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

Paul Gerson Unschuld (1) , Marcus Ising (1) , Darina Roeske (1) , Angelika Erhardt (1) , Michael Specht (1) , Stefan Kloiber (1) , Manfred Uhr (1) , Bertram Müller-Myhsok (1) , Florian Holsboer (1) , Elisabeth Binder (1)

1 Genetics of Anxiety disorders

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 role of GAL in stress-related disorders. By using a tag SNP approach covering the locus encoding GAL (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 (AD). Within a larger sample of 541 in-patients 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 in-patient admission and discharge (n=298). Gender-specificity as well as dependence of the association on levels of circulating estrogens was analyzed. Genotyping revealed high LD 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, due to power limitations of both patient samples, small effects can not be excluded. The reported associations in independent samples of AD and MDD support an estrogen-dependent role of GAL in pathophysiology of anxiety and depression, affecting response to antidepressant treatment.

Mots clés: Depression; Unipolar/Bipolar; Mood/Anxiety/Stress Disorders; Neuroendocrinology; Pharmacogenetics/Pharmacogenomics; galanin; association; genetics; anxiety; response; estrogen

Paul Gerson Unschuld, Marcus Ising, Darina Roeske, Angelika Erhardt, Michael Specht, et al.. Gender specific association of galanin polymorphisms with HPA-axis dysregulation, symptom severity and antidepressant treatment response.. Neuropsychopharmacology, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/npp.2010.30⟩. ⟨hal-00518313⟩