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Adjustment for index event bias in genome-wide association studies of subsequent events

Author

Listed:
  • Frank Dudbridge

    (University of Leicester)

  • Richard J. Allen

    (University of Leicester)

  • Nuala A. Sheehan

    (University of Leicester)

  • A. Floriaan Schmidt

    (University of Groningen
    University College London
    University Medical Centre Utrecht)

  • James C. Lee

    (University of Cambridge School of Clinical Medicine)

  • R. Gisli Jenkins

    (Nottingham Respiratory Biomedical Research Centre, City Campus)

  • Louise V. Wain

    (University of Leicester
    Glenfield Hospital)

  • Aroon D. Hingorani

    (University College London)

  • Riyaz S. Patel

    (University College London)

Abstract

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn’s disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors.

Suggested Citation

  • Frank Dudbridge & Richard J. Allen & Nuala A. Sheehan & A. Floriaan Schmidt & James C. Lee & R. Gisli Jenkins & Louise V. Wain & Aroon D. Hingorani & Riyaz S. Patel, 2019. "Adjustment for index event bias in genome-wide association studies of subsequent events," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09381-w
    DOI: 10.1038/s41467-019-09381-w
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    Cited by:

    1. Osama Mahmoud & Frank Dudbridge & George Davey Smith & Marcus Munafo & Kate Tilling, 2022. "A robust method for collider bias correction in conditional genome-wide association studies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Linda Kachuri & Geno A. Guerra & Taishi Nakase & George A. Wendt & Helen M. Hansen & Annette M. Molinaro & Paige Bracci & Lucie McCoy & Terri Rice & John K. Wiencke & Jeanette E. Eckel-Passow & Robert, 2025. "Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival," Nature Communications, Nature, vol. 16(1), pages 1-13, December.

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