Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder

Abstract

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar. 1 Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs 2 and also in the action of mood stabilizing agents, particularly lithium carbonate. 3 Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain, 4 are strong candidates for a role in the genetic etiology of affective illness. We examined a structural variant of the serotonin 2C (5-HT2C) receptor gene (HTR2C) that gives rise to a cysteine to serine substitution in the N terminal extracellular domain of the receptor protein (cys23ser), 5 in 513 patients with recurrent major depression (MDD-R), 649 patients with bipolar (BP) affective disorder and 901 normal controls. The subjects were drawn from nine European countries participating in the European Collaborative Project on Affective Disorders. There was significant variation in the frequency of the HT2CR ser23 allele among the 10 population groups included in the sample (from 24.6% in Greek control subjects to 9.2% in Scots, 2 = 20.9, df 9, P = 0.01). Logistic regression analysis demonstrated that over and above this interpopulation variability, there was a significant excess of HT2CR ser23 allele carriers in patients compared to normal controls that was demonstrable for both the MDD ( 2 = 7.34, df 1, P = 0.006) and BP ( 2 = 5.45, df 1, P = 0.02) patients. These findings support a possible role for genetically based structural variation in 5-HT2C receptors in the pathogenesis of major affective disorder. Molecular Psychiatry (2001) 6, 579-585.It is widely accepted that the genetic basis of affective disorders, both unipolar (recurrent major depression) and bipolar (manic depressive illness) is complex and is likely to involve several genes and also environmental factors. 6,7 A principal aim of the European Collaborative Project on Affective Disorders (ECPAD) is to harness the statistical power potentially provided by the large numbers of subjects who can be recruited by the participating centers in order to elucidate the role of candidate genes and environmental factors in the pathogenesis of affective illness. 8 In the course of the project a very large sample has been recruited and clinically evaluated, with blood samples obtained for DNA extraction. The method of recruitment of patients has been described in detail by Souery et al 8 and is summarized below in the Methods section. Subjects were genotyped for the HT2CR cys23ser polymorphism in the participating laboratories according to a standardized protocol (see below). Clinical and genotype data were centralized in the ECPAD database in Brussels and were electronically transferred to BL and FM for statistical analysis. After removal of subjects whose geographical origin was unclear, whose genotype data were ambiguous or contrad...

Serotonin Function in Panic Disorder: Important, But Why?

“…However, in our study, this polymorphism was significantly associated with PD in the total sample of patients with or without affective comorbidity (Maron et al, 2005b). Previously, a possible role for the Cys23Ser polymorphism was suggested in major depression and bipolar disorder (Lerer et al, 2001). Thus, this polymorphism may have nonspecific links to the comorbid phenotypes of PD, but its actual impact on the predisposition to PD remains unclear.…”

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.…”

HTR2C (cys23ser) polymorphism influences early onset in bipolar patients in a large European multicenter association study

“…In a second step, to assess whether AAO variation reflected the underlying genetic heterogeneity in BP, we examined the relationship of the HTR2C (cys23-ser) polymorphism (on chromosome Xq24) with EO-BP (cutoff of 16 years) in a subsample of BP patients previously reported by our group, 5 including 625 BP (of whom 66 were EO-BP) and 829 controls, recruited in eight collaborative centers (Athens, Bonn, Brussels, Edinburgh, Jerusalem, Milan, Sofia, Zagreb). All subjects were assessed by using criteria identified at standard diagnostic interviews, according to the DSM-IV.…”

“…5,7 We performed logistic regression analyses to evaluate the effect of the 'diagnosis status' (EO-BP, BP with AAO > 16 years and control subjects) and the 'center' as predictors of the dependent variable (alleles/Ser23 carrier status), permitting to determine the significance of the diagnosis, controlled for the potential confounding effect of center. A significant association emerged with an excess of HTR2C Ser23 allele (23.8%) in EO-BP patients compared to controls (14.4%) (P = 0.004; OR = 2.1, CI (1.3; 3.4)) and BP with AAO > 16 (16.5%) (P = 0.039; OR = 1.7, CI (1.02; 2.9)).…”

“…No difference was shown between BP group with AAO > 16 years and controls. We tested a 'dominant' role for Ser23 allele (because of the suggestive findings from our previous analyses 5 ), considering the response variable as 'Ser23 allele carrier status' (Ser23-Ser23 homozygous females, Ser23 hemizygous males and Cys23-Ser23 heterozygous females versus Cys23-Cys23 homozygous females and Cys23 hemizygous males). A significant excess of Ser23 allele carrier status emerged: 34.8% in EO-BP, 20.1% in control subjects (P = 0.002, OR = 2.4 (1.4-4.2)) and 23.8 % in BP > 16 years group (P = 0.028, OR = 1.9 (1.07-3.37)).…”