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

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,...

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Autores principales:	Lingyu Zhan, Jiajin Li, Brandon Jew, Jae Hoon Sul
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/98c878374d6c4512ba04482ca1e6ae92
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spelling	oai:doaj.org-article:98c878374d6c4512ba04482ca1e6ae922021-12-02T20:03:20ZRare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.1553-73901553-740410.1371/journal.pgen.1009772https://doaj.org/article/98c878374d6c4512ba04482ca1e6ae922021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009772https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Late-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.Lingyu ZhanJiajin LiBrandon JewJae Hoon SulPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009772 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Lingyu Zhan Jiajin Li Brandon Jew Jae Hoon Sul Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.
description	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.
format	article
author	Lingyu Zhan Jiajin Li Brandon Jew Jae Hoon Sul
author_facet	Lingyu Zhan Jiajin Li Brandon Jew Jae Hoon Sul
author_sort	Lingyu Zhan
title	Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.
title_short	Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.
title_full	Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.
title_fullStr	Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.
title_full_unstemmed	Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.
title_sort	rare variants in the endocytic pathway are associated with alzheimer's disease, its related phenotypes, and functional consequences.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/98c878374d6c4512ba04482ca1e6ae92
work_keys_str_mv	AT lingyuzhan rarevariantsintheendocyticpathwayareassociatedwithalzheimersdiseaseitsrelatedphenotypesandfunctionalconsequences AT jiajinli rarevariantsintheendocyticpathwayareassociatedwithalzheimersdiseaseitsrelatedphenotypesandfunctionalconsequences AT brandonjew rarevariantsintheendocyticpathwayareassociatedwithalzheimersdiseaseitsrelatedphenotypesandfunctionalconsequences AT jaehoonsul rarevariantsintheendocyticpathwayareassociatedwithalzheimersdiseaseitsrelatedphenotypesandfunctionalconsequences
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Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences.

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