Whole‐Genome Sequencing and Single‐Cell Transcriptomics Identify Human Leukocyte Antigen Loci and a COG5 Variant in Aortic Dissection
Open accessAbstract
Background: Aortic dissection (AD) is a lethal cardiovascular emergency with a complex and underexplored genetic basis. Methods: We performed whole‐genome sequencing on 151 patients with sporadic Stanford type B AD and 965 healthy controls in a Chinese population as a discovery phase analysis to assess both common and rare variants. Cross‐ancestry meta‐analyses incorporating 4 external genome‐wide association data sets were used to identify population‐specific risk loci. To pinpoint functional candidates, we integrated epigenomic profiles and single‐cell transcriptomes from human aortic tissues. Results: Whole‐genome sequencing analysis identified 21 candidate common loci and 2 low‐frequency variants associated with AD in this discovery cohort. Two candidate common variants in the human leukocyte antigen region (rs9260945 near HLA‐A and rs9276409 within HLA‐DQA2 ) showed strong associations and colocalized with regulatory elements in aortic and immune cells, indicating immune‐mediated vascular pathology. A low‐frequency missense variant in the COG5 gene (rs1203229795, effect allele frequency=0.019) emerged as an independent AD risk factor, likely affecting extracellular matrix glycosylation. Single‐cell transcriptomic analysis of AD‐associated variants in human aortic tissues demonstrated enhanced interactions among fibroblasts, vascular smooth muscle cells, and macrophages, supporting their roles in AD pathogenesis. Integrated gene‐based and expression analyses further highlighted TPM4 , a marker of vascular smooth muscle cell dedifferentiation, as a putative susceptibility gene in AD. Conclusions: This multiomics investigation expands the genetic landscape of sporadic AD in Chinese individuals, revealing immune‐related human leukocyte antigen loci and a functionally supported candidate COG5 variant. Our findings offer new insights into AD pathogenesis and identify candidate targets for future diagnostic and therapeutic strategies.
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Flagged first, then by citations
- Authors
- Lin, J., Wu, S., Lin, C., Jin, S., Chen, L., Luo, J., Xu, S., Jin, L., Yu, M., Zheng, Y., & Si, Y.
- Affiliations
- Fudan University (CN)
- Human Phenome Institute, Fudan University
- Corresponding author
- Yu, Mengyao
- Zheng, Yan
- Si, Yi
- Venue
- Journal of the American Heart Association
- Published
- 2026-10-20
- Volume
- 15
- Issue
- 20
- Pages
- e050327-e050327
- ISSN
- 2047-9980 (ISSN-L)
- OpenAlex
- W7221360411
- Cited by
- 0
- References
- 82
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Aortic Disease and Treatment Approaches
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- aortic dissection, type B aortic dissection, genetic susceptibility, HLA-A, HLA-DQA2, vascular smooth muscle cell dedifferentiation, TPM4, macrophage-fibroblast interaction, regulatory elements, Chinese population
- MeSH terms
- Whole Genome Sequencing, Single-Cell Gene Expression Analysis, Dissection, Thoracic Aorta, Adult, Aortic Dissection, China, Female, HLA Antigens, Humans, Male, Middle Aged, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression Profiling, Genome-Wide Association Study, Single-Cell Analysis, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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