Genome wide association study of hippocampal subfield volume in PTSD cases and trauma-exposed controls

Abstract

Behavioral, structural, and functional neuroimaging have implicated the hippocampus as a critical brain region in PTSD pathogenesis. We conducted a GWAS of hippocampal subfield volumes in a sample of recent military veteran trauma survivors (n=157), including some with PTSD (n=66). Covariates in our analysis included lifetime PTSD diagnosis, sex, intracranial volume, genomic estimates of ancestry, and childhood trauma. Interactions between genetic variants and lifetime PTSD or childhood trauma were interrogated for SNPs with significant main effects. Several genetic associations surpassed correction for multiple testing for several hippocampal subfields, including fimbria, subiculum, cornu ammonis-1(CA1), and hippocampal amygdala transition area (HATA). One association replicated in an independent cohort of civilians with PTSD (rs12880795 in TUNAR with L-HATA volume, p=3.43 x 10-7 in the discovery and p=0.0004 in the replication cohort). However, the most significant association in the discovery data set was between rs6906714 in LINC02571 and R-fimbria volume (p=5.99 x10-8, q=0.0056). Interestingly, the effect of rs6906714 on R-fimbria volume increased with childhood trauma (G*E interaction p=0.022). In addition to variants in long intergenic non-coding RNAs (lincRNAs), we identified SNPs associated with hippocampal subfield volume, which are also quantitative trait loci (QTLs) for genes involved in RNA editing of glutamate receptor subunits (GluRs), oxidative stress, and autoimmune disorders. Genomic regions, some with putative regulatory roles, influence the volume of hippocampal subfields. Neuroimaging phenotypes may offer important insight into the genetic architecture and neurobiological pathways relevant to PTSD, as well as in the identification of potential biomarkers and drug targets for PTSD.