A DRD2/ANNK1- COMT Interaction, Consisting of Functional Variants, Confers Risk of Post-traumatic Stress Disorder in Traumatized Chinese

Kunlin Zhang; Li Wang; Chengqi Cao; Gen Li; Ruojiao Fang; Ping Liu; Shu Luo; Xiangyang Zhang; Israel Liberzon

doi:10.3389/fpsyt.2018.00170

A DRD2/ANNK1- COMT Interaction, Consisting of Functional Variants, Confers Risk of Post-traumatic Stress Disorder in Traumatized Chinese

Front Psychiatry. 2018 Apr 30:9:170. doi: 10.3389/fpsyt.2018.00170. eCollection 2018.

Authors

Kunlin Zhang^{1

2}, Li Wang^{1

2}, Chengqi Cao^{1

3}, Gen Li^{1

2}, Ruojiao Fang^{1

2}, Ping Liu⁴, Shu Luo⁴, Xiangyang Zhang^{1

2}, Israel Liberzon^{5

6}

Affiliations

¹ Laboratory for Traumatic Stress Studies and Center for Genetics and BioMedical Informatics Research, CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China.
² Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
³ Shenzhen Key Laboratory of Affective and Social Cognitive Science, Shenzhen University, Shenzhen, China.
⁴ People's Hospital of Deyang, Deyang, China.
⁵ Department of Psychiatry, University of Michigan and Mental Health Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, United States.
⁶ Department of Psychology, University of Michigan, Ann Arbor, MI, United States.

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 (P_interaction = 0.0008055 and P_corrected = 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, P_interaction = 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.

Keywords: DRD2/ANNK1–COMT interaction; dopaminergic genes; functional variants; modulate; post-traumatic stress disorder (PTSD).