HPA axis genes, and their interaction with childhood maltreatment, are related to cortisol levels and stress-related phenotypes

Lotte Gerritsen, Yuri Milaneschi, Christiaan H. Vinkers, Albert M. Van Hemert, Laura S van Velzen, Lianne Schmaal, Brenda W J H Penninx

Research output: Contribution to journalArticleAcademicpeer-review


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-valueso0.05. 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.
Original languageEnglish
Pages (from-to)2446-2455
Number of pages10
Issue number12
Publication statusPublished - 1 Nov 2017


  • AKR1D1 protein
  • AVPRA1 protein
  • cholesterol monooxygenase (side chain cleaving)
  • CRH protein
  • CYP17A1 protein
  • FKBP5 protein
  • HSD3B2 protein
  • hydrocortisone
  • mineralocorticoid receptor
  • NR3C2 protein
  • POMC protein
  • PROP1 protein
  • protein
  • steroid 5alpha reductase 1
  • transcription factor Pit 1
  • unclassified drug
  • adrenal gland
  • adult
  • allele
  • amygdala
  • arousal
  • article
  • brain size
  • child abuse
  • cohort analysis
  • dexamethasone suppression test
  • endophenotype
  • female
  • gene interaction
  • gene mutation
  • genome-wide association study
  • hippocampus
  • human
  • hypophysis
  • hypothalamus
  • lifespan
  • major clinical study
  • major depression
  • male
  • mental stress
  • molecular pathology
  • multicenter study
  • neuroimaging
  • neuropathology
  • nuclear magnetic resonance imaging
  • phenotype
  • pleiotropy
  • priority journal
  • regulatory mechanism
  • single nucleotide polymorphism


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