Interplay between biological aging and neuropsychiatric phenotypes after trauma

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

PROJECT SUMMARY Psychological trauma is often unavoidable and an established contributor to persistent neuropsychiatric sequelae (PNS). Yet only a proportion of trauma-exposed persons are vulnerable to PNS, and the mechanisms underlying this vulnerability are largely unknown. Trauma and related PNS have been associated with advanced biological aging, measured with both molecular markers and brain imaging. Among molecular markers, epigenomic markers (so-called “epigenetic aging”) combine DNA methylation (DNAm) at multiple age-related genomic sites to predict disease outcomes. Complementarily, telomere shortening is another molecular marker independently associated with aging and disease. The overall objective of this application is to determine the extent to which molecular aging markers right after trauma and their changes over time predict and co-occur with PNS trajectories and age-related brain alterations. The central hypothesis is that advanced molecular age contributes to high risk for PNS and concomitant age-related alterations in brain function and structure after trauma. The rationale for this application is that combining integrative assessments of molecular age with longitudinal deep phenotyping and brain imaging data after trauma can yield novel predictors and insights to guide interventions for promoting brain health and alleviating PNS across the age spectrum. The central hypothesis will be tested with three specific aims: 1) Determine the extent to which integrative molecular aging markers at the time of trauma predict PNS; 2) Uncover the temporal and genomic site-specific dynamics of molecular age along PNS trajectories; 3) Define the functional and structural brain alterations dynamically associated with molecular age after trauma. To this end, the application leverages established multi-ancestry discovery and replication cohorts of women and men presenting to the emergency department (ED) right after psychological trauma exposure. Participants have provided whole blood DNA at ED presentation and then were followed with deep neuropsychiatric phenotyping, functional and structural brain imaging, and additional DNA sampling over the ensuing 12 months. Leveraging this unique study design and already available DNA in both cohorts, integrative molecular age will be longitudinally determined by measuring epigenetic aging and telomere length. Moreover, longitudinal whole methylome sequencing (WMS) data will be generated in a cohort subset to develop unbiased, novel epigenomic markers of aging in association with PNS. Lastly, key findings will be generalized to non-ED settings using larger-scale DNAm data available in neuropsychiatric cases and trauma- exposed controls from diverse military and civilian cohorts of the Psychiatric Genomics Consortium. This research is innovative as it will assess molecular age at the time of trauma as a predictor of PNS, interrogate the entire methylome with WMS, and integrate longitudinal molecular and phenotypic measures with brain imaging. This work is significant as it can establish molecular age measured at ED presentation and other settings as a novel predictor and potential treatment candidate for promoting brain health and alleviating trauma-related PNS.