SRD5A2 is associated with increased cortisol metabolism in schizophrenia spectrum disorders.
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.
Steen
Nils Eiel
NE
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
Tesli
Martin
M
Kähler
Anna K
AK
Methlie
Paal
P
Hope
Sigrun
S
Barrett
Elizabeth A
EA
Larsson
Sara
S
Mork
Erlend
E
Løvås
Kristian
K
Røssberg
Jan Ivar
JI
Agartz
Ingrid
I
Melle
Ingrid
I
Djurovic
Srdjan
S
Lorentzen
Steinar
S
Berg
Jens P
JP
Andreassen
Ole A
OA
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
D015415:Biomarkers; D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human; D006854:Hydrocortisone