Dataset Information

HPA Axis Genes, and Their Interaction with Childhood Maltreatment, are Related to Cortisol Levels and Stress-Related Phenotypes.

ABSTRACT: Stress responses are controlled by the hypothalamus pituitary adrenal (HPA)-axis and maladaptive stress responses are associated with the onset and maintenance of stress-related disorders such as major depressive disorder (MDD). Genes that play a role in the HPA-axis regulation may likely contribute to the relation between relevant neurobiological substrates and stress-related disorders. Therefore, we performed gene-wide analyses for 30 a priori literature-based genes involved in HPA-axis regulation in 2014 subjects (34% male; mean age: 42.5) to study the relations with lifetime MDD diagnosis, cortisol awakening response, and dexamethasone suppression test (DST) levels (subsample N=1472) and hippocampal and amygdala volume (3T MR images; subsample N=225). Additionally, gene by childhood maltreatment (CM) interactions were investigated. Gene-wide significant results were found for dexamethasone suppression (CYP11A1, CYP17A1, POU1F1, AKR1D1), hippocampal volume (CYP17A1, CYP11A1, HSD3B2, PROP1, AVPRA1, SRD5A1), amygdala volume (POMC, CRH, HSD3B2), and lifetime MDD diagnosis (FKBP5 and CRH), all permutation p-values<0.05. Interactions with CM were found for several genes; the strongest interactions were found for NR3C2, where the minor allele of SNP rs17581262 was related to smaller hippocampal volume, smaller amygdala volume, higher DST levels, and higher odds of MDD diagnosis only in participants with CM. As hypothesized, several HPA-axis genes are associated with stress-related endophenotypes including cortisol response and reduced brain volumes. Furthermore, we found a pleiotropic interaction between CM and the mineralocorticoid receptor gene, suggesting that this gene plays an important moderating role in stress and stress-related disorders.

SUBMITTER: Gerritsen L

PROVIDER: S-EPMC5645736 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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HPA Axis Genes, and Their Interaction with Childhood Maltreatment, are Related to Cortisol Levels and Stress-Related Phenotypes.

Gerritsen Lotte L Milaneschi Yuri Y Vinkers Christiaan H CH van Hemert Albert M AM van Velzen Laura L Schmaal Lianne L Penninx Brenda Wjh BW

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20170607 12

Stress responses are controlled by the hypothalamus pituitary adrenal (HPA)-axis and maladaptive stress responses are associated with the onset and maintenance of stress-related disorders such as major depressive disorder (MDD). Genes that play a role in the HPA-axis regulation may likely contribute to the relation between relevant neurobiological substrates and stress-related disorders. Therefore, we performed gene-wide analyses for 30 a priori literature-based genes involved in HPA-axis regula ...[more]

PMID: 28589964

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Project description:BackgroundThere is inconsistency in the literature regarding the nature of hypothalamic-pituitary-adrenal (HPA) axis functionality in post-traumatic stress disorder (PTSD).PurposeThe review aimed to investigate HPA axis functionality via the diurnal profile of cortisol as it relates to PTSD.MethodsThe authors conducted a systematic review of the literature from June 2017 - March 2019 in accordance with The PRISMA Statement in the following four databases: PubMed, MEDLINE, ScienceDirect and PsycINFO with Full Text. The search strategy was limited to articles in English language, published in peer-reviewed journals within the last decade and human studies. Search terms included "post-traumatic stress disorder" OR "PTSD", AND "hypothalamic pituitary adrenal axis" OR "HPA axis" AND "diurnal cortisol" OR "cortisol". PTSD sufferers of all trauma types, genders and socioeconomic statuses were included provided there was a "healthy" control group and an inclusion of reporting on inter-group measurements of diurnal cortisol profiles as a portrayal of HPA axis functionality.ResultsA total of 10 studies met the criteria for inclusion in this review. The association between HPA axis functionality and PTSD was evaluated by the measurement of salivary and/or plasma cortisol concentrations. Only two studies demonstrated an association between PTSD and diurnal cortisol when compared with respective control groups while three studies found no associations. The remaining five studies found partial, mostly negative associations between PTSD and diurnal cortisol.ConclusionDespite some indications of an association between PTSD and dysregulated HPA axis functionality as demonstrated by diurnal cortisol output, the current review has revealed mixed findings. As such, a complete understanding of HPA axis dysregulation as it relates to PTSD remains unestablished. Given the findings, further investigation into the relationship between PTSD trauma-exposed and non-PTSD trauma-exposed individuals and diurnal cortisol is warranted.

