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

Tuesday,2021-12-14 21:31 America/Los_Angeles — ecterry
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
U54 AG052427 / AG / NIA NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 AG042210 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
RF1 AG057440 / AG / NIA NIH HHS / United States
K08 AG034290 / AG / NIA NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
U01 AG049507 / AG / NIA NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
RF1 AG054014 / AG / NIA NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
U01 AG061356 / AG / NIA NIH HHS / United States
U01 AG052411 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
U01 AG046170 / AG / NIA NIH HHS / United States
R01 AG057907 / AG / NIA NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
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HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U01 HL096902 / HL / NHLBI NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R03 HL150604 / HL / NHLBI NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 AG049607 / AG / NIA NIH HHS / United States
UF1 AG047133 / AG / NIA NIH HHS / United States
U01 AG057659 / AG / NIA NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
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P30 AG010161 / AG / NIA NIH HHS / United States
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HHSN268201200036C / HL / NHLBI NIH HHS / United States
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HHSN268201100005I / HL / NHLBI NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
U01 AG049508 / AG / NIA NIH HHS / United States
U01 AG052410 / AG / NIA NIH HHS / United States
U01 HL096814 / HL / NHLBI NIH HHS / United States
RC2 AG036547 / AG / NIA NIH HHS / United States
R01 AG033040 / AG / NIA NIH HHS / United States
RF1 AG057473 / AG / NIA NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
K01 ES028064 / ES / NIEHS NIH HHS / United States
R01 HL070825 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
P01 AG003949 / AG / NIA NIH HHS / United States
U01 HL096899 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
U01 AG049506 / AG / NIA NIH HHS / United States
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U01 AG046161 / AG / NIA NIH HHS / United States
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R01 AG048015 / AG / NIA NIH HHS / United States
P50 AG025711 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
P01 AG017216 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
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R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
ePub date: 
21/09

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