DRD2 Schizophrenia-Risk Allele Is Associated With Impaired Striatal Functioning in Unaffected Siblings of Schizophrenia Patients

Abstract

A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n = 21) and noncarriers (n = 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location.

Using subjective expectations to model the neural underpinnings of proactive inhibition

“…Activation of the putamen during cues with 50% stop probability and when responses were slower is in line with our previous research showing that activation in the striatum, of which the putamen forms part, depended on subjective anticipation of stop‐signals, in the cue phase (Vink, de Leeuw, et al., ; Vink, Kaldewaij, et al., ) and during reactive inhibition (Pas et al., ). Similarly, Hu and Li () found bilateral activation in the putamen when looking at anticipatory motor preparation.…”

“…In doing so, we are able to investigate preparatory proactive processes associated with the cue independent from the actual stimulus and response. Immediately after the presentation of the cue, which indicated stop‐signal likelihood, subjects had to indicate whether or not they expected a stop‐signal in the upcoming stimulus (Vink, de Leeuw, et al., ; Vink, Kaldewaij, et al., ). With this task, we found that while the cues objectively represented an average stop‐signal likelihood, subjects varied in their subjective expectation whether or not a stop‐signal will occur and thus in the amount of proactive inhibitory control (Zandbelt et al., 2013).…”

Neuroimaging Intermediate Phenotypes of Executive Control Dysfunction in Schizophrenia

“…In two similar response inhibition paradigms, employed by the same group based at the University Medical Center Utrecht, reduced activity in the striatum has been reported in patients, siblings (42,43) and sibling carriers of risk alleles of DRD2 (44). The test-retest reliability of this paradigm has also been measured (45).…”

Changes in White Matter Organization in Adolescent Offspring of Schizophrenia Patients

“…Indeed, in a discordant twin study genetic overlap between reductions in white matter integrity and schizophrenia liability has been found primarily in frontal and subcortical regions (Bohlken et al, 2016). It may well be that this genetic vulnerability for changes in frontostriatal white matter together with risk alleles impacting dopamine function (Vink et al, 2016a) may contribute to altered FA values in this particular tract. Such a multifaceted origin may also explain why some white matter tracts are not (or less) affected than others.…”