Identifying genetic loci that are associated with changes in gene expression in PTSD in a South African cohort

Abstract

The molecular mechanisms underlying posttraumatic stress disorder (PTSD) are yet to be fully elucidated, especially in underrepresented population groups. Expression quantitative trait loci (eQTLs) are DNA sequence variants that influence gene expression, in a local (cis-) or distal (trans-) manner, and subsequently impact cellular, tissue, and system physiology. This study aims to identify genetic loci associated with gene expression changes in a South African PTSD cohort. Genome-wide genotype and RNA-sequencing data were obtained from 32 trauma-exposed controls and 35 PTSD cases of mixed-ancestry, as part of the SHARED ROOTS project. The first approach utilised 108 937 single-nucleotide polymorphisms (SNPs) (MAF > 10%) and 11 312 genes with Matrix eQTL to map potential eQTLs, while controlling for covariates as appropriate. The second analysis was focused on 5638 SNPs related to a previously calculated PTSD polygenic risk score for this cohort. SNP-gene pairs were considered eQTLs if they surpassed Bonferroni correction and had a false discovery rate <0.05. We did not identify eQTLs that significantly influenced gene expression in a PTSD-dependent manner. However, several known cis-eQTLs, independent of PTSD diagnosis, were observed. rs8521 (C > T) was associated with TAGLN and SIDT2 expression, and rs11085906 (C > T) was associated with ZNF333 expression. This exploratory study provides insight into the molecular mechanisms associated with PTSD in a non-European, admixed sample population. This study was limited by the cross-sectional design and insufficient statistical power. Overall, this study should encourage further multi-omics approaches towards investigating PTSD in diverse populations.

Keywords: RNA-seq; eQTL; gene regulation; genetic variation; transcriptome; trauma.

FIGURE 1

Global cis‐eQTL effects observed in this study sample. (a) rs8521 (chromosome 11, C > T) was associated with a change in expression of TAGLN and SIDT (b) The expression of AC007278.2 and IL18RAP was influenced by rs6758936 (chromosome 2, G > A). (c) SMG5 and C1orf85 expression was associated with the genotype of SNP rs933489 (chromosome 1, T > C) (p < 1.16 × 10⁻⁷ and FDR <0.05).

FIGURE 2

Two global cis‐eQTLs observed when using 5638 PTSD‐PRS related SNPs. (a) rs11085906 (C > T) and ZNF333. (b) rs3774402 (A > G) and ZTBTB47 (p < 2.25 × 10⁻⁶ and FDR <0.05).