Rare copy number variation in Post-traumatic stress disorder using whole genome sequencing and biobank data.

Post-traumatic stress disorder (PTSD) has a significant genetic component ( h 2 = 24-72%). While the majority of prior studies have utilized common variants, recent research suggests rare variants also contribute to PTSD liability. Here, we examined the role of rare copy number variants (rCNVs; MAF < 1%) from multi-ancestry whole-genome sequencing data in the All of Us Research Program, using an electronic health record-defined PTSD phenotype. Genome-wide burden analyses utilizing all rCNV lengths revealed significant associations for deletion count across European-like (EUR-like; β = 0.005, SE = 0.001, P = 5.99 x 10 -6, , FDR P = 3.59 x 10 -5 ) and African-like (AFR-like; β = 0.003, SE = 0.001, P = 0.005, FDR P =0.02) ancestries. We conducted rCNV burden analyses within and across EUR-like (N case = 1,179, N control = 33,689), AFR-like (N case = 504, N control = 12,216), and Admixed American (AMR-like) (N case = 418, N control = 11,935) ancestries using three separate domains of gene-sets previously implicated in neuropsychiatric disorders: neurodevelopmental disorders (NDD; N = 53), abnormal behavior mouse mutant-derived (N = 146), and PTSD (N = 5). Within-ancestry analyses across all three domains yielded one significant brain-expressed gene-set within the EUR-like cohort. Meta-analyzing across ancestries identified 11 NDD gene-sets enriched for rCNV count (FDR P < 0.05). rCNVs with lengths greater than 10kb were examined, but observed no significant signals. Future research using larger samples and detailed PTSD phenotypes, integrated with functional genomic data and brain-region-specific expression profiles, is needed to fully map the disorder's genetic landscape.