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

Abstract
Data availability
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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

(2022) Pleiotropy of UK Biobank Metabolites [preliminary]
Dryad Digital Repository, doi:10.5061/dryad.79cnp5hxs.

https://dx.doi.org/10.5061/dryad.79cnp5hxs

The following previously published data sets were used

1. Bycroft et al.
(2018) The UK Biobank resource with deep phenotyping and genomic data
UK Biobank http://www.ukbiobank.ac.uk/register-apply/.

https://www.nature.com/articles/s41586-018-0579-z

Article and author information

Author details

Courtney J Smith

Department of Genetics, Stanford University, Stanford, United States

For correspondence
courtrun@stanford.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-7812-0083
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.
Anna Cichońska

Nightingale Health Plc, Helsinki, Finland

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

Nightingale Health Plc, Helsinki, Finland

Competing interests
Heli Julkunen, is an employee and holds stock options with Nightingale Health Plc..

"This ORCID iD identifies the author of this article:" 0000-0002-4282-0248
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..
Peter Würtz

Nightingale Health Plc, Helsinki, Finland

Competing interests
Peter Würtz, is an employee and shareholder of Nightingale Health Plc..

"This ORCID iD identifies the author of this article:" 0000-0002-5832-0221
Jonathan K Pritchard

Departments of Genetics and Biology, Stanford University, Stanford, United States

For correspondence
pritch@stanford.edu

Competing interests
No competing interests declared.

"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

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.