Rapid, reference-free human genotype imputation with denoising autoencoders

  1. Raquel Dias
  2. Doug Evans
  3. Shang-Fu Chen
  4. Kai-Yu Chen
  5. Salvatore Loguercio
  6. Leslie Chan
  7. Ali Torkamani  Is a corresponding author
  1. University of Florida, United States
  2. Scripps Research Institute, United States

Abstract

Genotype imputation is a foundational tool for population genetics. Standard statistical imputation approaches rely on the co-location of large whole-genome sequencing-based reference panels, powerful computing environments, and potentially sensitive genetic study data. This results in computational resource and privacy-risk barriers to access to cutting-edge imputation techniques. Moreover, the accuracy of current statistical approaches is known to degrade in regions of low and complex linkage disequilibrium. Artificial neural network-based imputation approaches may overcome these limitations by encoding complex genotype relationships in easily portable inference models. Here we demonstrate an autoencoder-based approach for genotype imputation, using a large, commonly used reference panel, and spanning the entirety of human chromosome 22. Our autoencoder-based genotype imputation strategy achieved superior imputation accuracy across the allele-frequency spectrum and across genomes of diverse ancestry, while delivering at least 4-fold faster inference run time relative to standard imputation tools.

Data availability

The data that support the findings of this study are available from dbGAP and European Genome-phenome Archive (EGA), but restrictions apply to the availability of these data, which were used under ethics approval for the current study, and so are not openly available to the public. The computational pipeline for autoencoder training and validation is available at https://github.com/TorkamaniLab/Imputation_Autoencoder/tree/master/autoencoder_tuning_pipeline. The python script for calculating imputation accuracy is available at https://github.com/TorkamaniLab/imputation_accuracy_calculator. Instructions on how to access the unique information on the parameters and hyperparameters of each one of the 256 autoencoders is shared through our source code repository at https://github.com/TorkamaniLab/imputator_inference. We also shared the pre-trained autoencoders and instructions on how to use them for imputation at https://github.com/TorkamaniLab/imputator_inference.Imputation data format. The imputation results are exported in variant calling format (VCF) containing the imputed genotypes and imputation quality scores in the form of class probabilities for each one of the three possible genotypes (homozygous reference, heterozygous, and homozygous alternate allele). The probabilities can be used for quality control of the imputation results.

The following previously published data sets were used

Article and author information

Author details

  1. Raquel Dias

    Department of Microbiology and Cell Science, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Doug Evans

    Scripps Research Translational Institute, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shang-Fu Chen

    Scripps Research Translational Institute, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kai-Yu Chen

    Scripps Research Translational Institute, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Salvatore Loguercio

    Scripps Research Translational Institute, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Leslie Chan

    Scripps Research Translational Institute, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ali Torkamani

    Scripps Research Translational Institute, Scripps Research Institute, La Jolla, United States
    For correspondence
    atorkama@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0232-8053

Funding

National Institutes of Health (R01HG010881)

  • Raquel Dias
  • Doug Evans
  • Shang-Fu Chen
  • Kai-Yu Chen
  • Salvatore Loguercio
  • Ali Torkamani

National Institutes of Health (KL2TR002552)

  • Raquel Dias

National Institutes of Health (U24TR002306)

  • Doug Evans
  • Shang-Fu Chen
  • Kai-Yu Chen
  • Ali Torkamani

National Institutes of Health (UL1TR002550)

  • Doug Evans
  • Shang-Fu Chen
  • Kai-Yu Chen
  • Ali Torkamani

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Matthew Stephens, University of Chicago, United States

Publication history

  1. Received: November 16, 2021
  2. Preprint posted: December 2, 2021 (view preprint)
  3. Accepted: September 19, 2022
  4. Accepted Manuscript published: September 23, 2022 (version 1)

Copyright

© 2022, Dias et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Raquel Dias
  2. Doug Evans
  3. Shang-Fu Chen
  4. Kai-Yu Chen
  5. Salvatore Loguercio
  6. Leslie Chan
  7. Ali Torkamani
(2022)
Rapid, reference-free human genotype imputation with denoising autoencoders
eLife 11:e75600.
https://doi.org/10.7554/eLife.75600

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