Proteome-wide Mendelian randomization identifies plasma targets for white-matter hyperintensities in chronic cerebral hypoperfusion

Liu Xiaoyan; Yu Zhuoyuan; Yang Mei

doi:10.13406/j.cnki.cyxb.003998

您当前的位置：

首页 >

文章列表页 >

Proteome-wide Mendelian randomization identifies plasma targets for white-matter hyperintensities in chronic cerebral hypoperfusion

Frontiers in brain science and neuropsychiatric disorders | 更新时间：2026-02-13

- Proteome-wide Mendelian randomization identifies plasma targets for white-matter hyperintensities in chronic cerebral hypoperfusion
- Journal of Chongqing Medical University Vol. 51, Issue 1, Pages: 55-65(2026)
- 作者机构：
  
  1.重庆医科大学基础医学院神经科学研究中心，重庆 400016
  2.重庆医科大学附属第一医院泌尿外科，重庆 400016
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003998
  CLC： R743
- Received：28 October 2025，
  
  Revised：2025-10-29，
  
  Accepted：20 November 2025，
  
  Published：28 January 2026
- 稿件说明：
移动端阅览
刘小燕，余卓远，杨美.基于慢性脑灌注不足的蛋白质组孟德尔随机化研究揭示白质高信号的血浆靶点[J].重庆医科大学学报，2026，51（1）：55-65.

Liu Xiaoyan,Yu Zhuoyuan,Yang Mei.Proteome-wide Mendelian randomization identifies plasma targets for white-matter hyperintensities in chronic cerebral hypoperfusion[J].Journal of Chongqing Medical University,2026,51(1):55-65.
刘小燕，余卓远，杨美.基于慢性脑灌注不足的蛋白质组孟德尔随机化研究揭示白质高信号的血浆靶点[J].重庆医科大学学报，2026，51（1）：55-65. DOI： 10.13406/j.cnki.cyxb.003998.

Liu Xiaoyan,Yu Zhuoyuan,Yang Mei.Proteome-wide Mendelian randomization identifies plasma targets for white-matter hyperintensities in chronic cerebral hypoperfusion[J].Journal of Chongqing Medical University,2026,51(1):55-65. DOI： 10.13406/j.cnki.cyxb.003998.

摘要

目的

以白质高信号（white matter hyperintensities，WMH）作为人群层面的主要生物标志物，旨在利用人类遗传学证据筛选并确定与之相关的血浆蛋白。

方法

在欧洲人群队列中系统性筛选了血浆蛋白定量性状位点（quantitative trait loci，QTL）集，并对每个蛋白质进行了两样本孟德尔随机化（Mendelian randomization，MR）分析。主要结局指标为WMH（

=37 355）。在血管周围间隙（perivascular space，PVS；

=38 598）和腔隙性卒中（Lacunar stroke，LS；

=232 596）中进行了方向性验证。采用贝叶斯共定位分析评估位点共享性，错误发现率控制在0.05。细胞类型注释信息来源于包含34种细胞类型的人类脑单核转录组图谱。因果推断仅限于WMH；PVS和LS仅用于方向一致性检验。

结果

共有13种蛋白质在多重检验校正后仍与WMH相关。对其中4个具有顺式（cis）遗传证据的蛋白质进行了深入分析：ACOX1、ART4、MGP以及以LAMC1为锚点的层粘连蛋白测定组。作用方向分析表明，ART4增加WMH风险，而ACOX1、MGP和层粘连蛋白具有保护作用。贝叶斯共定位分析进一步支持ART4和MGP与WMH共享相同的因果变异，从而增强了二者关联的可信度；而ACOX1倾向于独立的遗传信号，层粘连蛋白的共享证据较弱。其余9个仅由反式（trans）信号驱动的蛋白质作为假设生成项予以保留。在PVS和LS中，这些蛋白质的作用方向与WMH一致，但效应有所减弱。

