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Exome sequencing of Finnish isolates enhances rare-variant association power

Author

Listed:
  • Adam E. Locke

    (Washington University School of Medicine
    Washington University School of Medicine
    University of Michigan School of Public Health)

  • Karyn Meltz Steinberg

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Charleston W. K. Chiang

    (University of California Los Angeles
    University of Southern California
    University of Southern California)

  • Susan K. Service

    (University of California Los Angeles)

  • Aki S. Havulinna

    (University of Helsinki
    National Institute for Health and Welfare)

  • Laurel Stell

    (Stanford University)

  • Matti Pirinen

    (University of Helsinki
    University of Helsinki
    University of Helsinki)

  • Haley J. Abel

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Colby C. Chiang

    (Washington University School of Medicine)

  • Robert S. Fulton

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Anne U. Jackson

    (University of Michigan School of Public Health)

  • Chul Joo Kang

    (Washington University School of Medicine)

  • Krishna L. Kanchi

    (Washington University School of Medicine)

  • Daniel C. Koboldt

    (Washington University School of Medicine
    Nationwide Children’s Hospital
    The Ohio State University College of Medicine)

  • David E. Larson

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Joanne Nelson

    (Washington University School of Medicine)

  • Thomas J. Nicholas

    (Washington University School of Medicine
    University of Utah)

  • Arto Pietilä

    (National Institute for Health and Welfare)

  • Vasily Ramensky

    (University of California Los Angeles
    Federal State Institution “National Medical Research Center for Preventive Medicine” of the Ministry of Healthcare of the Russian Federation)

  • Debashree Ray

    (University of Michigan School of Public Health
    Johns Hopkins University)

  • Laura J. Scott

    (University of Michigan School of Public Health)

  • Heather M. Stringham

    (University of Michigan School of Public Health)

  • Jagadish Vangipurapu

    (University of Eastern Finland)

  • Ryan Welch

    (University of Michigan School of Public Health)

  • Pranav Yajnik

    (University of Michigan School of Public Health)

  • Xianyong Yin

    (University of Michigan School of Public Health)

  • Johan G. Eriksson

    (National Institute for Health and Welfare
    Folkhälsan Research Center
    University of Helsinki, Helsinki and Helsinki University Hospital)

  • Mika Ala-Korpela

    (Baker Heart and Diabetes Institute
    University of Oulu and Biocenter Oulu, University of Oulu
    University of Eastern Finland
    University of Bristol)

  • Marjo-Riitta Järvelin

    (University of Oulu
    University of Oulu
    Oulu University Hospital
    Imperial College London)

  • Minna Männikkö

    (University of Oulu
    University of Oulu)

  • Hannele Laivuori

    (University of Helsinki
    University of Helsinki and Helsinki University Hospital
    Tampere University Hospital and University of Tampere, Faculty of Medicine and Health Technology)

  • Susan K. Dutcher

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Nathan O. Stitziel

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Richard K. Wilson

    (Washington University School of Medicine
    Nationwide Children’s Hospital
    The Ohio State University College of Medicine)

  • Ira M. Hall

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Chiara Sabatti

    (Stanford University
    Stanford University)

  • Aarno Palotie

    (University of Helsinki
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Veikko Salomaa

    (National Institute for Health and Welfare)

  • Markku Laakso

    (University of Eastern Finland
    Kuopio University Hospital)

  • Samuli Ripatti

    (University of Helsinki
    University of Helsinki
    Broad Institute of MIT and Harvard)

  • Michael Boehnke

    (University of Michigan School of Public Health)

  • Nelson B. Freimer

    (University of California Los Angeles)

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.

Suggested Citation

  • 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. Jack, 2019. "Exome sequencing of Finnish isolates enhances rare-variant association power," Nature, Nature, vol. 572(7769), pages 323-328, August.
  • Handle: RePEc:nat:nature:v:572:y:2019:i:7769:d:10.1038_s41586-019-1457-z
    DOI: 10.1038/s41586-019-1457-z
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    Citations

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    Cited by:

    1. Magdalena Zimoń & Yunfeng Huang & Anthi Trasta & Aliaksandr Halavatyi & Jimmy Z. Liu & Chia-Yen Chen & Peter Blattmann & Bernd Klaus & Christopher D. Whelan & David Sexton & Sally John & Wolfgang Hube, 2021. "Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. David R. Blair & Thomas J. Hoffmann & Joseph T. Shieh, 2022. "Common genetic variation associated with Mendelian disease severity revealed through cryptic phenotype analysis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Xianyong Yin & Lap Sum Chan & Debraj Bose & Anne U. Jackson & Peter VandeHaar & Adam E. Locke & Christian Fuchsberger & Heather M. Stringham & Ryan Welch & Ketian Yu & Lilian Fernandes Silva & Susan K, 2022. "Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Zichen Zhang & Ye Eun Bae & Jonathan R. Bradley & Lang Wu & Chong Wu, 2022. "SUMMIT: An integrative approach for better transcriptomic data imputation improves causal gene identification," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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