Summary: DRD4 has not demonstrated clinical significance and is not currently included on the GeneSight® test panels. The DRD4 7R and 4R alleles have been mostly studied in relation to their effect on methylphenidate (MPH) response. The majority of studies show that the 7R allele has no significant effect on MPH response, while overall findings on the 4R allele are inconclusive at this time.
What is DRD4?
The dopamine receptor D4 (DRD4) gene is a regulator of dopamine synthesis and release as well as neuron firing rate.1 DRD4 codes for a protein that is distributed in the frontal cortex, striatum, hypothalamus, and hippocampus2 and has been mostly studied in relation to its effect on methylphenidate (MPH) response, which has an impact on the dopaminergic system. The DRD4 7R and 4R alleles have been the primary repeat variants studied in relation to MPH response. These variants are relatively common dependent upon population.3
What do the studies say about the effect of these DRD4 variants on MPH response?
The 7R allele is the most researched of the three variants. It has been shown that when the 7R allele is present, it causes a reduction in affinity of dopamine for the DRD4 receptor.4 However, 8 studies (n=797) show that this variant has no significant effect on MPH response5–12, while 2 studies (n=92) show a lessened response13,14, and 1 study (n=104) shows an improved response15.
The 4R allele is the most commonly found 48 base pair repeat variant in DRD4. Individuals with the 4R allele have double the affinity of dopamine when compared to the 7R allele.4 Studies on the 4R variant have produced mixed results regarding MPH response. Three studies (n=253) show that this variant results in significant increased effects of MPH.16–18 However, one of these studies only found significance for hyperactive-impulsive symptoms, but not inattentive symptoms18, while another study only found significance for math test outcomes, but not ADHD total symptoms17. Four other studies (n=380) found no significant effect of the 4R allele on MPH response.5,11,19,20
What is the clinical significance of DRD4 genotyping?
Extensive data regarding the effect of the DRD4 repeat variants on MPH response show a range of outcomes, from which no definitive association can be made. The 7R allele has been extensively studied and is unlikely to be clinically meaningful, while overall findings on the 4R allele are inconclusive at this time. More research is needed to demonstrate the clinical validity and utility of the DRD4 4R allele before its clinical use can be justified. At this time, DRD4 has not demonstrated clinical significance and is therefore not currently included on the GeneSight® test panels.
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