Genetic variation in HTR2A influences serotonin transporter binding potential as measured using PET and [11C]DASB

Abstract

In a previous study we showed that genetic variation in HTR2A, which encodes the serotonin 2A receptor, influenced outcome of citalopram treatment in patients with major depressive disorder. Since chronic administration of citalopram, which selectively and potently inhibits the serotonin transporter (5-HTT), putatively enhances serotonergic transmission, it is conceivable that genetic variation within HTR2A also influences pretreatment 5-HTT function or serotonergic transmission. The present study used positron emission tomography (PET) and the selective 5-HTT ligand, [11C]DASB, to investigate whether the HTR2A marker alleles that predict treatment outcome also predict differences in 5-HTT binding. Brain levels of 5-HTT were assessed in vivo using PET measures of the non-displaceable component of the [11C]DASB binding potential (BPND). DNA from 43 patients and healthy volunteers, all unmedicated, was genotyped with 14 single nucleotide polymorphisms located within or around HTR2A. Allelic association with BPND was assessed in eight brain regions, with covariates to control for race and ethnicity. We detected allelic association between [11C]DASB BPND in thalamus and three markers in a region spanning the 3' untranslated region and second intron of HTR2A (rs7333412, p=0.000045; rs7997012, p=0.000086; rs977003, p=0.000069). The association signal at rs7333412 remained significant (p<0.05) after applying corrections for multiple testing via permutation. Genetic variation in HTR2A that was previously associated with citalopram treatment outcome was also associated with thalamic 5-HTT binding. While further work is needed to identify the actual functional genetic variants involved, these results suggest that a relationship exists between genetic variation in HTR2A and either 5-HTT expression or central serotonergic transmission that influences the therapeutic response to 5-HTT inhibition in major depression.

Figure 1

Association results in thalamus and insula, HTR2A gene structure, physical positions and linkage disequilibrium relationships of the 14 studied markers (Draft Human Genome Sequence Build 34). Haploview was used to calculate linkage disequilibrium that is shown using r² values and coloring (darker shades indicate higher LD). Haplotype blocks were defined using the Four Gamete Test.

Figure 2

Serotonin transporter binding potential in thalamus by rs7333412 genotype. All data points are shown, along with mean (−) and median (+).

Figure 3

Voxel-based analysis showing increased thalamic 5-HTT binding potential in subjects with the AG or GG-genotypes compared to those with the AA-genotype (t=3.37, p=0.03).