结论

通过蛋白组学MR筛选，结合共定位分析、跨终点一致性验证和细胞类型定位，将ART4和MGP确认为WMH的高置信度靶点。ACOX1和层粘连蛋白虽显示保护性MR关联，但共定位结果不一致或较弱，需后续进行更精细的定位与功能验证。

Abstract

Objective

Chronic cerebral hypoperfusion（CCH） is an upstream driver of cerebral small vessel disease，yet with a lack of druggable pathways and targets. With white matter hyperintensities（WMH） as the primary biomarker at the population level，this article aims to identify related plasma proteins based on human genetic evidence.

Methods

The full set of plasma protein quantitative trait loci was identified in the European cohort，and two-sample Mendelian randomization（MR） was performed for every protein. WMH was the primary outcome measure（

=37 355）. In addition，directional validation was performed in perivascular spaces（PVS）（

=38598） and lacunar stroke（LS）（

=232596）. Bayesian colocalization was used to assess locus sharing，and the false discovery rate was controlled at 0.05. Cell-type annotation data were collected from a 34-cell-type human brain single-nucleus transcriptome atlas. Causal inference was only performed for WMH，and PVS and LS were only used for directional validation.

Results

There were 13 proteins associated with WMH after multiple tests. In-depth analysis was performed for 4 proteins with cis-acting genetic evidence，i.e.，ACOX1，ART4，MGP，and the laminin assay group anchored at LAMC1. Directionality analysis showed that ART4 increased the risk of WMH，whereas ACOX1，MGP，and laminin had a protective effect. The Bayesian colocalization analysis further supported a shared causal variant between ART4/MGP and WMH，thereby strengthening the confidence for the association between ART4 and MGP，conversely，ACOX1 appeared to have an independent genetic signal，while laminin showed weaker evidence for sharing. The remaining 9 trans-signal-driven proteins were retained as hypothesis-generating candidates. In PVS and LS，the directional effects of these proteins aligned with those observed in WMH，albeit with attenuated magnitudes.

Conclusion

Proteome-wide MR screening，combined with colocalization analysis，cross-endpoint checks，and cell-type mapping，identifies ART4 and MGP as high-confidence targets for WMH under the CCH framework. Although ACOX1 and laminin show protective MR associations，their inconsistent or weak colocalization results require further fine mapping and functional validation.

关键词

Keywords

references

Rajeev V ， Chai YL ， Poh L ， et al . Chronic cerebral hypoperfusion：a critical feature in unravelling the etiology of vascular cognitive impairment [J ] . Acta Neuropathol Commun ， 2023 ， 11 （ 1 ）： 93 ．

Guo WJ ， Shi J . White matter hyperintensities volume and cognition：A meta-analysis [J ] . Front Aging Neurosci ， 2022 ， 14 ： 949763 ．

Davey Smith G ， Hemani G . Mendelian randomization：genetic anchors for causal inference in epidemiological studies [J ] . Hum Mol Genet ， 2014 ， 23 （ R1 ）： R89 - R98 ．

Daghlas I ， Gill D . Mendelian randomization as a tool to inform drug development using human genetics [J ] . Camb Prism Precis Med ， 2023 ， 1 ： e16 ．

Schmidt AF ， Finan C ， Gordillo-Marañón M ， et al . Genetic drug target validation using Mendelian randomisation [J ] . Nat Commun ， 2020 ， 11 （ 1 ）： 3255 ．

Zhao HL ， Rasheed H ， Nøst TH ， et al . Proteome-wide Mendelian randomization in global biobank meta-analysis reveals multi-ancestry drug targets for common diseases [J ] . Cell Genom ， 2022 ， 2 （ 11 ）： 100195 ．

Sun BB ， Maranville JC ， Peters JE ， et al . Genomic atlas of the human plasma proteome [J ] . Nature ， 2018 ， 558 （ 7708 ）： 73 - 79 ．

