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

Betsy Ferguson, J. E. Hunter, J. Luty, S. L. Street, A. Woodall, Kathleen (Kathy) Grant

    Research output: Contribution to journalArticle

    10 Citations (Scopus)

    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

    Fingerprint

    Genetic Load
    Macaca
    Adrenocorticotropic Hormone
    Dexamethasone
    Hydrocortisone
    Genes
    Serotonin
    Genotype
    Major Depressive Disorder
    Post-Traumatic Stress Disorders
    Macaca mulatta
    Opioid Analgesics
    Alcoholism
    Haplorhini
    Neurotransmitter Agents
    Psychiatry
    Schizophrenia
    Alleles

    Keywords

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

    ASJC Scopus subject areas

    • Behavioral Neuroscience
    • Genetics
    • Neurology

    Cite this

    Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques. / Ferguson, Betsy; Hunter, J. E.; Luty, J.; Street, S. L.; Woodall, A.; Grant, Kathleen (Kathy).

    In: Genes, Brain and Behavior, Vol. 11, No. 8, 2012, p. 949-957.

    Research output: Contribution to journalArticle

    @article{34b90938d44f4a1fb399769246d574c9,
    title = "Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques",
    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.",
    keywords = "ACTH, CRH, Dexamethasone, DST, Polymorphism, Rhesus, Serotonin",
    author = "Betsy Ferguson and Hunter, {J. E.} and J. Luty and Street, {S. L.} and A. Woodall and Grant, {Kathleen (Kathy)}",
    year = "2012",
    doi = "10.1111/j.1601-183X.2012.00856.x",
    language = "English (US)",
    volume = "11",
    pages = "949--957",
    journal = "Genes, Brain and Behavior",
    issn = "1601-1848",
    publisher = "Wiley-Blackwell",
    number = "8",

    }

    TY - JOUR

    T1 - Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques

    AU - Ferguson, Betsy

    AU - Hunter, J. E.

    AU - Luty, J.

    AU - Street, S. L.

    AU - Woodall, A.

    AU - Grant, Kathleen (Kathy)

    PY - 2012

    Y1 - 2012

    N2 - 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.

    AB - 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.

    KW - ACTH

    KW - CRH

    KW - Dexamethasone

    KW - DST

    KW - Polymorphism

    KW - Rhesus

    KW - Serotonin

    UR - http://www.scopus.com/inward/record.url?scp=84876982256&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84876982256&partnerID=8YFLogxK

    U2 - 10.1111/j.1601-183X.2012.00856.x

    DO - 10.1111/j.1601-183X.2012.00856.x

    M3 - Article

    C2 - 22998353

    AN - SCOPUS:84876982256

    VL - 11

    SP - 949

    EP - 957

    JO - Genes, Brain and Behavior

    JF - Genes, Brain and Behavior

    SN - 1601-1848

    IS - 8

    ER -