Gender-specific association of galanin polymorphisms with HPA-axis dysregulation, symptom severity, and antidepressant treatment response

Abstract

Galanin (GAL) is an estrogen-inducible neuropeptide, highly expressed in brain regions reported to be involved in regulation of mood and anxiety. GAL possibly has a direct modulatory effect on hypothalamic-pituitary-adrenal (HPA)-axis regulation. Recent data from pharmacological and genetic studies indicate a significant function of GAL in stress-related disorders. By using a tag SNP approach covering the locus encoding preprogalanin (PPGAL), earlier findings of female-specific associations of polymorphisms in this locus with panic disorder were expanded to a larger sample of 268 outpatients with anxiety disorders (ADs). Within a larger sample of 541 inpatients with major depressive disorder (MDD), we then tested associations of one PPGAL tag SNP with specific depression symptom clusters and HPA-axis activity assessed by the combined dexamethasone-suppression/CRH-stimulation test both at inpatient admission and discharge (n=298). Gender specificity as well as dependence of the association on levels of circulating estrogens was analyzed. Genotyping revealed high linkage disequilibrium in the promoter area of the PPGAL gene, which includes several estrogen-response elements. Confirming earlier results, rs948854, tagging this promoter region, was associated with more severe anxiety pathology in female AD patients, but not in males. In premenopausal female MDD patients, the same allele of rs948854 was associated with more severe vegetative but not cognitive depressive symptoms at discharge and worse treatment response on antidepressant medication. Furthermore, this allele was associated with higher HPA-axis activity at admission. No significant case-control associations could be observed. However, because of power limitations of both patient samples, small effects cannot be excluded. The reported associations in independent samples of AD and MDD support an estrogen-dependent function of GAL in pathophysiology of anxiety and depression, affecting response to antidepressant treatment.

Figure 1

LD chart of the analyzed SNPs within the locus encoding GAL (PPGAL), displaying linkage of the particular markers (r^2) calculated using HaploView 4.0 (Barrett et al, 2005), with an MAF cut off at 5% and an r^2 cut off >0.8. Tagging SNPs are marked with ‘^*.'

Figure 2

The rs948854 allele distributions for HAMD 21 items (Hamilton, 1960), and the subscales vegetative and cognitive depression (Rhoades and Overall, 1983) at discharge. Associations significant after correction for multiple testing are labeled with ‘^**,' nominal significance with ‘^*.'

Figure 3

The rs948854-dependent levels of Cortisol (ng/ml) and ACTH (pg/ml) measured at admission and discharge of MDD inpatients, displayed separately for the analyzed subsamples: premenopausal women, postmenopausal women, and males. At 1502 hours, IV administration of 100 μg CRH was performed, the 1530 hours measurement of cortisol and ACTH was the first after stimulation. Solely in the subgroup of premenopausal women at admission, significant allele-dependent differences between cortisol and ACTH levels after stimulation could be observed.