Alzheimers Dement. 2024 Sep;20(9):5973-5995. doi: 10.1002/alz.14115. Epub 2024 Jul 24.
Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD.
We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors.
For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3).
Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD.
We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
痴呆症是一种多因素疾病，阿尔茨海默病（AD）和血管性痴呆（VaD）的病理变化贡献最大。然而，大多数全基因组关联研究（GWAS）都集中在 AD 上。
我们对所有原因痴呆症（ACD）进行了 GWAS，并研究了与 VaD 的遗传重叠。我们的数据集包括 800597 人，其中 ACD 和 VaD 的病例分别为 46902 例和 8702 例。已知与 ACD 和 VaD 相关的 AD 位点得到了复制。生物信息学分析优先考虑了与密切相关的特征和风险因素具有功能相关性和共享性的基因。
对于 ACD，新确定的与能量运输（SEMA4D）、神经元兴奋性（ANO3）、脑内淀粉样蛋白沉积（RBFOX1）和小血管疾病（SVD；HBEGF）磁共振成像标志物相关的新的 ACD 位点。新的 VaD 位点与高血压、糖尿病和神经元维持（SPRY2、FOXA2、AJAP1 和 PSMA3）相关。
我们的研究确定了 ACD 背后的遗传风险，证明了与神经退行性过程、血管风险因素和脑 SVD 的重叠。
我们进行了最大规模的全基因组关联研究，研究了所有原因痴呆症（ACD）和血管性痴呆（VaD）。已知与 AD 相关的遗传变异在 ACD 和 VaD 中得到了复制。功能分析确定了 ACD 和 VaD 的新的位点。ACD 的遗传风险与神经退行性变、血管风险因素和脑小血管疾病重叠。
