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Peer-reviewedCC BY-NC-NDJournal of the American Heart Association

Whole‐Genome Sequencing and Single‐Cell Transcriptomics Identify Human Leukocyte Antigen Loci and a COG5 Variant in Aortic Dissection

  • Jinran Lin1,2
  • Shishi Wu1,2
  • Chenhao Lin1,3
  • Shilin Jin1,2
  • Lu Chen1
  • Jingchun Luo1
  • Shuhua Xu1
  • Li Jin1
  • Mengyao Yu1,4
  • Yan Zheng1,2,5
  • Yi Si5,6,7
7 affiliations
  1. 1Human Phenome Institute, Fudan University
  2. 2Fudan University
  3. 3Fujian Agriculture and Forestry University
  4. 4Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Fudan University
  5. 5Zhongshan Hospital, Fudan University
  6. 6Institute of Vascular Surgery, Fudan University
  7. 7National Clinical Research Center for Interventional Medicine
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Abstract

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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Cite

BibTeXRIS
BibTeX
@article{lin2026wholegenome,
  title = {{Whole‐Genome Sequencing and Single‐Cell Transcriptomics Identify Human Leukocyte Antigen Loci and a COG5 Variant in Aortic Dissection}},
  author = {Jinran Lin and Shishi Wu and Chenhao Lin and Shilin Jin and Lu Chen and Jingchun Luo and Shuhua Xu and Li Jin and Mengyao Yu and Yan Zheng and Yi Si},
  journal = {Journal of the American Heart Association},
  year = {2026},
  month = oct,
  doi = {10.1161/jaha.126.050327},
  url = {https://www.ahajournals.org/doi/10.1161/JAHA.126.050327},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Whole‐Genome Sequencing and Single‐Cell Transcriptomics Identify Human Leukocyte Antigen Loci and a COG5 Variant in Aortic Dissection
AU  - Jinran Lin
AU  - Shishi Wu
AU  - Chenhao Lin
AU  - Shilin Jin
AU  - Lu Chen
AU  - Jingchun Luo
AU  - Shuhua Xu
AU  - Li Jin
AU  - Mengyao Yu
AU  - Yan Zheng
AU  - Yi Si
PY  - 2026
DA  - 2026/10/20
JO  - Journal of the American Heart Association
DO  - 10.1161/jaha.126.050327
UR  - https://www.ahajournals.org/doi/10.1161/JAHA.126.050327
AB  - 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.
SN  - 2047-9980
ER  -