Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT1A receptor gene as putative risk factors in major depression

Abstract

Scientific Correspondence 930Molecular Psychiatry with PD ( 2 = 5.14, 1 df, 2 P = 0.02), suggesting a tendency to heterozygosity in PD (Table 1).To date, most of the efforts to elucidate the genetic factors underlying PD have been focused on genes whose products are involved in its pathophysiology or that could mediate the biological effects caused by panicogenic agents. Changes in the expression or function of NTRK3 may alter synaptic plasticity through the change of local trophic support. This could possibly cause the abnormal release rates of certain neurotransmitters, like NA, in target areas that lead to the alteration of the individual's arousal threshold. The SNP we found more frequently in the PD sample is located in the putative promoter region of the gene, giving support to the hypothesis that the alteration of the normal amounts of messenger could participate in the pathophysiology of PD. Since most samples used in our study also have DUP25, the 5′ UTR SNP described above might be one of several genetic factors that contribute to modify the development and severity of panic disorder. Serotonin neurotransmission is involved in the regulation of mood, sleep, vigilance, memory and learning, feeding and sexual behaviour. All those functions have found to be altered to varying extents in depressed patients. The serotonin 1A receptor has been postulated as playing a major role in anxiety, depression and other psychiatric disorders. L1 This receptor regulates the firing of serotonergic neurones and mediates the action of non-serotonergic neurones prominently in the limbic regions.2 Moreover, the 5-HT 1A receptor has been hypothesised to have an important role in the modulation of clinical response to antidepressant drugs. Long-term treatment with SSRIs desensitises the somatodendritic 5-HT 1A receptors leading to an enhanced release of serotonin.3 In addition, it has been reported that a combination of SSRI drugs and blockade of these receptors may accelerate the therapeutic efficacy in depressive patients. 4 All these facts lead us to consider the 5-HT 1A receptor gene as a good candidate gene for association studies in major depression. The 5-HT 1A receptor gene (chromosome 15q11) is intronless and codes a 422-amino acid protein.5 A number of low frequency single nucleotide polymorphisms (SNPs) have been described on this gene. 6,7 Previous association studies investigating the putative role of the 5-HT 1A receptor gene in schizophrenia and major depression have failed to demonstrate any relation between these polymorphisms and the disorders. [6][7][8] Recently, a novel and relatively common polymorphism (C-1018G) that may provide useful information on the involvement of this receptor gene in mental disorders, has been described on the promoter region of the 5-HT 1A receptor gene. 9 We hypothesised that genetic variation in the 5-HT 1A receptor gene could be involved in the aetiology of major depression or in clinical features related to this complex disorder. To test this hypothesis, we have performed ind...

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression

“…8 The À1019G allele or the homozygous À1019GG genotype has been associated with depression, suicide, bipolar disorder, panic disorder with agoraphobia, neuroticism and decreased antidepressant response. [8][9][10][11][12][13][14][15] We tested the hypothesis that the HTR1A À1019G allele increases depression risk in a Utah population. Observed frequencies of À1019G allele (350/688) and À1019GG genotype (89/344) were 1.10-and 1.34-fold higher among unrelated individuals affected with MDD compared to unaffected individuals (312/672 and 65/336; one-tailed Fisher's exact test P = 0.05 and 0.02, respectively).…”

Serotonin 1A receptor gene and major depressive disorder: an association study and meta-analysis

“…The heterogeneity may result from (1) different ancestries (Asian population versus Caucasian population), (2) incomplete genotyping rates or genotyping error rates in different studies. Although the studies by Arias et al 16 and Koks et al 18 reported that the major allele was 'G' , other studies showed that the major allele was 'C' . We contacted the corresponding authors with regard to the genotype data in these studies.…”

“…In the meta-analysis, seven population-based association studies, including this study, met our criteria for rs6295 4,6,[16][17][18][19] (Table 2). We found significant heterogeneity among ORs (Q¼16.2, df¼6, P(Q)¼0.0119).…”

<i>In utero</i> exposure to diesel exhaust particles induces anxiogenic effects on male offspring via chronic activation of serotonergic neuron in dorsal raphe nucleus

“…In fact, 5-HT selective reuptake inhibitors (SSRI), which increase serotonergic tone, are first-line anxiolytic and antidepressant treatments (Ballenger, 1999;Kugaya et al, 2003). A genetic variant that reduces expression of 5-HT transporter has been associated with elevated levels of anxiety-like traits, susceptibility to affective disorder, and depressive symptoms (Arias et al, 2002;Collier et al, 1996;Lesch et al, 1996). These findings suggest that in utero exposure to DEPs could affect 5-HT transporter function in the DRN of male offspring, providing a possible mechanism underlying the increase in anxiety-like behavior.…”