02976nas a2200265   4500008004100000022001400041245013700055210006900192260001200261300001300273490000700286520215200293653002202445653001602467653003402483653001102517653001402528653003602542653002802578100001702606700001502623700001702638700001902655856003602674       2021                        eng d  a1553-740400aRare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.0 aRare variants in the endocytic pathway are associated with Alzhe  c2021 09  ae10097720 v173 a<p>Late-onset Alzheimer's disease (LOAD) is the most common type of dementia causing irreversible brain damage to the elderly and presents a major public health challenge. Clinical research and genome-wide association studies have suggested a potential contribution of the endocytic pathway to AD, with an emphasis on common loci. However, the contribution of rare variants in this pathway to AD has not been thoroughly investigated. In this study, we focused on the effect of rare variants on AD by first applying a rare-variant gene-set burden analysis using genes in the endocytic pathway on over 3,000 individuals with European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations of rare-variant burden within the endocytic pathway with AD, which were successfully replicated in independent datasets. We further demonstrated that this endocytic rare-variant enrichment is associated with neurofibrillary tangles (NFTs) and age-related phenotypes, increasing the risk of obtaining severer brain damage, earlier age-at-onset, and earlier age-of-death. Next, by aggregating rare variants within each gene, we sought to identify single endocytic genes associated with AD and NFTs. Careful examination using NFTs revealed one significantly associated gene, ANKRD13D. To identify functional associations, we integrated bulk RNA-Seq data from over 600 brain tissues and found two endocytic expression genes (eGenes), HLA-A and SLC26A7, that displayed significant influences on their gene expressions. Differential expressions between AD patients and controls of these three identified genes were further examined by incorporating scRNA-Seq data from 48 post-mortem brain samples and demonstrated distinct expression patterns across cell types. Taken together, our results demonstrated strong rare-variant effect in the endocytic pathway on AD risk and progression and functional effect of gene expression alteration in both bulk and single-cell resolution, which may bring more insight and serve as valuable resources for future AD genetic studies, clinical research, and therapeutic targeting.</p>10aAlzheimer Disease10aEndocytosis10aGenome-Wide Association Study10aHumans10aPhenotype10aPolymorphism, Single Nucleotide10aWhole Genome Sequencing1 aZhan, Lingyu1 aLi, Jiajin1 aJew, Brandon1 aSul, Jae, Hoon  uhttps://chs-nhlbi.org/node/8918