Biology subjects

Wingo, A.

Publications and source records attributed to Wingo, A..

7 recordsLinked to original sources

bioRxiv2024

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations

INTRODUCTIONMulti-omics studies in Alzheimers disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD. METHODSTo bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTSWe generated multi-omics data and curated and harmonized phenotypic data from AA (n=306), LA (n=326), or AA and LA (n=4) brain donors plus Non-Hispanic White (n=252) and other (n=20) ethnic groups, to establish a foundational dataset enriched for AA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSIONInclusion of traditionally underrepresented groups in multi-omics studies is essential to discover the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

neuroscience↗

bioRxiv2023

Psychosocial experiences are associated with human brain mitochondrial biology

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies heavily on energy transformation by mitochondria oxidative phosphorylation (OxPhos), and two main lines of evidence bi-directionally link mitochondria as both targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and possibly mood states alter multiple aspects of mitochondrial biology; and on the other hand, functional variations in mitochondrial OxPhos capacity alter social behavior, stress reactivity, and mood. However, knowledge on whether positive or negative psychosocial exposures and experiences are linked to mitochondrial biology in the human brain is currently unknown. By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we found that positive experiences (e.g. higher well-being) are linked to greater abundance of the mitochondrial OxPhos machinery, whereas negative experiences (e.g. higher negative mood) are linked to lower OxPhos protein content. Combined, psychosocial factors explained 18% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. To increase the sensitivity of our approach, we next interrogated mitochondrial psychobiological associations in specific neuronal and non-neuronal brain cells with single-nucleus RNA sequencing. These results revealed strong cell type specific associations, particularly between positive psychosocial experiences and molecular mitochondrial phenotypes in glial cells, whereas neurons tended to show opposite associations. Accordingly, in bulk transcriptomic analyses where all cells are pooled, these RNA-based associations were masked. Thus, our results highlight the likely underestimation of effect sizes in bulk brain tissues, and document novel cell type specific mitochondrial psychobiological associations in the human brain. Cell type specific mitochondrial recalibrations represent a potential psychobiological pathway linking positive and negative psychosocial experiences to human brain biology. Significance statementPsychosocial experiences predict health trajectories, but the underlying mechanism remains unclear. We found that positive psychosocial experiences are linked to greater abundance of the mitochondrial energy transformation machinery, whereas negative experiences are linked to lower abundance. Overall, we found that psychosocial experiences explain 18% of the variance in abundance of complex I proteins, the main entry point of the mitochondrial oxidative phosphorylation (OxPhos) system. At single-cell resolution using single nucleus transcriptomics, positive psychosocial experiences were particularly related to glial cell mitochondrial phenotypes. Opposite associations between glial cells and neurons were naturally masked in bulk transcriptomic analyses. Our results suggest that mitochondrial recalibrations in specific brain cell types may represent a potential psychobiological pathway linking psychosocial experiences to human brain health.

cell biology↗

bioRxiv2023

Identifying latent genetic interactions in genome-wide association studies using multiple traits

Genome-wide association studies of complex traits frequently find that SNP-based estimates of heritability are considerably smaller than estimates from classic family-based studies. This missing heritability may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. To circumvent these challenges, we propose a new method to detect genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Our approach, Latent Interaction Testing (LIT), uses the observation that correlated traits with shared latent genetic interactions have trait variance and covariance patterns that differ by genotype. LIT examines the relationship between trait variance/covariance patterns and genotype using a flexible kernel-based framework that is computationally scalable for biobank-sized datasets with a large number of traits. We first use simulated data to demonstrate that LIT substantially increases power to detect latent genetic interactions compared to a trait-by-trait univariate method. We then apply LIT to four obesity-related traits in the UK Biobank and detect genetic variants with interactive effects near known obesity-related genes. Overall, we show that LIT, implemented in the R package lit, uses shared information across traits to improve detection of latent genetic interactions compared to standard approaches.

genetics↗

bioRxiv2021

Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimers disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.

cell biology↗

bioRxiv2019

Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline

ObjectiveCognitive decline is a hallmark of dementia; however, the brain epigenetic signature of cognitive decline is unclear. We investigated the associations between brain tissue-based DNA methylation and cognitive trajectory. MethodsWe performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex (dPFC). To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits (GAMuT) test to analyze the five measured cognitive domains simultaneously. ResultsWe found an epigenome-wide association for differential methylation of sites in the Claudin-5 (CLDN5) locus and cognitive trajectory (p-value x 9.96 x 10-7), which was robust to adjustment for cell type proportions (p-value = 8.52 x 10-7). This association was primarily driven by association with declines in episodic (p-value = 4.65 x 10-6) and working memory (p-value = 2.54 x 10-7). This association between methylation in CLDN5 and cognitive decline was independent of beta-amyloid and neurofibrillary tangle pathology and present in participants with low levels of neuropathology. In addition, only 13-31% of the association between methylation and cognitive decline was mediated through levels of neuropathology, whereas the major part of the association was independent of it. InterpretationWe identified methylation in CLDN5 as new epigenetic factor associated with cognitive trajectory. Higher levels of methylation in CLDN5 were associated with faster cognitive decline implicating the blood brain barrier in maintenance of cognitive trajectory.

genetics↗

bioRxiv2019

Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. However, little is known about its molecular effects on the human brain and how these alterations may contribute to dementia. Here, we investigated these questions using large-scale quantification of over 8300 proteins from 438 post-mortem brains from a discovery and replication cohort. A proteome-wide association study and protein network analysis of cerebral atherosclerosis found 114 proteins and 5 protein co-expression modules associated with cerebral atherosclerosis. Enrichment analysis of these proteins and modules revealed that cerebral atherosclerosis was associated with reductions in synaptic signaling and RNA splicing and increases in oligodendrocyte development and myelination. A subset of these proteins (n=23) and protein modules (n=2) were also associated with Alzheimers disease (AD) dementia, implicating a shared mechanism with AD through decreased synaptic signaling and regulation and increased myelination. Notably, neurofilament light (NEFL) and medium (NEFM) chain proteins were among these 23 proteins, and our data suggest they contribute to AD dementia through cerebral atherosclerosis. Together, our findings offer insights into effects of cerebral atherosclerosis on the human brain proteome, and how cerebral atherosclerosis contributes to dementia risk.

neuroscience↗

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↗