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Abstract:
BackgroundNeurosteroids 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.
MethodsWe 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).
ResultsCase-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.
ConclusionsThese 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.
