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Cited by 22Genetic Associations and EpidemiologyGenomics and Rare DiseasesMetabolomics and Mass Spectrometry Studies

Effects of protein-coding variants on blood metabolite measurements and clinical biomarkers in the UK Biobank

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Nag, Abhishek, Dhindsa, Ryan S., Middleton, Lawrence, Jiang, Xiao, Vitsios, Dimitrios, Wigmore, Eleanor, Allman, Erik L., Reznichenko, Anna +7 more·2023·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2023.02.002PMC PMC10027475
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Abstract

Genome-wide association studies (GWASs) have established the contribution of common and low-frequency variants to metabolic blood measurements in the UK Biobank (UKB). To complement existing GWAS findings, we assessed the contribution of rare protein-coding variants in relation to 355 metabolic blood measurements—including 325 predominantly lipid-related nuclear magnetic resonance (NMR)-derived blood metabolite measurements (Nightingale Health Plc) and 30 clinical blood biomarkers—using 412,393 exome sequences from four genetically diverse ancestries in the UKB. Gene-level collapsing analyses were conducted to evaluate a diverse range of rare-variant architectures for the metabolic blood measurements. Altogether, we identified significant associations (p < 1 × 10 −8 ) for 205 distinct genes that involved 1,968 significant relationships for the Nightingale blood metabolite measurements and 331 for the clinical blood biomarkers. These include associations for rare non-synonymous variants in PLIN1 and CREB3L3 with lipid metabolite measurements and SYT7 with creatinine, among others, which may not only provide insights into novel biology but also deepen our understanding of established disease mechanisms. Of the study-wide significant clinical biomarker associations, 40% were not previously detected on analyzing coding variants in a GWAS in the same cohort, reinforcing the importance of studying rare variation to fully understand the genetic architecture of metabolic blood measurements.

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  • 13 of the 14 cis-CDS pQTLs (93%) in five Olink proteins independently measured via immunoturbidimetric assays replicated in the biomarker ExWAS (P ≤ 1 × 10−8), with effect sizes showing complete directional concordance.

    “In total, 13 of the 14 cis-CDS pQTLs (93%) replicated in the biomarker ExWAS (P ≤ 1 × 10−8), with effect sizes showing complete directional concordance (Supplementary Table 6).”

    From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [17]

    The Material and methods section specifies a p < 1 × 10−8 threshold for ExWAS, but that does not establish the claimed replication result. Searches for Olink, cis-CDS pQTLs, immunoturbidimetric assays, 13 of 14 replications, and directional concordance found no passage in our copy reporting those findings. The indexed passages provide section labels but no page numbers. (LLM, conf=0.72)

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Authors
Nag, A., Dhindsa, R. S., Middleton, L., Jiang, X., Vitsios, D., Wigmore, E., Allman, E. L., Reznichenko, A., Carss, K., Smith, K. R., Wang, Q., Challis, B., Paul, D. S., Harper, A. R., & Petrovski, S.
Affiliations
  • AstraZeneca (United Kingdom) (GB)
  • Baylor College of Medicine (US)
  • AstraZeneca (Sweden) (SE)
  • AstraZeneca (United States) (US)
Corresponding author
Petrovski, Slavé
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2023-03
Volume
110
Issue
3
Pages
487-498
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2023.02.002
PMC
PMC10027475
OpenAlex
W4321370552
Cited by
22
References
3
Citations by year
2026: 7 · 2025: 8 · 2024: 5 · 2023: 2
FWCI
3.49
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • Bristol-Myers Squibb
  • Pfizer
  • AstraZeneca
  • Biogen
  • Alnylam Pharmaceuticals
  • Regeneron Pharmaceuticals
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
protein-coding variants, blood metabolites, clinical biomarkers, lipid metabolism, creatinine, PLIN1, CREB3L3, synaptotagmin 7, UK Biobank
MeSH terms
United Kingdom, Humans, Lipids, Biomarkers, Biological Specimen Banks, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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