VARIABILITY OF 5-HT2C RECEPTOR CYS23SER POLYMORPHISM IN EUROPEAN POPULATIONS AND VULNERABILITY TO AFFECTIVE DISORDERBernard Lerer1*, Julien Mendlewicz2 , R. Adolfsson3,, D. Blackwood4, R. Kaneva,5, F. Macciardi6, L. Oruc7, G.N. Papadimitriou8, P. Propping, R.H. Segman1, C. Van Broeckhoven,101Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Email: lerer@cc.huji.ac.il; 2Department of Psychiatry, Erasme Hospital, Free University, Brussels, Belgium, 3Umea, 4Edinburg, 5Sofia, 6Milan, 7Zaghreb, 8Athens, 9Bonn, 10Antwerp.
Dysfunction of brain serotonergic systems is thought to play an important role in the pathogenesis of unipolar (UP) and bipolar (BP) affective disorder. Thus, genetic variability in serotonin receptors could contribute to vulnerability to these disorders. The 5-HT2C receptor, which has been implicated in several areas of function relevant to affect, contains a common cysteine to serine substitution in the N-terminal extracellular domain of the receptor protein. We examined the distribution of this polymorphism among 513 UP patients, 649 BP patients and 902 control subjects drawn from 10 population groups in 9 European countries. The frequency of the 5-HT2Cser allele varied significantly among the population groups, ranging from 24.6% in Greek control subjects to 10.3% in Bulgarians and Croatian control (x2=20.9, df 9, p=.01). To control for this population effect, the relationship between HTR2C and affective disorder was examined by stepwise logistic regression. This showed that over and above the effect of ethnicity, there was a significantly higher 5-HT2C serine allele carriage rate in unipolar patients compared to controls (OR=1.62; 95%CI 1.25-2.11; p<0.0001) and in bipolar patients compared to controls (OR=1.38; 95%CI 1.08-1.77; p=0.01). These findings suggest a small but significant contribution of the 5-HT2C receptor gene to mood disorder susceptibility.
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