A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans

Abstract

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Figure 1.

Genotypic and allelic comparison of [¹¹C]WAY 100635 binding potentials. a, Scatter plot of BP values at insula by 5-HT_1A receptor genotype. b, Scatter plot of BP values at insula by 5-HTTLPR genotype. c, Scatter plot of BP values at raphe nucleus by 5-HT_1A receptor genotype. d, Line graph of 5-HT_1A receptor binding potential by 5-HTTLPR alleles (S vs L). a-c, Black circles, Males; white circles, females; dashes, the mean. d, Black circles with solid line, SS plus SL; black circles with hatched line, LL. The numbers in d correspond to the following regions: 1, hippocampus; 2, amygdala; 3, anterior medial temporal lobe^*; 4, anterior lateral temporal lobe^*; 5, parahippocampus^*; 6, superior temporal gyrus; 7, medial inferior temporal gyrus; 8, fusiform gyrus; 9, posterior temporal gyrus^*; 10, insula^*; 11, anterior cingulate^*; 12, posterior cingulate; 13, parietal lobe^*; 14, occipital lobe; 15, orbitofrontal gyrus^*; 16, gyrus frontomedialis^*; 17, gyrus precentralis^*; 18, gyrus frontoinferior^*; 19, gyrus frontomedius^*; 20, gyrus frontosuperior^*; 21, raphe. ^*p < 0.05 indicates significant group difference after post hoc t test.