Canon, S. M. | bioRxiv Science

bioRxiv2024

Genetic regulation of microRNAs in the older adult brain and their contribution to neuropsychiatric conditions

MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR- QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinsons disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.

genetics↗

bioRxiv2019

Brain microRNAs associated with late-life depressive symptoms are also associated with cognitive trajectory and dementia

ObjectiveLate-life depression is associated with an increased risk for dementia, but our knowledge of the molecular mechanisms underlying this association is limited. Hence, the authors investigated whether microRNAs, important post-transcriptional regulators of gene expression, contribute to this association.\n\nMethodLate-life depressive symptoms were assessed annually in 300 non-demented participants of the Religious Orders Study and Rush Memory and Aging Project for a mean of seven years using the Center for Epidemiological Studies Depression scale. Participants underwent annual cognitive testing, clinical assessment of cognitive status, and uniform neuropathologic examination after death. microRNAs were profiled from the prefrontal cortex using Nanostring platform. A global microRNA association study of late-life depressive symptoms was performed using linear mixed model adjusting for sex, age, Alzheimers dementia pathological burden, proportions of brain cell types, post-mortem interval, and RNA integrity.\n\nResultsFour brain microRNAs were associated with late-life depressive symptoms at adjusted p<0.05 (miR-484, miR-26b, miR-30d, and miR-197). Lower expressions of these miRNAs were associated with greater depressive symptoms. Furthermore, lower expressions of miR-484 and miR-197 were associated with faster decline of cognitive performance over time. Additionally, lower miR-484 level was associated with higher probability of having Alzheimers dementia. Lastly, the predicted targets of miR-484 were enriched in a brain protein co-expression module involving synaptic transmission and regulation of long-term neuronal synaptic plasticity.\n\nConclusionsThis is the first study to identify brain microRNAs associated with late-life depressive symptoms assessed longitudinally. Additionally, the authors found a link between late-life depressive symptoms and dementia through miR-484 and miR-197.

genomics↗