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Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Author

Listed:
  • Arthur Gilly

    (Wellcome Sanger Institute)

  • Daniel Suveges

    (Wellcome Sanger Institute)

  • Karoline Kuchenbaecker

    (Wellcome Sanger Institute
    University College of London
    University College London)

  • Martin Pollard

    (Wellcome Sanger Institute
    University of Cambridge)

  • Lorraine Southam

    (Wellcome Sanger Institute
    University of Oxford)

  • Konstantinos Hatzikotoulas

    (Wellcome Sanger Institute
    Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health)

  • Aliki-Eleni Farmaki

    (University of Leicester
    Harokopio University of Athens)

  • Thea Bjornland

    (Norwegian Institute of Science and Technology)

  • Ryan Waples

    (University of Copenhagen)

  • Emil V. R. Appel

    (University of Copenhagen)

  • Elisabetta Casalone

    (University of Torino)

  • Giorgio Melloni

    (Harvard Medical School)

  • Britt Kilian

    (Wellcome Sanger Institute)

  • Nigel W. Rayner

    (Wellcome Sanger Institute
    University of Oxford
    University of Oxford, Old Road, Headington)

  • Ioanna Ntalla

    (Queen Mary University of London)

  • Kousik Kundu

    (Wellcome Sanger Institute
    University of Cambridge)

  • Klaudia Walter

    (Wellcome Sanger Institute)

  • John Danesh

    (Wellcome Sanger Institute
    University of Cambridge
    University of Cambridge, Strangeways Research Laboratory)

  • Adam Butterworth

    (University of Cambridge
    University of Cambridge, Strangeways Research Laboratory
    Addenbrooke’s Hospital)

  • Inês Barroso

    (Wellcome Sanger Institute)

  • Emmanouil Tsafantakis

    (Anogia Medical Centre)

  • George Dedoussis

    (Harokopio University of Athens)

  • Ida Moltke

    (University of Copenhagen)

  • Eleftheria Zeggini

    (Wellcome Sanger Institute
    Institute of Translational Genomics, Helmholtz Zentrum München – German Research Center for Environmental Health)

Abstract

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10−8; APOC3 and triglyceride levels, P = 1.5 × 10−26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10−8), indicating a role for this gene in lipid metabolism.

Suggested Citation

  • Arthur Gilly & Daniel Suveges & Karoline Kuchenbaecker & Martin Pollard & Lorraine Southam & Konstantinos Hatzikotoulas & Aliki-Eleni Farmaki & Thea Bjornland & Ryan Waples & Emil V. R. Appel & Elisab, 2018. "Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07070-8
    DOI: 10.1038/s41467-018-07070-8
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    Cited by:

    1. Marcin Kierczak & Nima Rafati & Julia Höglund & Hadrien Gourlé & Valeria Lo Faro & Daniel Schmitz & Weronica E. Ek & Ulf Gyllensten & Stefan Enroth & Diana Ekman & Björn Nystedt & Torgny Karlsson & Ås, 2022. "Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Mihail Halachev & Viktoria-Eleni Gountouna & Alison Meynert & Gannie Tzoneva & Alan R. Shuldiner & Colin A. Semple & James F. Wilson, 2024. "Regionally enriched rare deleterious exonic variants in the UK and Ireland," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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