Project description:BACKGROUND: Laboratory routine procedures such as handling, injection, gavage or transportation are stressful events which may influence physiological parameters of laboratory animals and may interfere with the interpretation of the experimental results. Here, we investigated if female BALB/c mice derived from in-house breeding and BALB/c mice from a vendor which were shipped during their juvenile life differ in their HPA axis activity and stress responsiveness in adulthood. RESULTS: We show that already transferring the home cage to another room is a stressful event which causes an increased HPA axis activation for at least 24 hours as well as a loss of circulating lymphocytes which normalizes during a few days after transportation. However and important for the interpretation of experimental data, commercially available strain-, age- and gender-matched animals that were shipped over-night showed elevated glucocorticoid levels for up to three weeks after shipment, indicating a heightened HPA axis activation and they gained less body weight during adolescence. Four weeks after shipment, these vendor-derived mice showed increased corticosterone levels at 45-min after intraperitoneal ACTH challenge but, unexpectedly, no acute stress-induced glucocorticoid release. Surprisingly, activation of monoaminergic pathways were identified to inhibit the central nervous HPA axis activation in the vendor-derived, shipped animals since depletion of monoamines by reserpine treatment could restore the stress-induced HPA axis response during acute stress. CONCLUSIONS: In-house bred and vendor-derived BALB/c mice show a different stress-induced HPA axis response in adulthood which seems to be associated with different central monoaminergic pathway activity. The stress of shipment itself and/or differences in raising conditions, therefore, can cause the development of different stress response phenotypes which needs to be taken into account when interpreting experimental data.

Project description:BackgroundStress, elicited for example by aggressive interactions, has negative effects on various biological functions including immune defence, reproduction, growth, and, in livestock, on product quality. Stress response and aggressiveness are mutually interrelated and show large interindividual variation, partly attributable to genetic factors. In the pig little is known about the molecular-genetic background of the variation in stress responsiveness and aggressiveness. To identify candidate genes we analyzed association of DNA markers in each of ten genes (CRH g.233C>T, CRHR1 c.*866_867insA, CRHBP c.51G>A, POMC c.293_298del, MC2R c.306T>G, NR3C1 c.*2122A>G, AVP c.207A>G, AVPR1B c.1084A>G, UCN g.1329T>C, CRHR2 c.*13T>C) related to the hypothalamic-pituitary-adrenocortical (HPA) axis, one of the main stress-response systems, with various stress- and aggression-related parameters at slaughter. These parameters were: physiological measures of the stress response (plasma concentrations of cortisol, creatine kinase, glucose, and lactate), adrenal weight (which is a parameter reflecting activity of the central branch of the HPA axis over time) and aggressive behaviour (measured by means of lesion scoring) in the context of psychosocial stress of mixing individuals with different aggressive temperament.ResultsThe SNP NR3C1 c.*2122A>G showed association with cortisol concentration (p = 0.024), adrenal weight (p = 0.003) and aggressive behaviour (front lesion score, p = 0.012; total lesion score p = 0.045). The SNP AVPR1B c.1084A>G showed a highly significant association with aggressive behaviour (middle lesion score, p = 0.007; total lesion score p = 0.003). The SNP UCN g.1329T>C showed association with adrenal weight (p = 0.019) and aggressive behaviour (front lesion score, p = 0.029). The SNP CRH g.233C>T showed a significant association with glucose concentration (p = 0.002), and the polymorphisms POMC c.293_298del and MC2R c.306T>G with adrenal weight (p = 0.027 and p < 0.0001 respectively).ConclusionsThe multiple and consistent associations shown by SNP in NR3C1 and AVPR1B provide convincing evidence for genuine effects of their DNA sequence variation on stress responsiveness and aggressive behaviour. Identification of the causal functional molecular polymorphisms would not only provide markers useful for pig breeding but also insight into the molecular bases of the stress response and aggressive behaviour in general.

Dataset Information

HPA Axis Genes, and Their Interaction with Childhood Maltreatment, are Related to Cortisol Levels and Stress-Related Phenotypes.

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HPA Axis Genes, and Their Interaction with Childhood Maltreatment, are Related to Cortisol Levels and Stress-Related Phenotypes.

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