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Cited by 43Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenomics and Chromatin Dynamics

Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance

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Wang, Qingbo S., Hasegawa, Takanori, Namkoong, Ho, Saiki, Ryunosuke, Edahiro, Ryuya, Sonehara, Kyuto, Tanaka, Hiromu, Azekawa, Shuhei +24 more·2024·Nature Genetics
DOI 10.1038/s41588-024-01896-3PMC PMC11525184
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Abstract

Studying the genetic regulation of protein expression (through protein quantitative trait loci (pQTLs)) offers a deeper understanding of regulatory variants uncharacterized by mRNA expression regulation (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood mRNA and 2,932 plasma samples of protein expression, as part of the Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 variants validated with a massively parallel reporter assay. Fine-mapped pQTLs (n = 582) were enriched for missense variations on structured and extracellular domains, although the possibility of epitope-binding artifacts remains. Trans-eQTL and trans-pQTL analysis highlighted associations of class I HLA allele variation with KIR genes. We contrast the multi-tissue origin of plasma protein with blood mRNA, contributing to the limited colocalization level, distinct regulatory mechanisms and trait relevance of eQTLs and pQTLs. We report a negative correlation between ABO mRNA and protein expression because of linkage disequilibrium between distinct nearby eQTLs and pQTLs.

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  • Existing affinity-based proteomics studies exploring trans-pQTL often interpret pleiotropic trans-pQTL as biologically relevant signals, which may help confirm appropriate assay performance.

    “Existing affinity-based proteomics studies exploring trans-pQTL often interpret pleiotropic trans-pQTL as biologically relevant signals, which may help confirm appropriate assay performance36,37.”

    From Cross-ancestry comparison of aptamer and antibody protein measures (2026) · cites this paper as [36]

    In Results, ‘Characterizing the trans-pQTL effects’ (page unavailable), the paper reports a trans-pQTL hotspot at ABO and interprets HLA trans associations through a known molecular interaction. It says the trans-pQTL test-statistic distribution validates its analysis strategy, but does not say that pleiotropic trans-pQTLs confirm appropriate affinity-assay performance or that existing studies often use them for that purpose. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • pQTLs may provide greater power than eQTLs to map causal genes for complex traits.

    “Therefore, pQTLs may provide greater power than eQTLs to map causal genes for complex traits (8)”

    From Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease (2026) · cites this paper as [8]

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References 69 · Cited by 43

Research works printed but not linked: 55

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Authors
Wang, Q. S., Hasegawa, T., Namkoong, H., Saiki, R., Edahiro, R., Sonehara, K., Tanaka, H., Azekawa, S., Chubachi, S., Takahashi, Y., Sakaue, S., Namba, S., Yamamoto, K., Shiraishi, Y., Chiba, K., Tanaka, H., Makishima, H., Nannya, Y., Zhang, Z., Tsujikawa, R., Koike, R., Takano, T., Ishii, M., Kimura, A., Inoue, F., Kanai, T., Fukunaga, K., Ogawa, S., Imoto, S., Miyano, S., Okada, Y., & Japan COVID-19 Task Force
Affiliations
  • The University of Tokyo (JP)
  • Tokyo Medical and Dental University (JP)
  • Keio University (JP)
  • Kyoto University (JP)
  • The University of Osaka (JP)
  • Broad Institute (US)
  • National Cancer Center Research Institute (JP)
  • Kitasato University (JP)
  • Nagoya University (JP)
  • Institute of Medical Science, The University of Tokyo (JP)
  • RIKEN Center for Integrative Medical Sciences (JP)
Corresponding author
  • Wang, Qingbo S.
  • Namkoong, Ho
  • Okada, Yukinori
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2024-09-24
Volume
56
Issue
10
Pages
2054-2067
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-024-01896-3
PMC
PMC11525184
OpenAlex
W4402769478
Cited by
43
References
69
Citations by year
2026: 27 · 2025: 14 · 2024: 1 · 2023: 1
FWCI
11.15
Type
journal article
Language
en
Update notices
correction (2024-09-27)
Open access
Licence
Locations
  • Nature Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (24K02004, 23K19564, 23K14451, 22H00476)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
expression quantitative trait loci, protein quantitative trait loci, blood transcriptome, plasma protein expression, cis-eQTL, trans-eQTL, cis-pQTL, massively parallel reporter assay, missense mutations, epitope binding, HLA, KIR genes, ABO blood group system, linkage disequilibrium, gene expression regulation, COVID-19 pandemic
MeSH terms
COVID-19, SARS-CoV-2, Alleles, Chromosome Mapping, Gene Expression Regulation, Genotype, Humans, RNA, Messenger, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study

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