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Background <p>Apolipoprotein A-IV (apoA-IV) plays key roles in lipid metabolism, reverse cholesterol transport, and kidney function, yet its genetic determinants remain poorly defined. We conduct a genome-wide association study (GWAS) meta-analysis of apoA-IV concentrations measured by ELISA in 25,181 individuals and combine these with proteomic data from 33,995 UK Biobank participants (Olink platform), yielding a total sample of 59,176. We perform genetic correlations and colocalization analyses to explore links with lipid, renal, and other complex traits.</p> Results <p>The GWAS identifies several novel loci to be associated with apoA-IV concentrations (<i>TDRD5</i>, <i>DPP4</i>, <i>MYL3</i>, <i>MORC1</i>, <i>MCUB</i>, <i>GATA4</i>, <i>ZPR1</i>, <i>UMOD</i>, G<i>LP2R</i>, <i>SLC38A10</i> and <i>APOE</i>) besides two previously identified loci (<i>APOA5-A4-C3-A1</i> cluster and <i>KLKB1</i>). Cross-platform comparison shows strong concordance of effect directions and magnitudes, underscoring the robustness of findings across measurement techniques. Global genetic correlation reveals significant shared genetic architecture between apoA-IV, kidney function and HDL-cholesterol, while colocalization supports shared causal variants with lipid, renal, and hematological phenotypes, suggesting biologically relevant pathways.</p> Conclusion <p>These results provide a comprehensive overview of the genetic architecture of apoA-IV and suggest mechanistic links to lipid metabolism, kidney function and blood-related traits. Our findings refine the role of apoA-IV as a potential biomarker and inform future epidemiological research.</p>

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Genetic architecture and cross-platform validation of apolipoprotein A-IV concentrations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Adriana Koller,
  • Florian Schnitzer,
  • Barbara Kollerits,
  • Claudia Lamina,
  • Samuel Moix,
  • Annique Claringbould,
  • Binisha H. Mishra,
  • Haojie Lu,
  • Johanna F. Schachtl-Riess,
  • Lukas Forer,
  • Christian Gieger,
  • Azin Kheirkhah,
  • Terho Lehtimäki,
  • Pedro Marques-Vidal,
  • Sebastian Schönherr,
  • Klaus J. Stark,
  • Reinhard Würzner,
  • Kai-Uwe Eckardt,
  • Iris M. Heid,
  • Maryam Kavousi,
  • Anna Köttgen,
  • Olli Raitakari,
  • Eric J. G. Sijbrands,
  • Annette Peters,
  • Peter Vollenweider,
  • Florian Kronenberg

摘要

Background

Apolipoprotein A-IV (apoA-IV) plays key roles in lipid metabolism, reverse cholesterol transport, and kidney function, yet its genetic determinants remain poorly defined. We conduct a genome-wide association study (GWAS) meta-analysis of apoA-IV concentrations measured by ELISA in 25,181 individuals and combine these with proteomic data from 33,995 UK Biobank participants (Olink platform), yielding a total sample of 59,176. We perform genetic correlations and colocalization analyses to explore links with lipid, renal, and other complex traits.

Results

The GWAS identifies several novel loci to be associated with apoA-IV concentrations (TDRD5, DPP4, MYL3, MORC1, MCUB, GATA4, ZPR1, UMOD, GLP2R, SLC38A10 and APOE) besides two previously identified loci (APOA5-A4-C3-A1 cluster and KLKB1). Cross-platform comparison shows strong concordance of effect directions and magnitudes, underscoring the robustness of findings across measurement techniques. Global genetic correlation reveals significant shared genetic architecture between apoA-IV, kidney function and HDL-cholesterol, while colocalization supports shared causal variants with lipid, renal, and hematological phenotypes, suggesting biologically relevant pathways.

Conclusion

These results provide a comprehensive overview of the genetic architecture of apoA-IV and suggest mechanistic links to lipid metabolism, kidney function and blood-related traits. Our findings refine the role of apoA-IV as a potential biomarker and inform future epidemiological research.