Eldjarn GH ， Ferkingstad E ， Lund SH ， et al . Large-scale plasma proteomics comparisons through genetics and disease associations [J ] . Nature ， 2023 ， 622 （ 7982 ）： 348 - 358 ．

Aschenbrenner AJ ， Li Y ， Henson RL ， et al . Comparison of plasma and CSF biomarkers in predicting cognitive decline [J ] . Ann Clin Transl Neurol ， 2022 ， 9 （ 11 ）： 1739 - 1751 ．

Dammer EB ， Ping LY ， Duong DM ， et al . Multi-platform proteomic analysis of Alzheimer’s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome [J ] . Alzheimers Res Ther ， 2022 ， 14 （ 1 ）： 174 ．

Debette S ， Caro I ， Western D ， et al . Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease [J ] . Res Sq ， 2024 ：rs. 3. rs-rs. 4535534．

Duperron MG ， Knol MJ ， Le Grand Q ， et al . Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease [J ] . Nat Med ， 2023 ， 29 （ 4 ）： 950 - 962 ．

Traylor M ， Persyn E ， Tomppo L ， et al . Genetic basis of lacunar stroke：a pooled analysis of individual patient data and genome-wide association studies [J ] . Lancet Neurol ， 2021 ， 20 （ 5 ）： 351 - 361 ．

Koohi F ， Harshfield EL ， Shatunov A ， et al . Does thrombosis play a causal role in lacunar stroke and cerebral small vessel disease? [J ] . Stroke ， 2024 ， 55 （ 4 ）： 934 - 942 ．

Yu Z ， Liu X ， Yang X ， et al . Identification of Potential Therapeutic Targets in Dupuytren’s Contracture Through Integrated Multi-Omics Analysis [EB/OL ] . Rochester，NY ： Social Science Research Network ， 2025 [ 2025-09-06 ] . https://papers.ssrn.com/abstract=5278478 https://papers.ssrn.com/abstract=5278478 .

Pietzner M ， Wheeler E ， Carrasco-Zanini J ， et al . Mapping the proteo-genomic convergence of human diseases [J ] . Science ， 2021 ， 374 （ 6569 ）： eabj1541 ．

Ferkingstad E ， Sulem P ， Atlason BA ， et al . Large-scale integration of the plasma proteome with genetics and disease [J ] . Nat Genet ， 2021 ， 53 （ 12 ）： 1712 - 1721 ．

Sun BB ， Chiou J ， Traylor M ， et al . Plasma proteomic associations with genetics and health in the UK Biobank [J ] . Nature ， 2023 ， 622 （ 7982 ）： 329 - 338 ．

Sun BB ， Chiou J ， Traylor M ， et al . Genetic regulation of the human plasma proteome in 54 ， 306 UK Biobank participants[EB/OL ] . bioRxiv ，2022： 2022 . 06 .17. 496443 [ 2025-07-18 ] . https://www.biorxiv.org/content/10.1101/2022.06.17.496443v1 https://www.biorxiv.org/content/10.1101/2022.06.17.496443v1 .

Suhre K ， Arnold M ， Bhagwat AM ， et al . Connecting genetic risk to disease end points through the human blood plasma proteome [J ] . Nat Commun ， 2017 ， 8 ： 14357 ．

Folkersen L ， Gustafsson S ， Wang Q ， et al . Genomic and drug target evaluation of 90 cardiovascular proteins in 30，931 individuals [J ] . Nat Metab ， 2020 ， 2 （ 10 ）： 1135 - 1148 ．

Yao C ， Chen G ， Song C ， et al . Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease [J ] . Nat Commun ， 2018 ， 9 （ 1 ）： 3268 ．

Hemani G ， Zheng J ， Elsworth B ， et al . The MR-Base platform supports systematic causal inference across the human phenome [J ] . Elife ， 2018 ， 7 ： e34408 ．

