Rare variants in the endocytic pathway are associated with Alzheimer’s disease, its related phenotypes, and functional consequences
Open Access
- 13 September 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 17 (9), e1009772
- https://doi.org/10.1371/journal.pgen.1009772
Abstract
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.Funding Information
- National Institute of Environmental Health Sciences (K01 ES028064)
- National Science Foundation Grant (#1705197)
- National Institute of Neurological Disorders and Stroke (R01 NS102371)
- National Institute of Neurological Disorders and Stroke (R03 HL150604)
This publication has 131 references indexed in Scilit:
- Genome-wide association analysis of age-at-onset in Alzheimer's diseaseMolecular Psychiatry, 2011
- Genome-wide association study identifies five new schizophrenia lociNature Genetics, 2011
- Rare-Variant Association Testing for Sequencing Data with the Sequence Kernel Association TestAmerican Journal of Human Genetics, 2011
- Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's diseaseNature Genetics, 2011
- Hundreds of variants clustered in genomic loci and biological pathways affect human heightNature, 2010
- Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn DiseaseAmerican Journal of Human Genetics, 2009
- Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer diseaseFEBS Letters, 2008
- Ankyrin Repeat: A Unique Motif Mediating Protein−Protein InteractionsBiochemistry, 2006
- Principal components analysis corrects for stratification in genome-wide association studiesNature Genetics, 2006
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991