Thoracic aortic aneurysm and dissection (TAAD) is a category of aortopathy which includes aortic dilatation, aortic aneurysm or aortic dissection in thoracic aorta. Thoracic aortic aneurysm progressively enlarges over time and might cause spontaneously rupture or dissection, usually need emergent surgical repair or even lead to sudden cardiac death. Several factors are related to the development and progression of TAAD including genetic diseases, inflammatory conditions and factors that increased the aortic wall stress. About 20% of people with TAAD show a familial pattern of inheritance that follows an autosomal dominant trait. Identification of the pathogenic loci of heritable thoracic aortic disease (HTAD) is important because early screening of aortic aneurysm with prophylactic surgery could prevent the development of dissection. However, comprehensive research exploring the association between genetic variations and TAAD using Genome-wide association study (GWAS) in the Taiwanese population is limited. Identifying pathogenic loci associated with TAAD is crucial for initiating genetics-based management strategies, including regular monitoring and preventive surgery for carriers. Consequently, there is an urgent need to explore the genetic characteristics linked to TAAD in Taiwanese populations. This study aims to fill the existing knowledge gap by performing a comprehensive hospital-based GWAS. This study utilized data from China Medical University Hospital (CMUH) and its affiliated branches, collected via a unified system encompassing nearly 19 years of electronic medical records.

  Patients with TAD were selected from the China Medical University Hospital (CMUH) genetic biobank based on ICD 9/10 diagnostic codes of thoracic aortic aneurysm and thoracic aortic dissection. The CMUH biobank is a single center based genomic and precision medicine biobank. The genotyping process utilized a TPMv1 array plate (Thermo Fisher Scientific, Santa Clara, CA, USA) designed by the Taiwan Precision Medicine Initiative (TPMI) project, incorporating 714,461 probes. Because epidemiologic risk factors also contributed to the development of TAD, only patients younger than forty years were enrolled to emphasize the relationship between genetics and TAD. Only Han-Taiwanese population was included. Indigenous Taiwanese and New Immigrants were excluded to limit the genetic variation between populations.Controls were randomly selected from individuals without TAD, matched by gender, at a 10:1 ratio. We conducted a two steps GWAS. In first step, we analysis the genetic association of  TAD in Han-Taiwanese population but the result was inconclusive. Therefore, we restricted to test those genes published to be associated with TAD in the second step. According to current AHA guidelines and another review article, we identified 33 genes and checked the odd ratios and p-values. 

  A total of 1,154 individuals with ICD-9/10 of TAAD was identified. After restricting the age limit to individuals under 40 years, a total of 91 patients remained. The gender-matched control group was randomly selected from the entire group and 910 patients were identified. In the first step, 32 genes were identified suggestive significant (p < 1 × 10−6) but only WDR36 and PPP4R1 exceed genome-wide significance (p < 5 × 10−8). However, after checking ClinVar, GeneCards and GWAS catalog, these two genes showed less association with TAAD. In the second step, 3 genes with 7 different SNPs were found to be significant, including COL5A2、PRKG1 and SMAD4. Details of the second step were listed in Table 3. SNPs in COL5A2 demonstrated particularly high odds ratios, including rs1195959339 (OR: 62.16; 95% CI: 5.98–646.28, P=5.5X10-4), rs994493314 (OR: 57.3; 95% CI: 5.68–577.85, P=6.0X10-4), rs140578777 (OR: 6.22; 95% CI: 2.60–14.91, P=4.1X10-5), and rs141075174 (OR: 8.25; 95% CI: 3.01–22.63, P=4.1X10-5). Additionally, a SNP in PRKG1 (rs375518580) showed a strong association (OR: 12.35; 95% CI: 3.32–45.97, P=1.8X10-4). SNPs in SMAD4 were also significantly linked to TAAD, including rs1006794099 (OR: 11.3; 95% CI: 2.79–45.40, P=8.6X10-4) and rs1054669161 (OR: 7.22; 95% CI: 2.26–23.11 P=6.7X10-4). The forest spot of SNPs association was shown in Figure 3. Among those SNPs, the minor allele frequency (MAF) of rs994493314, rs1195959339, rs375518580, rs1054669161 and rs1006794099 were lower than 1% but almost undetectable in global and Ease Asia population. 

This study presents the largest GWAS-based genetic analysis of TAAD in the Han-Taiwanese population to date, identifying population-specific SNPs and highlighting WDR36 and PPP4R1 as potential novel susceptibility genes. These findings emphasize the importance of investigating ethnicity-specific genetic risks and warrant further validation through targeted sequencing and functional studies.