Meta-Analysis of Associations Between Hypothalamic-Pituitary-Adrenal Axis Genes and Risk of Posttraumatic Stress Disorder.
Level 3 - non-randomized controlled study
Meta-analysis of observational genetic association (case-control/cohort) studies
PubMed 32216170 · doi:10.1002/jts.22484
What was done
Researchers conducted a systematic search of PubMed and PsycINFO to identify genetic association studies evaluating hypothalamic-pituitary-adrenal (HPA) axis genes in posttraumatic stress disorder (PTSD). Eligible studies were original human research comparing trauma-exposed PTSD cases against trauma-exposed controls. Meta-analyses were conducted at both the single nucleotide polymorphism (SNP) level and the aggregate gene level across four genes with sufficient data (ADCYAP1R1, CRHR1, FKBP5, NR3C1) from 20 unique articles.
What was found
At the single-variant level, two SNPs were significantly associated with PTSD following correction for multiple testing: rs9296158 in FKBP5 (p = .001) and rs258747 in NR3C1 (p = .001). Gene-level analyses similarly showed significant, robust associations with PTSD for both FKBP5 and NR3C1 across sensitivity analyses. The abstract reported no effect sizes, odds ratios, or total participant sample sizes.
Why it matters
Candidate gene studies for PTSD have produced conflicting findings; this meta-analysis provides aggregate evidence supporting the involvement of FKBP5 and NR3C1 in genetic vulnerability to PTSD following trauma exposure.
Limits
Only four of six identified genes had enough data for meta-analysis, encompassing just 20 studies. The authors noted limitations including heterogeneous outcome definitions across included studies and an inability to evaluate potential moderating variables.
Cited by
- supports Variations in glucocorticoid-pathway genes including NR3C1, FKBP5, and CRHR1 impair cortisol receptor signaling and increase vulnerability to PTSD and depression.