Abstract
Objective: Post-traumatic stress disorder (PTSD) is a trauma- and stress-related psychiatric syndrome that occurs after exposure to extraordinary stressors. The neurotransmitter dopamine (DA) plays important roles in neurobiological processes like reward and stress, and a link between PTSD and the dopaminergic system has been reported. Thus, the investigation of an association between PTSD and gene–gene interaction (epistasis) within dopaminergic genes could uncover the genetic basis of dopamine-related PTSD symptomatology and contribute to precision medicine.Methods: We genotyped seven single nucleotide polymorphisms (SNPs) of three dopaminergic genes DRD2/ANNK1 (rs1800497 and rs1801028), COMT (rs6269, rs4633, rs4818 and rs4680) and DBH (rs1611115), in a Chinese predominantly adult cohort that had been exposed to an earthquake (156 PTSD cases and 978 controls).Results: Statistical genetics analysis identified a DRD2/ANNK1–COMT interaction (rs1800497 × rs6269), which is associated with PTSD diagnosis (Pinteraction = 0.0008055 and Pcorrected = 0.0169155). Single-variant and haplotype-based subset analyses showed that rs1800497 modulates the association directions of both the rs6269 G allele and the rs6269-rs4633-rs4818-rs4680 haplotype G-C-G-G. The interaction (rs1800497 × rs6269) was replicated in a Chinese young female cohort (32 cases and 581 controls, Pinteraction = 0.01329).Conclusions: Rs1800497 is related to the DA receptor D2 density and rs6269-rs4633-rs4818-rs4680 haplotypes affect the catechol O-methyltransferase level and enzyme activity. Thus, the interaction was inferred to be at protein–protein and DA activity level. The genotype combinations of the two SNPs indicate a potential origin of DA homeostasis abnormalities in PTSD development.
Highlights
According to the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5), post-traumatic stress disorder (PTSD) is diagnosed if a patient presents with at least one out of five intrusive symptoms, one out of two active avoidance symptoms, two out of seven negative alterations in cognitions and mood and two out of six alterations in arousal and reactivity symptoms; each must persist for at least 1 month after trauma exposure [1]
The genotype frequency (GF) of the seven single nucleotide polymorphisms (SNPs) in cases and controls is shown in Supplementary Table 1
Since rs6269 was in linkage disequilibrium (LD) with rs4818 (r2 = 0.94, calculated by Haploview and based on our cohort), the two interactions indexed the same signal and we only focused on the most significant result in following analyses
Summary
According to the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5), post-traumatic stress disorder (PTSD) is diagnosed if a patient presents with at least one out of five intrusive symptoms, one out of two active avoidance symptoms, two out of seven negative alterations in cognitions and mood and two out of six alterations in arousal and reactivity symptoms; each must persist for at least 1 month after trauma exposure [1]. Numerous smaller studies of genetic variants, mostly single nucleotide polymorphisms (SNPs), of PTSD candidate genes have been carried out, examining main genetic or gene– environment interaction effects of candidate genes on PTSD. Through these studies, more than 50 genes have been explored to investigate the association between them/their variants and PTSD; for each of these at least one significant result has been obtained. The overall number of PTSD genetic studies is small and the number of reported PTSD susceptibility genes is limited in comparison to some other mental diseases [7, 9], like schizophrenia, major depression disorder (MDD) and bipolar disorder (BD) [10,11,12]. N values are typically relatively small, underscoring the need for further research of the genetic mechanisms behind PTSD
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