Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment

Joseph A Boscarino1,2, Porat M Erlich1,3, Stuart N Hoffman4, Xiaopeng Zhang51Center for Health Research, Geisinger Clinic, Danville, PA, 2Department of Psychiatry, 3Department of Medicine, Temple University School of Medicine, Philadelphia, PA, 4Department of Neurology, 5Department of Anesthesiology, Geisinger Clinic, Danville, PA, USAObjective: The study aim was to assess the cumulative burden of polymorphisms located within four genetic loci previously associated with posttraumatic stress disorder (PTSD) among outpatients at risk for PTSD.Methods: Diagnostic interviews were completed and DNA samples collected among 412 pain patients to determine if FKBP5 (rs9470080), COMT (rs4680), CHRNA5 (rs16969968), and CRHR1 (rs110402) single nucleotide polymorphisms were cumulatively associated with increased risk for PTSD.Results: In bivariate analyses, it was found that a count of specific PTSD risk alleles located within FKBP5, COMT, CHRNA5, and CRHR1 genetic loci (allele range = 0–6, mean count = 2.92, standard deviation = 1.36) was associated with lifetime (t [409] = 3.430, P = 0.001) and early onset PTSD (t [409] = 4.239, P = 0.000028). In logistic regression, controlling for demographic factors, personality traits, and trauma exposures, this risk allele count remained associated with both lifetime (odds ratio = 1.49, P = 0.00158) and early onset PTSD (odds ratio = 2.36, P = 0.000093). Interaction effects were also detected, whereby individuals with higher risk allele counts and higher trauma exposures had an increased risk of lifetime PTSD (allele count × high trauma, P = 0.026) and early onset PTSD (allele count × high trauma, P = 0.016) in these logistic regressions. Those with no or few risk alleles appeared resilient to PTSD, regardless of exposure history.Conclusion: A cumulative risk allele count involving four single nucleotide polymorphisms located within the FKBP5, COMT, CHRNA5, and CRHR1 genes are associated with PTSD. Level of trauma exposure interacts with risk allele count, such that PTSD is increased in those with higher risk allele counts and higher trauma exposures. Since the single nucleotide polymorphisms studied encompass stress circuitry and addiction biology, these findings may have implications for neuropsychiatric research and treatment.Keywords: posttraumatic stress disorder, genetic association study, single nucleotide polymorphism, risk alleles, trauma exposure, neuroticism, childhood adversit