title: SRD5A2 is associated with increased cortisol metabolism in schizophrenia spectrum disorders.
abstract: OBJECTIVE
  Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is documented in bipolar disorder and schizophrenia, but the mechanism is unclear; recently, increased activity of cortisol metabolizing enzymes was indicated in these disorders. We investigated whether five genes involved in cortisol metabolism were associated with altered activity of cortisol metabolizing enzymes in bipolar disorder (BD) and schizophrenia spectrum disorders (SCZ).
  
  
  METHODS
  A case-control sample of subjects with BD (N=213), SCZ (N=274) and healthy controls (N=370) from Oslo, Norway, were included and genotyped from 2003 to 2008. A sub-sample (healthy controls: N=151; SCZ: N=40; BD: N=39) had estimated enzyme activities based on measurements of urinary free cortisol, urinary free cortisone and metabolites. A total of 102 single nucleotide polymorphisms (SNPs) in the SRD5A1, SRD5A2, AKR1D1, HSD11B1 and HSD11B2 genes were genotyped, and significant SNPs analyzed in the sub-sample.
  
  
  RESULTS
  There was a significant association of rs6732223 in SRD5A2 (5α-reductase) with SCZ (p=0.0043, Bonferroni corrected p=0.030, T risk allele). There was a significantly increased 5α-reductase activity associated with rs6732223 (T allele) within the SCZ group (p=0.011).
  
  
  CONCLUSIONS
  The present data suggest an interaction between SCZ and SRD5A2 variants coding for the enzyme 5α-reductase, giving rise to increased 5α-reductase activity in SCZ. The findings may have implications for cortisol metabolizing enzymes as possible drug targets.
authors.affiliation: Section for Psychosis Research, Clinic of Mental Health and Addiction, Oslo University Hospital, Ullevål Hospital, P.O. Box 4956 Nydalen, 0424 Oslo, Norway. n.e.steen@medisin.uio.no
authors.forename: Nils Eiel
authors.initials: NE
authors.lastname: Steen
authors.forename: Martin
authors.initials: M
authors.lastname: Tesli
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kähler
authors.forename: Paal
authors.initials: P
authors.lastname: Methlie
authors.forename: Sigrun
authors.initials: S
authors.lastname: Hope
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Barrett
authors.forename: Sara
authors.initials: S
authors.lastname: Larsson
authors.forename: Erlend
authors.initials: E
authors.lastname: Mork
authors.forename: Kristian
authors.initials: K
authors.lastname: Løvås
authors.forename: Jan Ivar
authors.initials: JI
authors.lastname: Røssberg
authors.forename: Ingrid
authors.initials: I
authors.lastname: Agartz
authors.forename: Ingrid
authors.initials: I
authors.lastname: Melle
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Steinar
authors.initials: S
authors.lastname: Lorentzen
authors.forename: Jens P
authors.initials: JP
authors.lastname: Berg
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001714:Bipolar Disorder / Q000201:enzymology / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000201:enzymology* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human; D006854:Hydrocortisone