A latent genetic factor underlies multiple component phenotypes of cerebral small vessel disease.
- 1The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, China.
- 2Hunan Biological and Electromechanical Polytechnic, Changsha, Hunan, 410127, China. [email protected].
- 3The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, China. [email protected].
Abstract
Background
Cerebral small vessel disease (cSVD) encompasses white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), intracerebral hemorrhage (ICH), small vessel stroke (SVS), and cognitive impairment-phenotypes that frequently co-occur yet have been studied as independent genetic endpoints. Whether a shared genetic architecture underlies these co-occurring cSVD-related phenotypes remains unclear.Methods
We applied Genomic SEM to GWAS summary statistics from six phenotypes (WMH, PVS, ICH, SVS, cognitive performance, systolic blood pressure), followed by multivariate association scanning, Bayesian fine-mapping (SuSiE/FINEMAP), gene-level (MAGMA) and transcriptome-wide (sCCA-TWAS/FOCUS) analyses, pathway enrichment, cell-type specificity (CELLECT) and spatial developmental mapping (gsMap).Results
A common-factor model fit the data well (CFI = 1.00, SRMR = 0.061). The multivariate scan identified 1,423 genome-wide significant SNPs, resolving into 20 independent lead SNPs mapped to 14 distinct genomic loci, of which 2 were not detected at genome-wide significance in any constituent single-trait GWAS. Fine-mapping prioritized three high-confidence causal variants at EFEMP1, ICOSLG, and AC098824.6. Gene-level and transcriptome-wide analyses converged on effector genes at 17q25.1 (TRIM47/TRIM65), 10q24.33 (SH3PXD2A), and 2q33.1 (NBEAL1). MAGMA additionally identified APOE at 19q13.32. Pathway analysis highlighted epigenetic dysregulation, cellular senescence, and amyloid fiber formation. CELLECT identified vascular endothelial cells and pericytes as enriched cell types. gsMap revealed developmental enrichment in lung, kidney, and meninges exceeding brain tissue.Conclusions
These findings delineate a coherent latent genetic structure linking multiple cSVD-related phenotypes, rooted in vascular wall cell biology, epigenetic regulation, and cellular senescence, with developmental origins spanning multiple organ microvascular beds.
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BibTeX
@article{zeng2026latent,
title = {{A latent genetic factor underlies multiple component phenotypes of cerebral small vessel disease.}},
author = {Yan Zeng and Xiaoqian Huang and Yubiao Yang and Chun Guo},
journal = {BMC neuroscience},
year = {2026},
month = jul,
doi = {10.1186/s12868-026-01031-4},
url = {https://europepmc.org/article/MED/42907737},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A latent genetic factor underlies multiple component phenotypes of cerebral small vessel disease.
AU - Yan Zeng
AU - Xiaoqian Huang
AU - Yubiao Yang
AU - Chun Guo
PY - 2026
DA - 2026/07/01
JO - BMC neuroscience
DO - 10.1186/s12868-026-01031-4
UR - https://europepmc.org/article/MED/42907737
AB - Background Cerebral small vessel disease (cSVD) encompasses white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), intracerebral hemorrhage (ICH), small vessel stroke (SVS), and cognitive impairment-phenotypes that frequently co-occur yet have been studied as independent genetic endpoints. Whether a shared genetic architecture underlies these co-occurring cSVD-related phenotypes remains unclear.Methods We applied Genomic SEM to GWAS summary statistics from six phenotypes (WMH, PVS, ICH, SVS, cognitive performance, systolic blood pressure), followed by multivariate association scanning, Bayesian fine-mapping (SuSiE/FINEMAP), gene-level (MAGMA) and transcriptome-wide (sCCA-TWAS/FOCUS) analyses, pathway enrichment, cell-type specificity (CELLECT) and spatial developmental mapping (gsMap).Results A common-factor model fit the data well (CFI = 1.00, SRMR = 0.061). The multivariate scan identified 1,423 genome-wide significant SNPs, resolving into 20 independent lead SNPs mapped to 14 distinct genomic loci, of which 2 were not detected at genome-wide significance in any constituent single-trait GWAS. Fine-mapping prioritized three high-confidence causal variants at EFEMP1, ICOSLG, and AC098824.6. Gene-level and transcriptome-wide analyses converged on effector genes at 17q25.1 (TRIM47/TRIM65), 10q24.33 (SH3PXD2A), and 2q33.1 (NBEAL1). MAGMA additionally identified APOE at 19q13.32. Pathway analysis highlighted epigenetic dysregulation, cellular senescence, and amyloid fiber formation. CELLECT identified vascular endothelial cells and pericytes as enriched cell types. gsMap revealed developmental enrichment in lung, kidney, and meninges exceeding brain tissue.Conclusions These findings delineate a coherent latent genetic structure linking multiple cSVD-related phenotypes, rooted in vascular wall cell biology, epigenetic regulation, and cellular senescence, with developmental origins spanning multiple organ microvascular beds.
SN - 1471-2202
ER -