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X. Zhao

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Open access Aug 2026

PTSD is Associated with Advanced Epigenetic Age in 45,091 US Military Veterans

Background: Posttraumatic stress disorder (PTSD) has been associated with advanced biological age in DNA methylation data, but results have been inconsistent. This study evaluated PTSD in association with epigenetic age in the largest cohort to date (by about 20 fold). Methods: Participants were 45,091 US Veterans (92.76% male) enrolled in the VA Million Veteran Program, with VA electronic health record (EHR), self-report PTSD severity (n = 22,835), and DNA methylation and genotype data. PTSD diagnoses predated the blood draw for obtaining DNA by > = one year. Results: PTSD diagnosis, severity, and duration were associated with age-adjusted metrics of epigenetic age (age residuals) per the Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE epigenetic age algorithms after multiple testing adjustment. The strongest and most robust effect (to additional covariates) was evident for PTSD severity in association with GrimAge residuals (B = .029, adjusted-p = 2.48e-53, up to 2 years advanced age). The relationships between PTSD severity and GrimAge and PhenoAge residuals were stronger among younger vs. older Veterans. In stratified analyses, all PTSD variables were associated with all epigenetic age residuals in the European ancestry subgroup (n = 27,578), but significant associations only emerged for GrimAge and DunedinPACE in the African ancestry participants (n = 11,690). Conclusions: PTSD was associated with advanced epigenetic aging in the largest study to date to evaluate this question. Effects were generally small in magnitude, though meaningful when considering the personal and healthcare system impact of advanced aging in the large population of VA users with PTSD.

E. Wolf, R. Zhang, X. Zhao et al. · medRxiv · 0 citations

Open access Aug 2026

A high-resolution human pangenome structural variant resource for improved disease association

Long-read sequencing (LRS) and diploid genome assembly have enabled nearly complete structural variant (SV) discovery. Using 293 nearly complete genomes, we characterize the full spectrum of genetic variation and show that while 99% of the variants between any two genomes are single base-pair substitutions, 88% of the euchromatic variant base pairs are SVs, including insertions, deletions, duplications, and inversions. We identify 24 gene-rich regions subject to megabase-scale variation, 2,293 potentially unstable tandem repeats, and 890 novel expression quantitative trait loci associated with SVs in humans. Expanding to 1,218 LRS samples from the 1000 Genomes Project and applying a newly developed cross-platform breakpoint evaluation tool, BoostSV, we construct a nonredundant callset comprising 614,522 SVs. We demonstrate the utility of this population-level SV reference callset by filtering >99% of the common variation from 44 unsolved LRS probands from the Undiagnosed Diseases Network to discover likely disease-causing SVs. Second, we genotype 1,053 high-impact biallelic SVs from the pangenome callset in 232,090 samples from All of Us and discover 105 SVs with significant associations, including 26% where the SV is the lead variant. This publicly available pangenome SV resource will drive new disease associations and further our understanding of the missing heritability of human genetic disease.

J. Lin, J. Gustafson, J. Wertz et al. · medRxiv · 0 citations