Golgi apparatus, endoplasmic reticulum and mitochondrial function implicated in Alzheimer's disease through polygenic risk and RNA sequencing.

Autor: Crawford K; UK Dementia Research Institute (UKDRI) at Cardiff University, College of Biomedical and Life Sciences, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK.; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, School of Medicine, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Leonenko G; UK Dementia Research Institute (UKDRI) at Cardiff University, College of Biomedical and Life Sciences, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Baker E; UK Dementia Research Institute (UKDRI) at Cardiff University, College of Biomedical and Life Sciences, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Grozeva D; UK Dementia Research Institute (UKDRI) at Cardiff University, College of Biomedical and Life Sciences, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK.; Centre for Trials Research, Cardiff University, Cardiff, CF24 4HQ, UK., Lan-Leung B; UK Dementia Research Institute (UKDRI) at Cardiff University, College of Biomedical and Life Sciences, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Holmans P; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, School of Medicine, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Williams J; UK Dementia Research Institute (UKDRI) at Cardiff University, College of Biomedical and Life Sciences, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., O'Donovan MC; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, School of Medicine, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Escott-Price V; MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, School of Medicine, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK., Ivanov DK; UK Dementia Research Institute (UKDRI) at Cardiff University, College of Biomedical and Life Sciences, Hadyn Ellis Building, Cardiff, CF24 4HQ, UK. IvanovD1@cardiff.ac.uk.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2023 Mar; Vol. 28 (3), pp. 1327-1336. Date of Electronic Publication: 2022 Dec 28.
DOI: 10.1038/s41380-022-01926-8
Abstrakt: Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and they have been shown to predict lifetime risk of Alzheimer's disease (AD) development. However, the relationship between PRS and AD pathogenesis is largely unknown. To this end, we performed a differential gene-expression and associated disrupted biological pathway analyses of AD PRS vs. case/controls in human brain-derived cohort sample (cerebellum/temporal cortex; MayoRNAseq). The results highlighted already implicated mechanisms: immune and stress response, lipids, fatty acids and cholesterol metabolisms, endosome and cellular/neuronal death, being disrupted biological pathways in both case/controls and PRS, as well as previously less well characterised processes such as cellular structures, mitochondrial respiration and secretion. Despite heterogeneity in terms of differentially expressed genes in case/controls vs. PRS, there was a consensus of commonly disrupted biological mechanisms. Glia and microglia-related terms were also significantly disrupted, albeit not being the top disrupted Gene Ontology terms. GWAS implicated genes were significantly and in their majority, up-regulated in response to different PRS among the temporal cortex samples, suggesting potential common regulatory mechanisms. Tissue specificity in terms of disrupted biological pathways in temporal cortex vs. cerebellum was observed in relation to PRS, but limited tissue specificity when the datasets were analysed as case/controls. The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.
(© 2022. The Author(s).)
Databáze: MEDLINE
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