Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques

B. Ferguson, J. E. Hunter, J. Luty, S. L. Street, A. Woodall, K. A. Grant

    Research output: Contribution to journalArticle

    10 Scopus citations

    Abstract

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisolwas robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from -21% to 66%. Thirtyseven monkeys from the high and low ends of the ACTH suppression distribution (18 'high' and 19 'low' animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH-2610C>T, rhTPH2 2051A>C and rh5-HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the 'risk' genotypes from these three loci was detected, with an increasing number of 'risk' genotypes associated with a blunted ACTH response (P =0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone.

    Original languageEnglish (US)
    Pages (from-to)949-957
    Number of pages9
    JournalGenes, Brain and Behavior
    Volume11
    Issue number8
    DOIs
    StatePublished - 2012

    Keywords

    • ACTH
    • CRH
    • DST
    • Dexamethasone
    • Polymorphism
    • Rhesus
    • Serotonin

    ASJC Scopus subject areas

    • Genetics
    • Neurology
    • Behavioral Neuroscience

    Fingerprint Dive into the research topics of 'Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques'. Together they form a unique fingerprint.

  • Cite this