背景:痴呆是一种多因素疾病,其中阿尔茨海默病(AD)和血管性痴呆(VaD)的病理贡献最大。然而,大多数全基因组关联研究(GWAS)都集中在AD上。
方法:我们进行了全因痴呆(ACD)的GWAS,并检查了VaD的遗传重叠。我们的数据集包括800,597个人,有46,902和8702例ACD和VaD,分别。复制了ACD和VaD的已知AD基因座。生物信息学分析优先考虑可能在功能上相关并与密切相关的性状和风险因素共享的基因。
结果:对于ACD,鉴定出的新基因座与能量传输(SEMA4D)有关,神经元兴奋性(ANO3),大脑中的淀粉样蛋白沉积(RBFOX1),和小血管疾病的磁共振成像标志物(SVD;HBEGF)。新的VaD位点与高血压有关,糖尿病,和神经元维持(SPRY2,FOXA2,AJAP1和PSMA3)。
结论:我们的研究确定了ACD潜在的遗传风险,表现出与神经退行性过程的重叠,血管危险因素,和大脑SVD。
结论:我们对全因痴呆(ACD)和血管性痴呆(VaD)进行了最大的全基因组关联研究。与AD相关的已知遗传变异体被复制用于ACD和VaD。功能分析确定了ACD和VaD的新基因座。ACD的遗传风险与神经变性重叠,血管危险因素,和脑小血管病。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD.
CONCLUSIONS: 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.