Biological Underpinnings of Trauma and Post-Traumatic Stress Disorder: Focusing on Genetics and Epigenetics

Figures & data

Figure 1. A simplified diagram showing some of the genes involved in hypothalamic–pituitary–adrenal axis signaling.

The hypothalamic–pituitary–adrenal (HPA)-axis is one of the main signaling pathways activated in response to stress and trauma. These external cues are interpreted by the amygdala where it is processed and a distress signaling sent to the hypothalamus. CRH (or CRF) and AVP are released from the hypothalamic paraventricular nucleus and bind to their principal receptors, CRHR1 and AVPR1A. This in turn activates transcription of POMC, which is cleaved into ACTH and secreted from the anterior pituitary gland. In turn, this acts on the adrenal cortex to trigger release of glucocorticoids (e.g. cortisol) into the bloodstream. Upon binding of cortisol to the corticosteroid receptor, including the GR (encoded by NR3C1), this complex translocates into the nucleus and can bind to glucocorticoid responsive elements in the promoter regions of various target genes. This triggers the downstream signaling pathways which are necessary for the body’s physiological response to stress. The functions of the GRs are partly moderated by chaperone-binding proteins. FKBP5 is a co-chaperone of Hsp90 and binds to the GR complex. When bound, the receptor has decreased affinity for cortisol and nuclear translocation is less efficient. FKBP5 thus plays an important role in the HPA-axis negative feedback loop and the levels of this protein increase in response to GR activation. The GR also plays a critical role in regulating the HPA-axis through a negative feedback loop, blocking further cortisol secretion.

ACTH: Adrenocorticotropic hormone; AVP: Arginine vasopressin; CRH: Corticotrophin-releasing hormone; GR: Glucocorticoid receptor.

Table 1. Candidate genes investigated in genetic or epigenetic studies of post-traumatic stress disorder.

Pathway and gene	Gene-association studies			DNA methylation studies
	Symbol	Region	Risk of PTSD	Tissue and sites	Risk of PTSD^†
Dopaminergic signaling
Dopamine receptor D2	DRD2	Various SNPs	Some associations [15,16]	NI
Ankyrin repeat and kinase domain containing 1	ANKK1	rs1800497	↑ with T allele; others no association [17–19]	NI
Dopamine receptor D4	DRD4	Exon 3 VNTR	↑ with L allele^† [20]	NI
Dopamine transporter	DAT1; SLC6A3	VNTR in 3′UTR	↑ with nine repeat [21,22]	Blood, two loci in promoter (using HM27K array data)	No independent association. Gene × methylation interaction [21]
Serotonin signaling
Serotonin transporter	5-HTT; SLC6A4	5-HTTLPR, VNTR	↑ risk with S allele (predominantly) [23–29]	Blood, two loci in promoter (using HM27K array data)	No independent association. Trauma–methylation interaction [30,31]
Serotonin receptor 2A	HTR2A	rs6311	↑ with G allele^† [24]	NI
HPA-axis signaling
Corticotrophin-releasing hormone receptor 1	CRHR1	Various SNPs	Some associations^† [32,33]	NI
Glucocorticoid receptor	NR3C1	Various SNPs	No associations^† [34]	Various, regions in exon one promoter	↓ Methylation [35–38]
FK506 binding protein 5	FKBP5	Various SNPs	↑ risk with rs9470080 T allele; others mixed findings [39,40]		↓ Methylation and longitudinal change [41]
Other genes
Pituitary adenylate cyclase-activating polypeptide type I receptor	ADCYAP1R1	rs2267735	↑ risk with C allele in females [42–44]	Blood, one loci in promoter (using HM27K array data)	↑ Methylation [42]
Apolipoprotein E	APOE	rs7412, rs429358	Mixed findings^† [45]		NI
Brain-derived neurotrophic factor	BDNF	rs6265	↑ with A allele; others no association [46–48]	Saliva, exon IV promoter	No association [49]
Cannabinoid receptor	CNR1	Various SNPs	No association^† [50]		NI
Catechol-O-methyltransferase	COMT	rs4680	↑ with A allele; others no association [51]	Blood, 41 loci across gene (using HM450K array data)	↑ Methylation with fear inhibition in PTSD [51]
C-reactive protein	CRP	rs1130864	↑ with T allele^† [52]		NI
Mannosidase alpha class 2C member 1	MAN2	NI			No independent association. Trauma × methylation interaction [53]
Opioid receptor-like 1 gene	OPRL1	rs6010719	↑ with G allele^† [54]		NI
Protein kinase C alpha	PRKCA	rs4790904	Mixed findings [55,56]		NI
Spindle and kinetochore-associated complex subunit 2	SKA2	rs7208505	No independent association^† [57]	Blood, one loci	↑ Methylation [57]

↑: Increased; ↓: Decreased.

^†Based on only a couple of studies.

HM27K array: Methylation data obtained from the Infinium HumanMethylation27 BeadChip array; HM450K array: Methylation data obtained from the Infinium HumanMethylation450K BeadChip array; HPA-axis: Hypothalamic–pituitary–adrenal axis; NI: Not investigated; PTSD: Post-traumatic stress disorder; UTR: Untranslated region; VNTR: Variable number tandem repeat.

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