Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

  1. Ardalan Naseri
  2. Degui Zhi  Is a corresponding author
  3. Shaojie Zhang  Is a corresponding author
  1. The University of Texas Health Science Center at Houston, United States
  2. University of Central Florida, United States

Abstract

Runs of homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE, to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 SNPs and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended HLA region and autoimmune disorders. We found an association between a diplotype covering the HFE gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (P-value=1.82×10-11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.

Data availability

This research has been conducted using the UK Biobank Resource under Application Number 24247.The source code is available at https://github.com/ZhiGroup/ROH-DICE.

The following previously published data sets were used

Article and author information

Author details

  1. Ardalan Naseri

    School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2747-2193
  2. Degui Zhi

    School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, United States
    For correspondence
    degui.zhi@uth.tmc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7754-1890
  3. Shaojie Zhang

    Department of Computer Science, University of Central Florida, Orlando, United States
    For correspondence
    shzhang@cs.ucf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4051-5549

Funding

National Institutes of Health (R01 HG010086)

  • Ardalan Naseri
  • Degui Zhi
  • Shaojie Zhang

National Institutes of Health (R56 HG011509)

  • Ardalan Naseri
  • Degui Zhi
  • Shaojie Zhang

National Institutes of Health (OT2 OD002751)

  • Ardalan Naseri
  • Degui Zhi

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

Ethics

Human subjects: Our analysis was approved by The University of Texas Health Science Center at Houston committee for the protection of human subjects under No. HSC-SBMI-23-0583. UK Biobank (UKBB) has secured informed consent from the participants in the use of their data for approved research projects. UKBB data was accessed via approved project 24247.

Copyright

© 2024, Naseri 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.

Metrics

  • 1,376
    views
  • 159
    downloads
  • 4
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ardalan Naseri
  2. Degui Zhi
  3. Shaojie Zhang
(2024)
Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank
eLife 13:e81698.
https://doi.org/10.7554/eLife.81698

Share this article

https://doi.org/10.7554/eLife.81698

Further reading

    1. Computational and Systems Biology
    2. Neuroscience
    Cesare V Parise, Marc O Ernst
    Research Article

    Audiovisual information reaches the brain via both sustained and transient input channels, representing signals’ intensity over time or changes thereof, respectively. To date, it is unclear to what extent transient and sustained input channels contribute to the combined percept obtained through multisensory integration. Based on the results of two novel psychophysical experiments, here we demonstrate the importance of the transient (instead of the sustained) channel for the integration of audiovisual signals. To account for the present results, we developed a biologically inspired, general-purpose model for multisensory integration, the multisensory correlation detectors, which combines correlated input from unimodal transient channels. Besides accounting for the results of our psychophysical experiments, this model could quantitatively replicate several recent findings in multisensory research, as tested against a large collection of published datasets. In particular, the model could simultaneously account for the perceived timing of audiovisual events, multisensory facilitation in detection tasks, causality judgments, and optimal integration. This study demonstrates that several phenomena in multisensory research that were previously considered unrelated, all stem from the integration of correlated input from unimodal transient channels.

    1. Computational and Systems Biology
    Franck Simon, Maria Colomba Comes ... Herve Isambert
    Tools and Resources

    Live-cell microscopy routinely provides massive amounts of time-lapse images of complex cellular systems under various physiological or therapeutic conditions. However, this wealth of data remains difficult to interpret in terms of causal effects. Here, we describe CausalXtract, a flexible computational pipeline that discovers causal and possibly time-lagged effects from morphodynamic features and cell–cell interactions in live-cell imaging data. CausalXtract methodology combines network-based and information-based frameworks, which is shown to discover causal effects overlooked by classical Granger and Schreiber causality approaches. We showcase the use of CausalXtract to uncover novel causal effects in a tumor-on-chip cellular ecosystem under therapeutically relevant conditions. In particular, we find that cancer-associated fibroblasts directly inhibit cancer cell apoptosis, independently from anticancer treatment. CausalXtract uncovers also multiple antagonistic effects at different time delays. Hence, CausalXtract provides a unique computational tool to interpret live-cell imaging data for a range of fundamental and translational research applications.