Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

Abstract

Keywords: major depressive disorder (MDD); tryptophan hydroxylase (TPH); serotonin transporter promoter region (5-HTTLPR); serotonin receptor 2A (HTR2A); serotonin receptor 2C (HTR2C); catechol-O-methyl transferase (COMT); dopamine D4 receptor (DRD4); dopamine transporter (DAT1)Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%. 1 The importance of the genetic component is well accepted, 2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.Pharmacological studies have suggested that MDD is associated with an impairment of brain neurotransmitters. The role of serotonin (5-HT), which is based mainly on the efficacy of selective and nonselective 5-HT reuptake inhibitors in the treatment of MDD, was reviewed by Maes and Meltzer. 3 Dopamine (DA), has also been implicated in the pathophysiology of mood disorders and hypoactivity of the mesolimbic DA pathway may be connected to depressive symptoms. 4 Thus, genes that control the brain 5-HT and DA pathways seem to be good candidates for mediating genetic susceptibility to MDD.Association of polymorphisms in seven genes from the serotonergic and dopaminergic pathways was studied in 102 unipolar patients and 172 healthy control subjects. The patient population was subdivided according to ethnic origin (63 Ashkenazi and 39 nonAshkenazi Jews) and compared to the corresponding group of mentally healthy controls. The distribution of genotypes and alleles in the different populations is shown in Table 1. Comparison of healthy individuals of Ashkenazi and non-Ashkenazi origin revealed that although frequencies of genotypes and alleles showed some differences, they did not reach statistical significance. Nevertheless, in order to avoid possible errors caused by population stratifications we compared the patients with their ethnic counterparts.When unipolar MDD patients were compared to healthy controls of the same ethnic origin (Table 1), the distribution of genotypes and alleles of the seven polymorphisms studied (TPH, HTR2A, HTR2C, 5-HTTLPR, DAT1, DRD4 and COMT) did not show statistically significant differences.Molecular genetic studies in mood disorders performed thus far, have focus...

Association of the COMT val158met Variant with Antidepressant Treatment Response in Major Depression

“…The present observations do not support a major role of the COMT val158met variant in the pathogenesis of major depression, confirming previous findings (Kunugi et al, 1997;Frisch et al, 1999;Cusin et al, 2002;Serretti et al, 2003).…”

“…However, the valine allele appears to be less expressed in the brain as compared to the methionine allele (Bray et al, 2003;Zhu et al, 2004), which slightly mitigates the effect to about 40% increased enzyme activity as conferred by the valine allele (Chen et al, 2004). The COMT val158met polymorphism has repeatedly been investigated for association with major depression with contradictory reports of no association (Kunugi et al, 1997;Frisch et al, 1999;Cusin et al, 2002;Serretti et al, 2003), possible association with the valine allele (Massat et al, 2005;Funke et al, 2005) or conversely the methionine allele (Ohara et al, 1998). Two published studies on the role of the COMT val158met polymorphism in antidepressant treatment response investigating samples of 102 and 346 patients, respectively, report a tentative negative effect of the COMT 158met/met genotype on mirtazapine and citalopram response in major depression (Szegedi et al, 2005;Arias et al, 2006).…”

Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression

“…Association studies of DRD2 gene polymorphisms and alcoholism or ADHD have suggested that this mechanism might play a role in psychiatric conditions (Comings and MacMurray 2000). However, only one out of eleven other studies investigating the association between 5-HTTLPR and major depression also found that heterozygous subjects are more at risk than the homozygotes, indicating that it is highly unlikely that negative heterosis is present (Bellivier et al 1998;Collier et al 1996;Frisch et al 1999;Furlong et al 1998;Hauser et al 2003;Hoehe et al 1998;Kunugi et al 1997;Mendlewicz et al 2004;Rees et al 1997;Serretti et al 2002;Willis-Owen et al 2005).…”

Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression

“…Two out of four studies found an increased frequency of the serine variant, indicating that this variant may be associated with major depression (Frisch et al 1999;Lerer et al 2001;Holmes et al 2003;Kö ks et al 2006). 5-HT2C receptor RNA undergoes adenosine-to-inosine RNA modification.…”

“…5-HT2A receptor polymorphisms are generally not associated with major depression (Zhang et al 1997;Frisch et al 1999;Tsai et al 1999;Minov et al 2001;Oswald et al 2003;Choi et al 2004;Khait et al 2005;Levinson 2005). …”