image: A schematic overview of the study design. AD = Alzheimer's disease; ADNI = Alzheimer's disease Neuroimaging Initiative; ADSP = Alzheimer's disease Sequencing Project; cis-GReX = cis-genetically regulated expression; FOCUS = Fine-mapping of causal gene sets; GWAS = Genome-wide association study; IGAP = International Genomics of Alzheimer's Project; PGC-ALZ = Alzheimer's disease working group of the Psychiatric Genomics Consortium; TWAS = Transcriptome-wide association study; UKBB = UK Biobank. view more
Credit: Liu N, et al., 2021, PLOS Genetics
A research team led by Chunshui Yu and Mulin Jun Li of Tianjin Medical University has discovered two new genes potentially involved in Alzheimer's disease. They identified them by exploring which genes were turned on and off in the hippocampus of people who suffered from the disease. The team's new findings are published February 25th in PLOS Genetics.
Alzheimer's disease is a neurodegenerative disorder that involves worsening dementia and the formation of protein plaques and tangles in the brain. The hippocampus, part of the brain involved in memory, is one of the first regions to sustain damage. To better understand which genes contribute to the progression of this heritable disease, the researchers identified genes expressed at higher or lower levels in the hippocampus of people with Alzheimer's disease compared to healthy brains. They identified 24 Alzheimer's-related genes that appear to have an effect through the hippocampus, using previous genomic and hippocampus gene expression data. Many genes were already known to contribute to the disease, such as APOE, but two were unknown, PTPN9 and PCDHA4. Additionally, several are involved in biological process related to Alzheimer's disease, such as plaque formation and cell death.
The research team further validated their findings by comparing gene expression for the two dozen genes to images of the individuals' brains. In Alzheimer's disease, damage and loss of neurons causes the hippocampus to shrink, which can be measured through medical imaging. The researchers established that expression of two of the genes is related to the size of the hippocampus and a diagnosis of Alzheimer's disease.
Overall, the new findings improve our understanding of the genetic and cellular mechanisms that cause Alzheimer's disease. The next step will be to investigate the roles of the two novel genes and how they contribute to this devastating disease.
The authors add, "The study identifies two novel genes associated with Alzheimer's disease in the context of hippocampal tissue and reveals candidate hippocampus-mediated neurobiological pathways from gene expression to Alzheimer's disease."
###
Peer-reviewed; Simulation / modelling
In your coverage please use this URL to provide access to the freely available article in PLOS Genetics:
http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009363
Citation: Liu N, Xu J, Liu H, Zhang S, Li M, Zhou Y, et al. (2021) Hippocampal transcriptome-wide association study and neurobiological pathway analysis for Alzheimer's disease. PLoS Genet 17(2): e1009363. https://doi.org/10.1371/journal.pgen.1009363
Funding: This work was supported by the National Key Research and Development Program of China (2018YFC1314300) to CY, the National Natural Science Foundation of China to CY (82030053, 81425013), the National Natural Science Foundation of China to MJL (31871327), the National Natural Science Foundation of China to JX (82001797), the National Natural Science Foundation of China to HL (81701668) and the Tianjin Key Technology R&D Program (17ZXMFSY00090) to CY. The authors report no biomedical financial interests or potential conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Journal
PLoS Genetics