Xue Diane, Bush William S, Renton Alan E, Marcora Edoardo A, Bis Joshua C, Kunkle Brian W, Boerwinkle Eric, DeStefano Anita L, Farrer Lindsay, Goate Alison, Mayeux Richard, Pericak-Vance Margaret, Schellenberg Gerard, Seshadri Sudha, Wijsman Ellen, Haines Jonathan L, Blue Elizabeth E
Institute for Public Health Genetics University of Washington Seattle Washington USA.
Department of Population and Quantitative Health Sciences and Department of Genetics and Genome Sciences Case Western Reserve University Cleveland Ohio USA.
Alzheimers Dement (Amst). 2021 Dec 31;13(1):e12255. doi: 10.1002/dad2.12255. eCollection 2021.
Genes implicated by genome-wide association studies and family-based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project (ADSP) may bridge this gap and highlight shared biological mechanisms.
We performed structured literature review of genes prioritized by ADSP studies, genes underlying familial dementias, and genes nominated by genome-wide association studies. Gene set enrichment analyses of each list identified enriched pathways.
The genes prioritized by the ADSP, familial dementia studies, and genome-wide association studies minimally overlapped. Each gene set identified dozens of enriched pathways, several of which were shared (e.g., regulation of amyloid beta clearance).
Alternative study designs provide unique insights into AD genetics. Shared pathways enriched by different genes highlight their relevance to AD pathogenesis, while the patterns of pathway enrichment unique to each gene set provide additional targets for functional studies.
全基因组关联研究和基于家族的阿尔茨海默病（AD）研究所涉及的基因在很大程度上不一致。我们推测，像阿尔茨海默病测序项目（ADSP）这样的测序研究所确定的基因可能会弥合这一差距，并突出共同的生物学机制。
我们对ADSP研究确定优先级的基因、家族性痴呆相关基因以及全基因组关联研究提名的基因进行了结构化文献综述。对每个列表进行基因集富集分析以确定富集的通路。
ADSP、家族性痴呆研究和全基因组关联研究确定优先级的基因极少重叠。每个基因集都确定了数十个富集通路，其中有几个是共同的（例如，淀粉样β清除的调节）。
不同的研究设计为AD遗传学提供了独特的见解。不同基因富集的共同通路突出了它们与AD发病机制的相关性，而每个基因集独特的通路富集模式为功能研究提供了额外的靶点。
