Rare variants in the endocytic pathway are associated with Alzheimer’s disease, its related phenotypes, and functional consequences

• DOI: 10.1371/journal.pgen.1009772
• Publication Date: 2021-09-13T17:33:21Z
• Authors: Lingyu Zhan; Jiajin Li; Brandon Jew; Jae Hoon Sul
• Keywords: Genome-wide Association Study

Late-onset Alzheimer’s disease (LOAD) is the most common type of dementia causing irreversible brain damage to elderly and presents a major public health challenge. Clinical research genome-wide association studies have suggested potential contribution endocytic pathway AD, with an emphasis on loci. However, rare variants in this AD has not been thoroughly investigated. In study, we focused effect by first applying rare-variant gene-set burden analysis using genes over 3,000 individuals European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations within which were successfully replicated independent datasets. further demonstrated that enrichment associated neurofibrillary tangles (NFTs) age-related phenotypes, increasing risk obtaining severer damage, earlier age-at-onset, age-of-death. Next, aggregating each gene, sought identify single NFTs. Careful examination NFTs revealed one significantly ANKRD13D . To functional associations, integrated bulk RNA-Seq data 600 tissues found two expression (eGenes), HLA-A SLC26A7 , displayed influences their gene expressions. Differential expressions between patients controls these examined incorporating scRNA-Seq 48 post-mortem samples distinct patterns across cell types. Taken together, our results strong progression alteration both single-cell resolution, may bring more insight serve as valuable resources for future genetic studies, clinical research, therapeutic targeting.