title: Gender-specific association of variants in the AKR1C1 gene with dimensional anxiety in patients with panic disorder: additional evidence for the importance of neurosteroids in anxiety?
abstract: BACKGROUND
  Neurosteroids are synthesized both in brain and peripheral steroidogenic tissue from cholesterol or steroidal precursors. Neurosteroids have been shown to be implicated in neural proliferation, differentiation, and activity. Preclinical and clinical studies also suggest a modulatory role of neurosteroids in anxiety-related phenotypes. However, little is known about the contribution of genetic variants in genes relevant for the neurosteroidogenesis to anxiety disorders.
  
  
  METHODS
  We performed an association analysis of single nucleotide polymorphisms (SNPs) in five genes related to the neurosteroidal pathway with emphasis on progesterone and allopregnanolone biosynthesis (steroid-5-alpha-reductase 1A (SRD5A1), aldo-keto reductase family 1 C1-C3 (AKR1C1-AKR1C3) and translocator protein 18 kDA (TSPO) with panic disorder (PD) and dimensional anxiety in two German PD samples (cases N = 522, controls N = 1,115).
  
  
  RESULTS
  Case-control analysis for PD and SNPs in the five selected genes was negative in the combined sample. However, we detected a significant association of anticipatory anxiety with two intronic SNPs (rs3930965, rs41314625) located in the gene AKR1C1 surviving correction for multiple testing in PD patients. Stratification analysis for gender revealed a female-specific effect of the associations of both SNPs.
  
  
  CONCLUSIONS
  These results suggest a modulatory effect of AKR1C1 activity on anxiety levels, most likely through changes in progesterone and allopregnanolone levels within and outside the brain. In summary, this is the first evidence for the gender-specific implication of the AKR1C1 gene in the expression of anticipatory anxiety in PD. Further analyses to unravel the functional role of the SNPs detected here and replication analyses are needed to validate our results.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Quast
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Tanja
authors.initials: T
authors.lastname: Brückl
authors.forename: Hildegard
authors.initials: H
authors.lastname: Pfister
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Thomas
authors.initials: T
authors.lastname: Lang
authors.forename: Alfons
authors.initials: A
authors.lastname: Hamm
authors.forename: Lydia
authors.initials: L
authors.lastname: Fehm
authors.forename: Andreas
authors.initials: A
authors.lastname: Ströhle
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
authors.forename: Tilo
authors.initials: T
authors.lastname: Kircher
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Wittchen
authors.forename: Paul
authors.initials: P
authors.lastname: Pauli
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerlach
authors.forename: Georg W
authors.initials: GW
authors.lastname: Alpers
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deckert
authors.forename: Rainer
authors.initials: R
authors.lastname: Rupprecht
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: Angelika
authors.initials: A
authors.lastname: Erhardt
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics*; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D000328:Adult; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001007:Anxiety / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D016584:Panic Disorder / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D020641:Polymorphism, Single Nucleotide; D011280:Pregnanolone / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism*; D018079:Receptors, GABA / Q000235:genetics; D012737:Sex Factors; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D015089:20-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000074425:Aldo-Keto Reductase Family 1 Member C3; D006911:Hydroxyprostaglandin Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D008565:Membrane Proteins; D011280:Pregnanolone; D011374:Progesterone; D018079:Receptors, GABA; C499229:TSPO protein, human; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C487341:AKR1C3 protein, human; C548467:SRD5A1 protein, human
keywords: SNPs; anxiety; association; gender-specific; neurosteroids; panic disorder