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

Abstract

Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.

Keywords: galanin receptors; mood disorders; network-based analysis; neurogenesis; transmitter coexistence.

Fig. 1.

Summary figure of the SNP association and SNP × environment interaction results. This figure shows the −log P values (vertical axis) of the genetic main effects (G), gene and childhood adversity interaction (G×CHA), and gene and recent negative life events interaction (G×RLE) analysis (additive genetic model in PLINK v1.07, http://pngu.mgh.harvard.edu/purcell/plink). The red line represents P = 0.05 nominal significance level; above that line significant results can be seen. Outcome variables were lifetime depression (DEP), current depression scores (BSIDEP), and current anxiety scores (BSIANX). Age and sex were covariate in all analysis. Horizontal axis lists the investigated SNPs, the genes and their chromosomal positions, and the tagged functional variants based on in silico functional analysis (see also Table S7). TFBS, transcription factor-binding site; splicing, SNPs that are located at 2 base pairs of intron–exon junction region; miRNA, miRNA binding site activity; nsSNP, SNPs in protein-coding regions that can cause amino acid change; stop codon, SNPs that may lead to premature termination of peptides (nonsense), which would disable the protein function.

Fig. 2.

Comparison of posterior probabilities of relevance for the total population and for subpopulations under the influence of different environmental factors. Subpopulations were created by dividing the original sample into two groups based on childhood adversity (CHA) and recent negative life events (RLE). The posteriors range from 0 to 1 and are estimated with respect to all three phenotypes (reported lifetime depression, current depression, and anxiety). A high posterior probability indicates that the corresponding factor is highly relevant. GAL, GALR1, and GALR3 represent corresponding diplotypes, whereas GALR2 denotes the single related SNP. Age and sex were included as cofactors. (A) The posterior probability of relevance of factors for the total population, not taking into account life stressors. Age and sex are highly relevant, but none of the genetic factors are relevant. (B) The posterior probability of relevance of factors for patients with low-medium CHA versus patients with high CHA. None of the genetic factors are relevant in the low-medium CHA group. In contrast, in case of patients with high CHA there is at least one highly relevant genetic factor, the GALR1 with a high posterior probability (Pr = 0.96). Furthermore, the corresponding log posterior ratio is high (6.09), which means that there is a strong difference between the relevance of GALR1 in the two subpopulations. (C) A comparison of the posterior probability of relevance of factors in case of patients with low or medium RLE versus patients with high RLE. In the case of the former subpopulation, none of the genetic factors are relevant, contrary to the high RLE group, where several factors are found to be relevant. The results indicate that GALR2 is the most relevant factor in case of high RLE having a relatively high posterior probability for relevance (Pr = 0.75). GALR3 has the second largest probability score, although it is only moderately relevant (Pr = 0.51). Furthermore, GAL and GALR1 are even less relevant, and can be considered as weak results. (D) To compare the Bayesian posteriors across exposures we calculated log posterior ratios. The high (>3) log posterior ratios indicate in case of every genetic factor that there is a substantial difference in terms of posterior probability of relevance between those who experienced high life stresses and who did not. In contrast, the effects of age and sex factors do not differ substantially between those who experienced high life stresses and who did not.

Fig. 3.

Galanin mechanisms hypothetically involved in MDD in humans. Galanin, a neuropeptide, and its receptors are colocalized in some monoaminergic neurons in the brain. The galanin system is highly sensitive to experimental and naturalistic stressors. Stress-induced activation of the galanin system represents the first phase in the development of depression. Recent analysis of human brain has shown that the Gi protein-coupled GALR3 (and not GALR1 as in rodents) is the main galanin receptor in NA-LC and probably 5-HT dorsal raphe nucleus cells, and that the Gi protein-coupled GALR1 is the main receptor in the forebrain. Antidepressive effects may be achieved by (i) GALR3 antagonists (71), by reinstating normal monoamine turnover in the brainstem, and by (ii) GALR1 antagonists in the forebrain by normalization of limbic system activity, or by (iii) agonists at GALR2, a Gq protein-coupled receptor, promoting neuroprotection. The present genetic analysis suggests that GALR1 risk variants may compromise galanin signaling during childhood, whereas GALR2 signaling may be influenced by recent negative life events. In addition, all four galanin system genes have relevant roles in the development of depression-related phenotypes in those persons who were highly exposed to life stressors.