Genetic variation in serotonin receptor linked to bipolar disorder
MedWire News: Variations in the gene encoding serotonin receptor 2C (5HTR2C) are associated with the incidence of bipolar disorder, according to the results of a population study.
While the findings corroborate existing evidence linking 5HTR2C to bipolar disorder, the association in the present study was in the opposite direction to that previously reported.
Laura Mandelli (University of Bologna, Italy) and colleagues note that 5HTR2C has emerged as a promising candidate gene after a large study in 2001 found a robust association between bipolar disorder and a G>C substitution at the rs6318 single nucleotide polymorphism (SNP) of the gene.
This variation, which results in a cysteine to serine amino acid substitution, has since been shown to affect the receptor's affinity for serotonin, and some observers have hypothesized that the C allele (serine) influences variations in behavior between individuals and susceptibility to mental disorders.
There is also evidence that 5HTR2C is involved in drug reward, and there is increasing interest in the receptor as a target for treating drug addiction.
In the current study, the researchers set out to replicate the association between 5HTR2C and bipolar disorder and to further investigate whether it has a modifying effect on bipolar disorder with comorbid substance use disorder (SUD).
They genotyped 131 individuals with bipolar disorder and 65 mentally healthy controls for three 5HTR2C SNPs: rs6318, rs2428707, and rs4272555.
Among the female population (n=100), the rs6318 GG homozygote genotype and the rs2428707 CC homozygote genotype were significantly over-represented in bipolar disorder individuals compared with controls (GG frequencies: 0.667 in bipolar disorder, 0.432 in controls; CC frequencies: 0.714 in bipolar disorder, 0.405 in controls).
Among men (n=96), the presence of one or more rs2428707 C alleles was significantly associated with bipolar disorder (C frequencies: 0.897 in bipolar disorder, 0.679 in controls).
There were no significant associations with regards to genotype frequencies between bipolar disorder patients with or without SUD.
In the overall sample, the common G-C-C haplotype was significantly over-represented in bipolar disorder patients relative to controls, and the rare G-T-C haplotype was significantly more frequent in controls than in bipolar disorder patients.
Discussing the findings, the researchers note that for the rs6318 SNP, the association is in the opposite direction to that previously reported (other positive studies found an increase in frequency of the rarer C allele of rs6318 in cases).
"Interestingly, populations having high rates of the C allele also showed lower rates of this allele in bipolar disorder patients, as observed in our sample. Thus, the risk allele may be population specific, and rs6318 may be in high-linkage disequilibrium with other functional variants truly mediating the risk for bipolar disorder," Mandelli et al comment in the journal Psychiatry Research.
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By Andrew Czyzewski