Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior.
- Authors
- Roy, Alec; Hodgkinson, Colin A; Deluca, Vincenzo; Goldman, David; Enoch, Mary-Anne
- Year
- 2012
- Journal
- Journal of psychiatric research
- PMID
- 21978546
- DOI
- 10.1016/j.jpsychires.2011.09.009
- PMCID
- PMC3506169
Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Both factors increase risk for suicidal behavior. Corticotropin releasing hormone (CRH) regulates the HPA axis and its actions are moderated by a high-affinity binding protein (CRHBP). We hypothesized that CRHBP variation and interaction with childhood trauma might influence suicidal behavior. Moreover, there might be an additive effect with FKPB5, another HPA axis gene previously associated with suicidality in this dataset. African Americans were recruited: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). A total of 474 participants (112 suicide attempters) completed the Childhood Trauma Questionnaire (CTQ). Haplotype-tagging SNPs were genotyped across CRHBP and, for completeness, across CRH, CRHR1 and CRHR2. FKBP5 genotypes were available. Three CRHBP SNPs rs6453267, rs7728378 and rs10474485 showed a nominally significant interaction with the continuous CTQ score to predict suicide attempt; rs7728378 remained significant after FDR correction. There was an additive effect with FKBP5: in the group exposed to high trauma, the prevalence of suicide attempt was 0.35-0.30 in carriers of either the FKBP5 rs3800373 major homozygote or the CRHBP rs7728378 major homozygote and 0.58 in carriers of both major homozygotes. Individuals without either major homozygote were resilient to the effects of childhood trauma (suicide attempt prevalence 0.24). Main effects of CRHBP rs6453267 and CRHR1 rs9900679, both unique to African ancestry, were detected. CRHBP variation may predispose, independently and additively, to suicidal behavior in individuals who have experienced childhood trauma.
Flow chart detailing dataset.
Suicidal behavior is associated with increased childhood trauma in both substance dependent and non dependent men and women. Error bars are standard errors. N = number of individuals in each group.
CRHBP, CRH, CRHR1 and CRHR2 Haplotype block structure. The numbers in the squares refer to pairwise linkage disequilibrium measured as D′. Haplotype blocks were defined using a setting of average pairwise D′ within-block of ≥0.80. CRHBP: The direction of gene transcription is from left to right. Rectangles denote SNPs that had a main or G × E effect on suicidal behavior in the current study. *denotes SNPs that had significant effects on alcohol use disorders, anxiety disorders and EEG alpha power (Enoch et al., 2008). Circle denotes a SNP implicated in depressive symptoms (Kertes et al., 2010, Binder et al., 2010) and square denotes a SNP implicated in suicide in schizophrenics (De Luca et al., 2010). An arrow indicates the location of a SNP associated with stress-induced craving in heavy drinkers (Ray, 2011).
(A) Additive and (B) independent effects of CRHBP rs7728378 and FKBP5 rs3800373 variation on suicide risk after exposure to high childhood trauma. CRHBP rs7728378: CC/cc genotypes; FKBP5 rs3800373: FF/ff genotypes. CC, FF: major homozygote; cc, ff: minor homozygote + heterozygote. High level of childhood trauma defined as total CTQ score ≥ 1SD (≥48) above mean of non-substance dependent/no suicide attempt participants. Low level of childhood trauma defined as total CTQ score < 48. Panel A High Trauma: N’s: CC/FF (33), CC/ff (63), cc/FF (17), cc/ff (37); Panel A Low Trauma: N’s: CC/FF (60), CC/ff (109), cc/FF (47), cc/ff (68). Panel B High Trauma: N’s: FF (51), CC (103), ff (104), cc (61); Panel B Low Trauma: N’s: FF (108), CC (186), ff (181), cc (133). Note: the N’s do not correspond exactly since some individuals had genotypes for only one of the SNPs.
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