载脂蛋白A-IV浓度的遗传结构和跨平台验证
Genetic architecture and cross-platform validation of apolipoprotein A-IV concentrations.
摘要(中文译文)
载脂蛋白A-IV（apoA-IV）在脂质代谢、逆向胆固醇转运和肾功能中发挥关键作用，但其遗传决定因素仍不明确。我们对25,181名个体中通过ELISA测定的apoA-IV浓度进行了全基因组关联研究（GWAS）荟萃分析，并将其与33,995名英国生物银行参与者（Olink平台）的蛋白质组学数据相结合，总样本量为59,176人。我们进行了遗传相关性和共定位分析，以探索其与脂质、肾脏及其他复杂性状的关联。该GWAS除鉴定出两个先前已知的位点（APOA5-A4-C3-A1基因簇和KLKB1）外，还鉴定出多个与apoA-IV浓度相关的新位点（TDRD5、DPP4、MYL3、MORC1、MCUB、GATA4、ZPR1、UMOD、GLP2R、SLC38A10和APOE）。跨平台比较显示效应方向和幅度高度一致，凸显了研究结果在不同测量技术间的稳健性。全局遗传相关性揭示了apoA-IV、肾功能与高密度脂蛋白胆固醇之间存在显著的共享遗传结构，而共定位分析支持其与脂质、肾脏及血液学表型存在共享因果变异，提示存在具有生物学相关性的通路。这些结果全面概述了apoA-IV的遗传结构，并提示其与脂质代谢、肾功能及血液相关性状之间的机制联系。我们的发现进一步明确了apoA-IV作为潜在生物标志物的作用，并为未来的流行病学研究提供了依据。
Abstract
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. 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. 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.
如何引用
AMA
Adriana Koller, Florian Schnitzer, Barbara Kollerits, Claudia Lamina, Samuel Moix, Annique Claringbould, et al. Genetic architecture and cross-platform validation of apolipoprotein A-IV concentrations.. Genome biology. 2026; doi:10.1186/s13059-026-04196-7.
APA
Adriana Koller, Florian Schnitzer, Barbara Kollerits, Claudia Lamina, Samuel Moix, Annique Claringbould, et al (2026). Genetic architecture and cross-platform validation of apolipoprotein A-IV concentrations.. Genome biology. https://doi.org/10.1186/s13059-026-04196-7
GB/T 7714
Adriana Koller, Florian Schnitzer, Barbara Kollerits, Claudia Lamina, Samuel Moix, Annique Claringbould, et al. Genetic architecture and cross-platform validation of apolipoprotein A-IV concentrations.[J]. Genome biology, 2026 doi:10.1186/s13059-026-04196-7.
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