department of Medicine, Kuopio University Hospital, Kuopio, Finland
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41586-019-1457-z

    DOI

    http://dx.doi.org/10.1038/s41586-019-1457-z

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1120012066

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31367044


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