Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults

Abstract

Rationale: Chronic dysregulation of hypothalamus-pituitary-adrenal (HPA) axis activity is related to several neuropsychiatric disorders. Studies suggest that cortisol response to stress has a strong genetic etiology, and that FK506 binding protein 5 (FKBP5) and G-protein coupled type-I CRH receptor (CRHR1) are key proteins regulating response. Variations in the genes encoding these proteins, FKBP5 and CRHR1, have been associated with several neuropsychiatric disorders.

Objectives: We examined variation in these genes in relation to cortisol response to psychological stress in one of the largest Trier Social Stress Test (TSST) cohorts yet examined.

Methods: A total of 368 healthy, young adults underwent the TSST. Salivary cortisol was measured at multiple time points before and after the stressor. Nine variants in FKBP5 and four in CRHR1 were assessed. Single marker analyses were conducted. Secondary analyses assessed haplotypes and interaction with stress-related variables.

Results: The strongest association was for rs4713902 in FKBP5 with baseline cortisol (p dom = 0.0004). We also identified a male-specific effect of FKBP5 polymorphisms on peak response and response area under the curve (p = 0.0028 for rs3800374). In CRHR1, rs7209436, rs110402, and rs242924 were nominally associated with peak response (p rec = 0.0029-0.0047). We observed interactions between trait anxiety and rs7209436 and rs110402 in CRHR1 in association with baseline cortisol (p LRT = 0.0272 and p LRT = 0.0483, respectively).

Conclusions: We show association of variants in FKBP5 and CRHR1 with cortisol response to psychosocial stress. These variants were previously shown to be associated with neuropsychiatric disorders. These findings have implications for interindividual variation in HPA axis activity and potentially for the etiology of neuropsychiatric disorders.

Figure 1

Baseline cortisol by FKBP5 rs4713902 genotype. Shown are the unadjusted mean baseline cortisol levels (μg/dl).

Figure 2

Cortisol response over time by genotype for rs3800374 in FKBP5, by sex. Shown are unadjusted cortisol curves (μg/dl) for a) females and b) males.

Figure 3

Peak cortisol response by CRHR1 rs242924 genotype. Shown are the unadjusted mean peak cortisol levels (μg/dl).