Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

Abstract

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[11C]methyl)benperidol ([11C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5-12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1−), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1− was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [11C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. GRAPHICAL ABSTRACT We investigated the difference in striatal dopamine D2 receptor binding, as measured by PET with (N-[11C]methyl)benperidol ([11C]NMB), between A1 allele carriers (A1+) and individuals homozygous for the A2 allele (A1−) of the DRD2/ANKK1 TaqIA single nucleotide polymorphism. In Study 1, A1+ had 5-12% less striatal [11C]NMB binding than A1−.

Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia

“…Consistent with our previous report linking the DRD2 / ANKK1 rs1800497 to D2R in this sample (Eisenstein et al, 2016), MGP scores predicted dorsal striatal ( r 18 = 0.65, p = 0.02) but not NAc D2R BP ND ( r 18 = 0.46, p = 0.11). At the individual SNP/VNTR level, the DRD2 / ANKK1 rs1800497 polymorphism significantly related to dorsal striatal D2R BP ND , as previously reported (Eisenstein et al, 2016).…”

“…At the individual SNP/VNTR level, the DRD2 / ANKK1 rs1800497 polymorphism significantly related to dorsal striatal D2R BP ND , as previously reported (Eisenstein et al, 2016). None of the other polymorphism tested ( COMT rs4680, SLC6A3 DAT1 , DRD4 exon 3 48 bp) predicted dorsal striatal D2R binding (all r ≤ 0.47, p ≥ 0.10).…”

“…We have previously shown, in this same sample, that DRD2/ANKK1 TaqIA A1 allele carriers had lower dorsal striatal D2R specific binding relative to individuals homozygous for A2 (Eisenstein et al, 2016) . The presence of this relationship in this sample lends support to the use of [ 11 C]NMB as a valid PET radioligand to measure D2R binding.…”

“…The DRD2/ANKK1 TaqIA (rs1800497) A2 allele is associated with greater striatal D2R binding relative to the A1 allele (Eisenstein et al, 2016; Gluskin and Mickey, 2016). The COMT (rs4680) val allele may be associated with lower amounts of tonic DA transmission in cortical regions due to greater COMT activity, but it is thought to confer greater phasic DA transmission in striatum and other subcortical regions due to reduced tonic auto-inhibition relative to met/met (Bilder et al, 2004).…”

“…D2R BP ND s for each ROI were averaged across left and right hemispheres to reduce the number of comparisons for primary analyses. We recently published a report within this sample linking D2R binding to DRD2/ANKK1 TaqIA (rs1800497) genotype (Eisenstein et al, 2016). …”