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 ¼ 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.

Brain galanin system genes interact with life stresses in depression-related phenotypes

“…The GAL gene is widely expressed in the human brain [e.g., LC, forebrain, amygdala, and hypothalamus (26,51)], but its involvement in the development of depression is not well understood. Although previous studies indicated that it might have a sex-or estrogen-dependent effect (49), in our study the galanin system genetic variants significantly influenced the depressionrelated phenotypes both in males and in females, with similar magnitude of effect size, providing evidence that the excessive stress effect is not mediated by sex.…”

“…previous genetic studies on humans that the galanin system is involved in psychiatric disorders including alcoholism/addiction (43)(44)(45)(46)(47), panic disorder (48,49), and chronic pain-associated depression (50). Furthermore, recent functional studies provided the first evidence that polymorphisms in a highly conserved genetic region upstream from the GAL gene regulates GAL expression in brain areas, such as the amygdala and hypothalamus, implicated in the pathogenesis of depression (51,52).…”

Differential Activity by Polymorphic Variants of a Remote Enhancer that Supports Galanin Expression in the Hypothalamus and Amygdala: Implications for Obesity, Depression and Alcoholism

“…Furthermore, polymorphisms in and around the GAL gene have been associated with panic disorder and anxiety in female patients (Unschuld et al, 2008(Unschuld et al, , 2010. As a result of its expression in the amygdala (Miller et al, 1993b;Planas et al, 1994a) and its known role in mood modulation (Crawley et al, 2002;Hobson et al, 2006;Karlsson and Holmes, 2006;Madaan and Wilson, 2009;Paschos et al, 2009;Rotzinger et al, 2009), GAL and its three receptors have received a great deal of attention by researchers attempting to understand the role of the galaninergic system in chronic anxiety and depression and to develop novel therapies.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…In human studies, the sex-specific association of polymorphisms in the promoter region of the GAL gene in patients with anxiety disorder or major manic depression with the severity of anxiety symptoms, supports a role for galanin in the pathophysiology of clinical anxiety and depression and demonstrates the importance of sexand hormone-status-specific genetic associations (Unschuld et al, 2008(Unschuld et al, , 2010 (Table 6). Specifically, a meta-analysis of genome-wide association studies on over 10,000 individuals revealed a significant association between the GAL gene (rs2156464) and major depressive disorder (Wray et al, 2012).…”