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

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipol ar (recurrent major depression) and bipolar.(1) Modification of serotonergi c neurotransmission is pivotally implicated in the mechanism of action of a ntidepressant drugs(2) and also in the action of mood stabilizing agents, p articularly lithium carbonate.(3) Accordingly, genes that code for the mult iple subtypes of serotonin receptors that have been cloned and are expresse d 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 substit ution in the N terminal extracellular domain of the receptor protein (cys23 ser),(5) in 513 patients with recurrent major depression (MDD-R), 649 patie nts with bipolar (BP) affective disorder and 901 normal controls. The subje cts were drawn from nine European countries participating in the European C ollaborative Project on Affective Disorders. There was significant variatio n 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 Sc ots, chi (2)=20.9, df 9, P=0.01). Logistic regression analysis demonstrated that over and above this interpopulation variability, there was a signific ant excess of HT2CR ser23 allele carriers in patients compared to normal co ntrols that was demonstrable for both the MDD (chi (2) = 7.34, df 1, P = 0. 006) and BP (chi (2) = 5.45, df 1, P = 0.02) patients. These findings suppo rt a possible role for genetically based structural variation in 5-HT2C rec eptors in the pathogenesis of major affective disorder.