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The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization

Author

Listed:
  • Roxanna Korologou-Linden

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove)

  • Laxmi Bhatta

    (NTNU, Norwegian University of Science and Technology)

  • Ben M. Brumpton

    (NTNU, Norwegian University of Science and Technology
    Trondheim University Hospital
    Norwegian University of Science and Technology)

  • Laura D. Howe

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove)

  • Louise A. C. Millard

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove
    University of Bristol)

  • Katarina Kolaric

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove)

  • Yoav Ben-Shlomo

    (University of Bristol, Barley House, Oakfield Grove)

  • Dylan M. Williams

    (University College London
    Karolinska Institutet)

  • George Davey Smith

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove)

  • Emma L. Anderson

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove)

  • Evie Stergiakouli

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove)

  • Neil M. Davies

    (University of Bristol
    University of Bristol, Barley House, Oakfield Grove
    NTNU, Norwegian University of Science and Technology)

Abstract

Alzheimer’s disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.

Suggested Citation

  • Roxanna Korologou-Linden & Laxmi Bhatta & Ben M. Brumpton & Laura D. Howe & Louise A. C. Millard & Katarina Kolaric & Yoav Ben-Shlomo & Dylan M. Williams & George Davey Smith & Emma L. Anderson & Evie, 2022. "The causes and consequences of Alzheimer’s disease: phenome-wide evidence from Mendelian randomization," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32183-6
    DOI: 10.1038/s41467-022-32183-6
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    References listed on IDEAS

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    1. repec:ucp:bkecon:9780226320625 is not listed on IDEAS
    2. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    3. Gibran Hemani & Kate Tilling & George Davey Smith, 2017. "Orienting the causal relationship between imprecisely measured traits using GWAS summary data," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-22, November.
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