Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
Alzheimers Dement. 2024 Oct;20(10):7062-7078. doi: 10.1002/alz.14181. Epub 2024 Aug 11.
The heritability of Alzheimer's disease (AD) is estimated to be 58%-79%. However, known genes can only partially explain the heritability.
Here, we conducted gene-based exome-wide association study (ExWAS) of rare variants and single-variant ExWAS of common variants, utilizing data of 54,569 clinically diagnosed/proxy AD and related dementia (ADRD) and 295,421 controls from the UK Biobank.
Gene-based ExWAS identified 11 genes predicting a higher ADRD risk, including five novel ones, namely FRMD8, DDX1, DNMT3L, MORC1, and TGM2, along with six previously reported ones, SORL1, GRN, PSEN1, ABCA7, GBA, and ADAM10. Single-variant ExWAS identified two ADRD-associated novel genes, SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-β process pathways, microglia, and brain regions like hippocampus. The druggability evidence suggests that DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.
Our study contributes to the current body of evidence on the genetic etiology of ADRD.
Gene-based analyses of rare variants identified five novel genes for Alzheimer's disease and related dementia (ADRD), including FRMD8, DDX1, DNMT3L, MORC1, and TGM2. Single-variant analyses of common variants identified two novel genes for ADRD, including SLCO1C1 and NDNF. The identified genes were predominantly enriched in amyloid-β process pathways, microglia, and brain regions like hippocampus. DDX1, DNMT3L, TGM2, SLCO1C1, and NDNF could be effective drug targets.
阿尔茨海默病（AD）的遗传率估计为 58%-79%。然而，已知的基因只能部分解释遗传率。
在这里，我们利用来自英国生物库的 54569 例临床诊断/代理 AD 和相关痴呆（ADRD）和 295421 例对照的罕见变异基因和常见变异单变量外显子组关联研究（ExWAS），进行了罕见变异基因和常见变异单变量 ExWAS。
基因 ExWAS 确定了 11 个预测 ADRD 风险较高的基因，包括 5 个新基因，即 FRMD8、DDX1、DNMT3L、MORC1 和 TGM2，以及 6 个先前报道的基因，SORL1、GRN、PSEN1、ABCA7、GBA 和 ADAM10。单变量 ExWAS 确定了两个与 ADRD 相关的新基因，SLCO1C1 和 NDNF。确定的基因主要富集在淀粉样β过程途径、小胶质细胞和海马等大脑区域。药物开发证据表明，DDX1、DNMT3L、TGM2、SLCO1C1 和 NDNF 可能是有效的药物靶点。
我们的研究有助于当前 AD 遗传病因学的研究。
罕见变异基因的基于基因的分析确定了五个新的 AD 和相关痴呆（ADRD）基因，包括 FRMD8、DDX1、DNMT3L、MORC1 和 TGM2。常见变异单变量分析确定了两个 ADRD 新基因，包括 SLCO1C1 和 NDNF。确定的基因主要富集在淀粉样β过程途径、小胶质细胞和海马等大脑区域。DDX1、DNMT3L、TGM2、SLCO1C1 和 NDNF 可能是有效的药物靶点。
