Abstract
AIM: The role of vascular dementia (VaD)-associated genes in Alzheimer's disease (AD) remains elusive despite similar clinical and pathological features. We aimed to explore the relationship between these genes and AD in the Chinese population. METHODS: Eight VaD-associated genes were screened by a targeted sequencing panel in a sample of 3604 individuals comprising 1192 AD patients and 2412 cognitively normal controls. Variants were categorized into common variants and rare variants according to minor allele frequency (MAF). Common variant (MAF ≥ 0.01)-based association analysis was conducted by PLINK 1.9. Rare variant (MAF < 0.01) association study and gene-based aggregation testing of rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal (SKAT-O test), respectively. Age at onset (AAO) and Mini-Mental State Examination (MMSE) association studies were performed with PLINK 1.9. Analyses were adjusted for age, gender, and APOE ε4 status. RESULTS: Four common COL4A1 variants, including rs874203, rs874204, rs16975492, and rs1373744, exhibited suggestive associations with AD. Five rare variants, NOTCH3 rs201436750, COL4A1 rs747972545, COL4A1 rs201481886, CST3 rs765692764, and CST3 rs140837441, showed nominal association with AD risk. Gene-based aggregation testing revealed that HTRA1 was nominally associated with AD. In the AAO and MMSE association studies, variants in GSN, ITM2B, and COL4A1 reached suggestive significance. CONCLUSION: Common variants in COL4A1 and rare variants in HTRA1, NOTCH3, COL4A1, and CST3 may be implicated in AD pathogenesis. Besides, GSN, ITM2B, and COL4A1 are probably involved in the development of AD endophenotypes.