Anxiety and depression in children and adults: influence of serotonergic and neurotrophic genes?

Abstract

There are two major hypotheses regarding the etiology of anxiety and depression: the mono-amine hypothesis and the hypothesis of an abnormal stress response acting partly via reduced neurogenesis. Association studies have focused on genes involved in these processes, but with inconclusive results. This study investigated the effect of 45 single nucleotide polymorphisms (SNPs) in genes encoding for serotonin receptors 1A, 1D, 2A, catechol-O-methyltransferase (COMT), tryptophane hydroxylase type 2 (TPH2), brain derived neurotrophic factor (BDNF), PlexinA2 and regulators of G-protein-coupled signaling (RGS) 2, 4, 16. Anxious depression (A/D) symptoms were assessed five times in 11 years in over 11 000 adults with 1504 subjects genotyped and at age 7, 10, 12 and during adolescence in over 20 000 twins with 1078 subjects genotyped. In both cohorts, a longitudinal model with one latent factor loading on all A/D measures over time was analysed. The genetic association effect modeled at the level of this latent factor was 60% and 70% heritable in the children and adults, respectively, and explained around 50% of the total phenotypic variance. Power analyses showed that the samples contained 80% power to detect an effect explaining between 1.4% and 3.6% of the variance. However, no SNP showed a consistent effect on A/D. To conclude, this longitudinal study in children and adults found no association of SNPs in the serotonergic system or core regulators of neurogenesis with A/D. Overall, there has been no convincing evidence, so far, for a role of genetic variation in these pathways in the development of anxiety and depression.

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

“…Since the discovery of the tryptophan hydroxylase 2 (TPH2) isoenzyme (Walther et al, 2003)Fthe rate-limiting enzyme of 5-HT synthesis in the brainFTPH2 polymorphisms in humans have been associated with anxiety traits, depressive disorders, and suicidality (Gutknecht et al, 2007;Reuter et al, 2007;Van Den Bogaert et al, 2006;Zhang et al, 2005;Zill et al, 2004a, b) yet these results have not been supported by other studies (De Luca et al, 2006;Garriock et al, 2005;Juhasz et al, 2010;Mann et al, 2008;Middeldorp et al, 2010). These discrepancies might be partially attributed to the fact that different SNPs in the TPH2 gene were analyzed.…”

“…This 703G/T TPH2 SNP was also shown to be associated with increased reactivity of the amygdala in an emotional face-processing task (Brown et al, 2005;Canli et al, 2005). However, recent studies (Juhasz et al, 2010;Middeldorp et al, 2010) could not confirm a correlation between anxiety symptom scores and several TPH2 polymorphisms but reported on reduced risk-taking behavior in subjects with the most prevalent TPH2 haplotype (Juhasz et al, 2010). In contrast to the conflicting human studies, our homozygous 1473G C57BL/6N mice displayed a defined anxiety phenotype in several conflict-based paradigms and in behavioral tasks investigating anxiety toward novelty.…”

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

“…The possibility that the Met allele is only associated with risk for a subset of symptoms may be one plausible reason that some studies do not replicate an association between depression risk and the BDNF Val/Met polymorphism Figueira et al, 2010;Middeldorp et al, 2010;Ribeiro et al, 2007;Suchanek et al, 2011;Wray et al, 2008). There may also be treatment implications.…”

“…The Met allele has also been associated with increased suicide risk (Kanellopoulos et al, 2011;Pregelj et al, 2011;Sarchiapone et al, 2008), various depression-related traits (Beevers et al, 2009;Gatt et al, 2008;Gatt et al, 2010;Hayden et al, 2010;Jiang et al, 2005;Lau et al, 2010;Montag et al, 2010;Montag et al, 2008;Montag et al, 2009), and occasionally, a depression diagnosis (Aguilera et al, 2009;Borroni et al, 2009;Kim et al, 2008;Lavebratt et al, 2010). However, there are multiple studies in which this association with depression has not been replicated Figueira et al, 2010;Middeldorp et al, 2010;Ribeiro et al, 2007;Suchanek et al, 2011;Wray et al, 2008).…”

Childhood Depression As Emerging Public Health Problem: A Systematic Review

“…al [15] the etiology of depression and anxiety has been extensively investigated in recent years. Given the accumulating evidence about the high prevalence and debilitating related to childhood depression, a better understanding of the etiology of depression in youth is needed [16,17] Several investigations have demonstrated a wide variation in the prevalence of depression in children and differences according to the criteria of diagnostic classification adopted, mainly due to the diverse mode of presentation of depression and the association of this disorder with other psychopathologies [18].…”