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

TitleRare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.
Publication TypeJournal Article
Year of Publication2021
AuthorsZhan, L, Li, J, Jew, B, Sul, JHoon
JournalPLoS Genet
Volume17
Issue9
Paginatione1009772
Date Published2021 09
ISSN1553-7404
KeywordsAlzheimer Disease, Endocytosis, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Whole Genome Sequencing
Abstract<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>
DOI10.1371/journal.pgen.1009772
Alternate JournalPLoS Genet
PubMed ID34516545
PubMed Central IDPMC8460036
Grant ListN01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
HHSN271201300031C / DA / NIDA NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
R01 NS102371 / NS / NINDS NIH HHS / United States
U01 AG046152 / AG / NIA NIH HHS / United States
U01 HL096812 / HL / NHLBI NIH HHS / United States
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R01 AG042210 / AG / NIA NIH HHS / United States
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U54 HG003067 / HG / NHGRI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
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K08 AG034290 / AG / NIA NIH HHS / United States
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KL2 RR024151 / RR / NCRR NIH HHS / United States
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ePub date: 
21/09