Burgess S ， Butterworth A ， Thompson SG . Mendelian randomization analysis with multiple genetic variants using summarized data [J ] . Genet Epidemiol ， 2013 ， 37 （ 7 ）： 658 - 665 ．

Bowden J ， Del Greco M F ， Minelli C ， et al . Improving the accuracy of two-sample summary-data Mendelian randomization：moving beyond the NOME assumption [J ] . Int J Epidemiol ， 2019 ， 48 （ 3 ）： 728 - 742 ．

Bowden J ， Davey Smith G ， Haycock PC ， et al . Consistent estimation in mendelian randomization with some invalid instruments using a weighted Median estimator [J ] . Genet Epidemiol ， 2016 ， 40 （ 4 ）： 304 - 314 ．

Benjamini Y ， Hochberg Y . Controlling the false discovery rate：a practical and powerful approach to multiple testing [J ] . J R Stat Soc Ser B Methodol ， 1995 ， 57 （ 1 ）： 289 - 300 ．

Giambartolomei C ， Vukcevic D ， Schadt EE ， et al . Bayesian test for colocalisation between pairs of genetic association studies using summary statistics [J ] . PLoS Genet ， 2014 ， 10 （ 5 ）： e1004383 ．

1000 Genomes Project Consortium ; Auton A ， Brooks LD ， et al . A global reference for human genetic variation [J ] . Nature ， 2015 ， 526 ( 7571 )： 68 - 74 .

Berger J ， Dorninger F ， Forss-Petter S ， et al . Peroxisomes in brain development and function [J ] . Biochim Biophys Acta ， 2016 ， 1863 （ 5 ）： 934 - 955 ．

Kassmann CM . Myelin peroxisomes–Essential organelles for the maintenance of white matter in the nervous system [J ] . Biochimie ， 2014 ， 98 ： 111 - 118 ．

Yao YC ， Shahbazian A ， Boström KI . Proline and gamma-carboxylated glutamate residues in matrix Gla protein are critical for binding of bone morphogenetic protein-4 [J ] . Circ Res ， 2008 ， 102 （ 9 ）： 1065 - 1074 ．

Xu LL ， Nirwane A ， Yao Y . Basement membrane and blood-brain barrier [J ] . Stroke Vasc Neurol ， 2018 ， 4 （ 2 ）： 78 - 82 ．

Shibata M ， Ohtani R ， Ihara M ， et al . White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion [J ] . Stroke ， 2004 ， 35 （ 11 ）： 2598 - 2603 ．

Kakae M ， Kawashita A ， Onogi H ， et al . Bilateral common carotid artery stenosis in mice：a model of chronic cerebral hypoperfusion-induced vascular cognitive impairment [J ] . Bio Protoc ， 2024 ， 14 （ 13 ）： e5022 ．

Xu WQ ， Bai QK ， Dong Q ， et al . Blood-brain barrier dysfunction and the potential mechanisms in chronic cerebral hypoperfusion induced cognitive impairment [J ] . Front Cell Neurosci ， 2022 ， 16 ： 870674 ．

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Research advances in the treatment of cerebral small vessel disease with anti-platelet aggregation drugs

Advances in the treatment of non-arteriosclerotic cerebral small vessel disease

Causality between nasal diseases and COPD: a two-sample Mendelian randomization analysis

Correlation of serum thyroxine and Apelin with cognitive impairment in patients with cerebral small vessel disease

Related Author

Liu Jianhui

Huang Li

Zhang Pengju

Fan Kuan

Tian Yu

Hu Xiao

Yang Hui

Xu Zucai

Related Institution

Department of Neurology，Affiliated Hospital of Zunyi Medical University

Department of Neurology， Guizhou Provincial People’s Hospital

Department of Neurology， The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine

Department of Neurology，Huashan Hospital，Fudan University

School of Traditional Chinese Medicine， Anhui University of Chinese Medicine

⁰