1. Genetics and Genomics

Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation

  1. Courtney J Smith  Is a corresponding author
  2. Nasa Sinnott-Armstrong  Is a corresponding author
  3. Anna Cichońska
  4. Heli Julkunen
  5. Eric B Fauman
  6. Peter Würtz
  7. Jonathan K Pritchard  Is a corresponding author
  1. Stanford University, United States
  2. Fred Hutchinson Cancer Research Center, United States
  3. Nightingale Health Plc, Finland
  4. Pfizer, United States
https://doi.org/10.7554/eLife.79348
Share this article
Cite this article
  1. Courtney J Smith
  2. Nasa Sinnott-Armstrong
  3. Anna Cichońska
  4. Heli Julkunen
  5. Eric B Fauman
  6. Peter Würtz
  7. Jonathan K Pritchard
(2022)
Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation
eLife 11:e79348.
https://doi.org/10.7554/eLife.79348
  2. Download BibTeX
  3. Download .RIS

Abstract

Pleiotropy and genetic correlation are widespread features in GWAS, but they are often difficult to interpret at the molecular level. Here, we perform GWAS of 16 metabolites clustered at the intersection of amino acid catabolism, glycolysis, and ketone body metabolism in a subset of UK Biobank. We utilize the well-documented biochemistry jointly impacting these metabolites to analyze pleiotropic effects in the context of their pathways. Among the 213 lead GWAS hits, we find a strong enrichment for genes encoding pathway-relevant enzymes and transporters. We demonstrate that the effect directions of variants acting on biology between metabolite pairs often contrast with those of upstream or downstream variants as well as the polygenic background. Thus, we find that these outlier variants often reflect biology local to the traits. Finally, we explore the implications for interpreting disease GWAS, underscoring the potential of unifying biochemistry with dense metabolomics data to understand the molecular basis of pleiotropy in complex traits and diseases.

Data availability

The source data and analyzed data have been deposited in Dryad. Code are available at the github link (https://github.com/courtrun/Pleiotropy-of-UKB-Metabolites). The raw individual level data are available through application to UK Biobank.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Courtney J Smith

    Department of Genetics, Stanford University, Stanford, United States
    For correspondence
    courtrun@stanford.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7812-0083

  2. Nasa Sinnott-Armstrong

    Herbold Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    nasa@fredhutch.org
    Competing interests
    No competing interests declared.

  3. Anna Cichońska

    Nightingale Health Plc, Helsinki, Finland
    Competing interests
    Anna Cichońska, is a former employee and holds stock options with Nightingale Health Plc..

  4. Heli Julkunen

    Nightingale Health Plc, Helsinki, Finland
    Competing interests
    Heli Julkunen, is an employee and holds stock options with Nightingale Health Plc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4282-0248

  5. Eric B Fauman

    Internal Medicine Research Unit, Pfizer, Cambridge, United States
    Competing interests
    Eric B Fauman, is affiliated with Pfizer Worldwide Research, has no financial interests to declare, contributed as an individual and the work was not part of a Pfizer collaboration nor was it funded by Pfizer..

  6. Peter Würtz

    Nightingale Health Plc, Helsinki, Finland
    Competing interests
    Peter Würtz, is an employee and shareholder of Nightingale Health Plc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5832-0221

  7. Jonathan K Pritchard

    Departments of Genetics and Biology, Stanford University, Stanford, United States
    For correspondence
    pritch@stanford.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8828-5236

Funding

Stanford Knight-Hennessy Scholars Program (Graduate Student Fellowship)

  • Courtney J Smith

National Science Foundation (Graduate Student Fellowship)

  • Courtney J Smith

National Institute of Health (5R01HG011432 and 5R01AG066490)

  • Jonathan K Pritchard

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

Ethics

Human subjects: All participants provided written informed consent and ethical approval was obtained from the North West Multi-Center Research Ethics Committee (11/NW/0382). The current analysis was approved under UK Biobank Project 24983 and 30418.

Copyright

© 2022, Smith 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

  • 4,421
    views
  • 741
    downloads
  • 29
    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. Courtney J Smith
  2. Nasa Sinnott-Armstrong
  3. Anna Cichońska
  4. Heli Julkunen
  5. Eric B Fauman
  6. Peter Würtz
  7. Jonathan K Pritchard
(2022)
Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation
eLife 11:e79348.
https://doi.org/10.7554/eLife.79348

Share this article

https://doi.org/10.7554/eLife.79348

Categories and tags

Research organism

Further reading

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease

    Control of pili synthesis and putrescine homeostasis in Escherichia coli

    Iti Mehta, Jacob B Hogins ... Larry Reitzer
    Research Article

    Polyamines are biologically ubiquitous cations that bind to nucleic acids, ribosomes, and phospholipids and, thereby, modulate numerous processes, including surface motility in Escherichia coli. We characterized the metabolic pathways that contribute to polyamine-dependent control of surface motility in the commonly used strain W3110 and the transcriptome of a mutant lacking a putrescine synthetic pathway that was required for surface motility. Genetic analysis showed that surface motility required type 1 pili, the simultaneous presence of two independent putrescine anabolic pathways, and modulation by putrescine transport and catabolism. An immunological assay for FimA—the major pili subunit, reverse transcription quantitative PCR of fimA, and transmission electron microscopy confirmed that pili synthesis required putrescine. Comparative RNAseq analysis of a wild type and ΔspeB mutant which exhibits impaired pili synthesis showed that the latter had fewer transcripts for pili structural genes and for fimB which codes for the phase variation recombinase that orients the fim operon promoter in the ON phase, although loss of speB did not affect the promoter orientation. Results from the RNAseq analysis also suggested (a) changes in transcripts for several transcription factor genes that affect fim operon expression, (b) compensatory mechanisms for low putrescine which implies a putrescine homeostatic network, and (c) decreased transcripts of genes for oxidative energy metabolism and iron transport which a previous genetic analysis suggests may be sufficient to account for the pili defect in putrescine synthesis mutants. We conclude that pili synthesis requires putrescine and putrescine concentration is controlled by a complex homeostatic network that includes the genes of oxidative energy metabolism.

    1. Genetics and Genomics

    UBR-1 deficiency leads to ivermectin resistance in Caenorhabditis elegans

    Yi Li, Long Gong ... Shangbang Gao
    Research Article

    Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.

    1. Genetics and Genomics

    Dimeric R25CPTH(1–34) activates the parathyroid hormone-1 receptor in vitro and stimulates bone formation in osteoporotic female mice

    Minsoo Noh, Xiangguo Che ... Sihoon Lee
    Research Article

    Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.