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Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

Author

Listed:
  • Gustav Ahlberg

    (University Hospital of Copenhagen
    University of Copenhagen)

  • Lena Refsgaard

    (University Hospital of Copenhagen
    University of Copenhagen)

  • Pia R. Lundegaard

    (University Hospital of Copenhagen
    University of Copenhagen)

  • Laura Andreasen

    (University Hospital of Copenhagen
    University of Copenhagen)

  • Mattis F. Ranthe

    (Statens Serum Institute)

  • Nora Linscheid

    (University of Copenhagen
    University of Copenhagen)

  • Jonas B. Nielsen

    (University of Copenhagen)

  • Mads Melbye

    (Statens Serum Institute
    University of Copenhagen
    Stanford University School of Medicine)

  • Stig Haunsø

    (University Hospital of Copenhagen)

  • Ahmad Sajadieh

    (Copenhagen University Hospital, Bispebjerg)

  • Lu Camp

    (The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care)

  • Søren-Peter Olesen

    (University of Copenhagen)

  • Simon Rasmussen

    (Technical University of Denmark)

  • Alicia Lundby

    (University of Copenhagen
    University of Copenhagen)

  • Patrick T. Ellinor

    (Cardiovascular Research Centre, Massachusetts General Hospital
    The Broad Institute of Harvard and MIT)

  • Anders G. Holst

    (University Hospital of Copenhagen)

  • Jesper H. Svendsen

    (University Hospital of Copenhagen
    University of Copenhagen)

  • Morten S. Olesen

    (University Hospital of Copenhagen
    University of Copenhagen)

Abstract

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10−6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10−6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

Suggested Citation

  • Gustav Ahlberg & Lena Refsgaard & Pia R. Lundegaard & Laura Andreasen & Mattis F. Ranthe & Nora Linscheid & Jonas B. Nielsen & Mads Melbye & Stig Haunsø & Ahmad Sajadieh & Lu Camp & Søren-Peter Olesen, 2018. "Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06618-y
    DOI: 10.1038/s41467-018-06618-y
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    Cited by:

    1. Alan Selewa & Kaixuan Luo & Michael Wasney & Linsin Smith & Xiaotong Sun & Chenwei Tang & Heather Eckart & Ivan P. Moskowitz & Anindita Basu & Xin He & Sebastian Pott, 2023. "Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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