Epidemiological support for genetic variability at hypothalamic-pituitary-adrenal axis and serotonergic system as risk factors for major depression

Abstract

Background: Major depressive disorder (MDD) is a serious, and common psychiatric disorder worldwide. By the year 2020, MDD will be the second cause of disability in the world. The GranadΣp study is the first, to the best of our knowledge, epidemiological study of mental disorders carried out in Andalusia (South Spain), being one of its main objectives to identify genetic and environmental risk factors for MDD and other major psychiatric disorders. In this study, we focused on the possible association of 91 candidate single nucleotide polymorphisms (SNPs) with MDD.

Methods: A total of 711 community-based individuals participated in the GranadΣp study. All individuals were extensively assessed for clinical, psychological, sociodemographic, life style, and other environmental variables. A biological sample was also collected for subsequent genetic analyses in 91 candidate SNPs for MDD. DSM-IV diagnosis of MDD was used as the outcome variable. Logistic regression analysis assuming an additive genetic model was performed to test the association between MDD and the genetic data. The experiment-wide significance threshold adjusted with the SNP spectral decomposition method provided a maximum P-value (8×10(-3)) required to identify an association. Haplotype analyses were also performed.

Results: One SNP (rs623580) located in the tryptophan hydroxylase 1 gene (TPH1; chromosome 11), one intergenic variant (rs9526236) upstream of the 5-hydroxytryptamine receptor 2A gene (HTR2A; chromosome 13), and five polymorphisms (rs17689966, rs173365, rs7209436, rs110402, and rs242924) located in the corticotropin-releasing hormone receptor 1 gene (CRHR1; chromosome 17), all showed suggestive trends for association with MDD (P<0.05). Within CRHR1 gene, the TATGA haplotype combination was found to increase significantly the risk for MDD with an odds ratio =1.68 (95% CI: 1.16-2.42, P=0.006).

Conclusion: Although limited, perhaps due to insufficient sample size power, our results seem to support the notion that the hypothalamic-pituitary-adrenal and serotonergic systems are likely to be involved in the genetic susceptibility for MDD. Future studies, including larger samples, should be addressed for further validation and replication of the present findings.

Keywords: HPA axis; genetic association analysis; major depression; serotonergic system.

Figure 1

Granad∑p study sample and response rates. Abbreviation: QC, quality control.

Figure 2

Manhattan plot displaying association results between the 85 SNPs and MDD. Note: Dotted lines represent the P-value 0.05 and 0.001 thresholds. Abbreviations: Chr, chromosome; MDD, major depressive disorder; SNPs, single nucleotide polymorphisms.