Jean C. Beckham’s research while affiliated with The Mental Illness Research, Education and Clinical Centers and other places

Objective Posttraumatic stress disorder (PTSD) is associated with poor health, and prior research suggests that accelerated epigenetic aging could help explain this association. A recent study found that veterans with both PTSD and obesity had greater risk for accelerated epigenetic aging compared to those with either PTSD or obesity individually, or neither condition. The objective of this study was to conduct a replication and extension of this prior work. Methods This study included models approximating the recent study’s analytic approach in a sample of 1,828 post-9/11 veterans. Our extension also included additional aging measures (PC-GrimAge and DunedinPACE), a more diverse sample, additional covariates (chronological age, smoking), and use of continuous measures of PTSD, obesity, and accelerated aging. Results In contrast with the original report, we did not find evidence that obesity moderated the association of PTSD and aging, indicating that veterans with both conditions had greater risk for accelerated aging. Although several significant interactions were observed, they were in the opposite direction of the original study findings (i.e., PTSD was more strongly associated with aging scores among veterans with less body mass). Our results instead demonstrated that PTSD was associated with accelerated aging across all continuously measured aging scores (0.08 ≤all βs ≤0.10), and that obesity was associated with faster DunedinPACE aging scores (β=0.36, 95% CI [0.28, 0.44]). Conclusions Our findings provide additional evidence that PTSD and obesity may be useful targets for interventions aiming to slow aging and improve health.

Importance Glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have nephroprotective properties beyond those related to weight loss and glycemic control. Objective To investigate the association of genetically proxied GLP-1RAs with kidney disease progression. Design, Setting, and Participants This genetic association study assembled a national retrospective cohort of veterans aged 18 years or older from the US Department of Veterans Affairs Million Veteran Program between January 10, 2011, and December 31, 2021. Data were analyzed from November 2023 to February 2024. Exposures Genetic risk score for systemic GLP1R gene expression that was calculated for each study participant based on genetic variants associated with GLP1R mRNA levels across all tissue samples within the Genotype-Tissue Expression project. Main Outcomes and Measures The primary composite outcome was incident end-stage kidney disease or a 40% decline in estimated glomerular filtration rate. Cox proportional hazards regression survival analysis assessed the association between genetically proxied GLP-1RAs and kidney disease progression. Results Among 353 153 individuals (92.5% men), median age was 66 years (IQR, 58.0-72.0 years) and median follow-up was 5.1 years (IQR, 3.1-7.2 years). Overall, 25.7% had diabetes, and 45.0% had obesity. A total of 4.6% experienced kidney disease progression. Overall, higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression in the unadjusted model (hazard ratio [HR], 0.96; 95% CI, 0.92-0.99; P = .02) and in the fully adjusted model accounting for baseline patient characteristics, body mass index, and the presence or absence of diabetes (HR, 0.96; 95% CI, 0.92-1.00; P = .04). The results were similar in sensitivity analyses stratified by diabetes or obesity status. Conclusions and Relevance In this genetic association study, higher GLP1R gene expression was associated with a small reduction in risk of kidney disease progression. These findings support pleiotropic nephroprotective mechanisms of GLP-1RAs independent of their effects on body weight and glycemic control.

Insomnia, characterized by difficulty initiating or maintaining sleep, is a robust transdiagnostic correlate of suicidal ideation (SI). Nevertheless, there remains a lack of research exploring factors that may account for this association. One approach to advancing our understanding of these associations, is to draw from theoretical models of suicide including the interpersonal theory of suicide (IPTS). According to the IPTS, the desire for suicide emerges when one feels intractably socially disconnected (i.e., lonely and perceiving oneself as a burden). Initial research suggests that social disconnectedness explains, in part, the association between insomnia and suicidal ideation severity. However, less research has investigated this veterans in underserved communities, a sample at heightened risk for suicide. Using an outpatient treatment seeking sample of veterans (N = 83; M age = 53.51 SD = 15.04; 52% Black/African American; 81% male), we modeled the indirect effect of insomnia severity on SI severity through social disconnectedness. Although insomnia severity was not directly associated with SI severity, there was a positive and statistically significant indirect effect of insomnia on SI severity through social disconnectedness. These findings extend prior research examining mechanisms that may help explain the link between insomnia and suicidality. Results highlight the importance of including transdiagnostic risk markers like insomnia and social disconnectedness in comprehensive suicide risk assessment. Future research should seek to establish the temporal nature of these relationships.

Background The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB . Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

Cannabis use problems are on the rise in the USA, and there is a significant need for novel approaches to increase heavy cannabis users’ access to evidence-based treatment. The objective of this randomized clinical trial (RCT) was to evaluate the efficacy of mobile contingency management (mCM) to reduce cannabis use among individuals with heavy cannabis use. Participants completed 2 weeks of daily ecological momentary assessments and twice daily video saliva tests during a baseline ad lib cannabis use period. Participants randomly assigned to mCM then received 6 weeks of the mCM intervention, whereas control participants received non-contingent payments. Consistent with our main hypothesis, participants in the mCM condition reported significantly greater reductions in bioverified use days (43.1% reduction vs 1.3% reduction) and self-reported grams used (80.9% reduction vs 5.1% reduction). This RCT provides the strongest evidence to date that mCM is effective at reducing cannabis use among heavy cannabis users.

Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27–46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown. The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits. Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase. Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder.