Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis

Abstract

Background: Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level.Methods: Two hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis.Results: Association at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23–6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95).Conclusion: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.

Psychiatric symptoms in adolescents: FKBP5 genotype—early life adversity interaction effects

“…The findings indicate that the least common functional variations of the FKBP5 gene, a regulator of glucocorticoid receptor function, in an interaction with adverse life events, are associated with symptoms of mental ill-health among both 12 and 17 year-old adolescents. This is in line with previous findings in adults of a FKBP5 genotypeby-childhood maltreatment interaction effect on clinical phenotypes, such as depression, PTSD, psychosis, suicide attempts, and on aggressive behaviour [18,22,23,26,28,51,52], suicidal tendencies, as well as on threat-related right dorsal amygdala reactivity in adolescents reactivity [30].…”

“…They are in line with the previous results of clinical, psychophysiological and neuroimaging studies for FKBP5, indicating the T allele as a risk factor for psychopathology [6, 8, 10, 12, 14, 15, 19-27, 29, 30]. In fact, the TT genotype of rs1360780, which leads to higher FKBP5 protein levels [7,8], has been associated with an altered physiological stress response and heightened risk of stress [6][7][8][9][10][11][12][13][14][15][16][17][18]. Binder and colleagues suggested a putative enhancing function on gene transcription for the T allele by the formation of a TATA box, as well as differential chromatin conformations and interactions of longrange enhancers with the transcription start site, which would influence the response to the glucocorticoid receptor activation triggered by early life adversity [6].…”

“…Homozygosity for the minor allele T of the rs1360780 SNP is associated with twice the amount of FKPB5 protein levels in lymphocytes, relative to the other genotypes [8]. The T allele or TT genotype of the SNP rs1360780 (and consequentially the minor allele of the closely linked SNP rs3800373) has been associated with endocrine correlates: higher FKPB5 protein levels [8]; higher FKPB5 mRNAplasma cortisol positive correlation [8][9][10][11][12]; reduced basal cortisol levels [8,9,[12][13][14][15]; differential glucocorticoidmediated response [12,15,16]; and heightened cortisol response after psychological stress in adults, adolescents and infants (in some cases moderated by childhood adversity) [10,11,17,18]. Clinical associations have also been reported for this allele with better anti-depressant treatment response [8,10,19,20]; greater risk of depression [12,14,15,21,22], suicidal tendencies [8,23], comorbid anxietydepression [24], posttraumatic stress disorder [6,15,23], and alcohol withdrawal severity [25]; as well as with major depression, aggressive behaviour, suicide attempts, and psychosis in an interaction with adverse life events [15,[26][27][28].…”

Lack of Evidence for Regional Brain Volume or Cortical Thickness Abnormalities in Youths at Clinical High Risk for Psychosis: Findings From the Longitudinal Youth at Risk Study: Table 1.

“…In general, it is not very likely that our negative findings are attributable to the ethnical characteristics of our sample alone. Nevertheless, a different genetic background may modify the susceptibility of the brain to different etiological factors 61 and could impact the neuroanatomical correlates of the pathophysiological process.…”

Interaction of both positive and negative daily-life experiences with FKBP5 haplotype on psychosis risk

“…Recent G Â E studies indicate that the interaction of genetic variants on the FK506 binding protein 5 (FKBP5) gene with psychosocial stressors is associated with psychotic experiences (PEs) in clinical and nonclinical samples [5][6][7][8]. Compelling evidence has suggested that individual variation in the FKBP5 gene is linked to the dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis, which has been identified as a critical neurobiological mechanism underlying the emergence of psychotic symptoms [9].…”