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The impact of non-additive genetic associations on age-related complex diseases

Author

Listed:
  • Marta Guindo-Martínez

    (Barcelona Supercomputing Center (BSC))

  • Ramon Amela

    (Barcelona Supercomputing Center (BSC))

  • Silvia Bonàs-Guarch

    (Barcelona Supercomputing Center (BSC)
    The Barcelona Institute of Science and Technology
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas)

  • Montserrat Puiggròs

    (Barcelona Supercomputing Center (BSC))

  • Cecilia Salvoro

    (Barcelona Supercomputing Center (BSC))

  • Irene Miguel-Escalada

    (Barcelona Supercomputing Center (BSC)
    The Barcelona Institute of Science and Technology
    CIBER de Diabetes y Enfermedades Metabólicas Asociadas)

  • Caitlin E. Carey

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Joanne B. Cole

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School
    Boston Children’s Hospital)

  • Sina Rüeger

    (University of Helsinki)

  • Elizabeth Atkinson

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Aaron Leong

    (Harvard Medical School
    Massachusetts General Hospital)

  • Friman Sanchez

    (Barcelona Supercomputing Center (BSC))

  • Cristian Ramon-Cortes

    (Barcelona Supercomputing Center (BSC))

  • Jorge Ejarque

    (Barcelona Supercomputing Center (BSC))

  • Duncan S. Palmer

    (Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    GENOMICS plc)

  • Mitja Kurki

    (University of Helsinki)

  • Krishna Aragam

    (Broad Institute of MIT and Harvard
    Cardiology Division, Massachusetts General Hospital
    Massachusetts General Hospital)

  • Jose C. Florez

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Rosa M. Badia

    (Barcelona Supercomputing Center (BSC))

  • Josep M. Mercader

    (Barcelona Supercomputing Center (BSC)
    Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • David Torrents

    (Barcelona Supercomputing Center (BSC)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

Abstract

Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases.

Suggested Citation

  • Marta Guindo-Martínez & Ramon Amela & Silvia Bonàs-Guarch & Montserrat Puiggròs & Cecilia Salvoro & Irene Miguel-Escalada & Caitlin E. Carey & Joanne B. Cole & Sina Rüeger & Elizabeth Atkinson & Aaron, 2021. "The impact of non-additive genetic associations on age-related complex diseases," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21952-4
    DOI: 10.1038/s41467-021-21952-4
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