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A robust method for collider bias correction in conditional genome-wide association studies

Author

Listed:
  • Osama Mahmoud

    (University of Essex
    Helwan University)

  • Frank Dudbridge

    (University of Leicester)

  • George Davey Smith

    (University of Bristol
    University of Bristol)

  • Marcus Munafo

    (University of Bristol
    University of Bristol)

  • Kate Tilling

    (University of Bristol
    University of Bristol)

Abstract

Estimated genetic associations with prognosis, or conditional on a phenotype (e.g. disease incidence), may be affected by collider bias, whereby conditioning on the phenotype induces associations between causes of the phenotype and prognosis. We propose a method, ‘Slope-Hunter’, that uses model-based clustering to identify and utilise the class of variants only affecting the phenotype to estimate the adjustment factor, assuming this class explains more variation in the phenotype than any other variant classes. Simulation studies show that our approach eliminates the bias and outperforms alternatives even in the presence of genetic correlation. In a study of fasting blood insulin levels (FI) conditional on body mass index, we eliminate paradoxical associations of the underweight loci: COBLLI; PPARG with increased FI, and reveal an association for the locus rs1421085 (FTO). In an analysis of a case-only study for breast cancer mortality, a single region remains associated with more pronounced results.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28119-9
    DOI: 10.1038/s41467-022-28119-9
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    References listed on IDEAS

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    1. 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.
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