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

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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.

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Acknowledgments

This work was supported by the grants R01MH076953, U01 AA020890, and K05AA020342 (GSW) and a gift from the Kenneth Lattman Foundation.

Conflict of interest

All authors report no competing interests.

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Authors and Affiliations

  1. The Johns Hopkins Mood Disorders Center, Baltimore, MD, USA

    Pamela Belmonte Mahon & Peter P. Zandi

  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Pamela Belmonte Mahon, Peter P. Zandi & Gerald Nestadt

  3. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Peter P. Zandi

  4. Department of Psychiatry, University of Iowa, Iowa City, IA, USA

    James B. Potash

  5. Department of Medicine, Johns Hopkins School of Medicine, 720 Rutland Avenue, Ross 863, Baltimore, MD, 21205, USA

    Gary S. Wand

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  1. Pamela Belmonte Mahon
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Correspondence to Gary S. Wand.

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Mahon, P.B., Zandi, P.P., Potash, J.B. et al. Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults. Psychopharmacology 227, 231–241 (2013). https://doi.org/10.1007/s00213-012-2956-x

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