背景:阿尔茨海默病(AD)的遗传率估计为58%-79%。然而,已知基因只能部分解释遗传力。
方法:这里,我们进行了罕见变异的基于基因的全外显子组关联研究(ExWAS)和常见变异的单变异ExWAS,利用来自英国生物库的54,569例临床诊断/代理AD和相关痴呆(ADRD)和295,421例对照的数据。
结果:基于基因的ExWAS确定了11个预测ADRD风险较高的基因,包括五个小说,即FRMD8,DDX1,DNMT3L,MORC1和TGM2,以及之前报道的六个,SORL1,GRN,PSEN1,ABCA7,GBA,ADAM10单变体ExWAS鉴定出两个与ADRD相关的新基因,SLCO1C1和NDNF。鉴定的基因主要富集在淀粉样蛋白-β过程途径中,小胶质细胞,和海马等大脑区域。可药用性证据表明DDX1,DNMT3L,TGM2、SLCO1C1和NDNF可能是有效的药物靶点。
结论:我们的研究为目前关于ADRD遗传病因的大量证据做出了贡献。
结论:基于基因的罕见变异分析确定了阿尔茨海默病和相关痴呆(ADRD)的五个新基因,包括FRMD8,DDX1,DNMT3L,MORC1和TGM2。对常见变异的单变异分析确定了ADRD的两个新基因,包括SLCO1C1和NDNF。鉴定的基因主要富集在淀粉样蛋白-β过程途径中,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。
BACKGROUND: The heritability of Alzheimer\'s disease (AD) is estimated to be 58%-79%. However, known genes can only partially explain the heritability.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Our study contributes to the current body of evidence on the genetic etiology of ADRD.
CONCLUSIONS: 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.