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Whole-Genome Sequencing and Single-Cell Transcriptomics Identify Human Leukocyte Antigen Loci and a COG5 Variant in
Jinran Lin1,2, Shishi Wu1,2, Chenhao Lin1,3
1State Key Laboratory of Genetics and Development of Complex Phenotypes, Center for Evolutionary Biology, and School of Life Sciences Human Phenome Institute, Fudan University Shanghai China.
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.