Test Catalog

Test ID: DRD4    
Dopamine Receptor D4 Genotype (DRD4), Blood

Useful For Suggests clinical disorders or settings where the test may be helpful

Influencing the target dose of methylphenidate treatment for patients with attention deficit/hyperactivity disorder

 

Determining possible cause for poor response to methylphenidate in treated patients with attention deficit/hyperactivity disorder

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

 

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

The dopamine receptor D4 gene (DRD4) is located near the telomeric region of chromosome 11q and is a highly variable gene. A 48-base pair (bp) variable number tandem repeat polymorphism in exon 3 of DRD4, which ranges from 2 to 11 repeats, creates a 32- to 176-amino acid variation in the third intracellular loop on the dopamine receptor. The frequency of these alleles is shown in the table. The DRD4 7-repeat allele (7R) has functional consequences and is associated with lower affinity for dopamine receptor agonists and reduced signal transduction (eg, cAMP levels) compared to the more common DRD4 4-repeat allele (4R). The effect of other copy number repeats is not as well defined to date.

 

Frequency of alleles with various DRD4 exon 3 48-bp repeats:

Allele/Number of repeats (R)

Allelic Frequency (%)

2R

8.8

3R

2.4

4R

65.1

5R

1.6

6R

2.2

7R

19.2

8R

0.6

9R

<0.1

10R

<0.1

11R

<0.1

 

The DRD4 protein is expressed in a number of brain regions, with higher levels of expression in the prefrontal cortex, where animal models suggest that it inhibits neuronal firing.

 

Attention Deficit/Hyperactivity Disorder (ADHD):

Several studies have found associations between the DRD4 7R allele and ADHD.(1,2) Similarly, a long form (240-bp variant) of a DRD4 promotor repeat polymorphism is associated with ADHD susceptibility, possibly due to linkage disequilibrium with the DRD4 7R allele.(3)

 

Pharmacogenetics:

Several studies demonstrate that the presence of the DRD4 7R allele, alone or in combination with the SLC6A4 long/long promotor polymorphism of the serotonin transporter, is associated with lower responsiveness of ADHD to methylphenidate (eg, Ritalin, Concerta), the main treatment for ADHD.(4) Methylphenidate dosage may have to be increased to effectively treat individuals with the DRD4 7R allele. The effect of other repeat numbers has not been defined to date and, if other alleles than the 4R and 7R are present, caution should be exercised in using methylphenidate to treat ADHD because the impact of these alleles on treatment response is not known. A recent meta-analysis found that children with a 4R/4R genotype had a 66% greater chance of responding to methylphenidate than those with other genotypes. Nonsignificant results were obtained when comparing the 7R variant to other genotypes.(5)

 

Attempts to find an association between DRD4 genotype and the variability of response to antipsychotic drugs, especially clozapine, have been largely unsuccessful or have yielded conflicting results.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic hematopoietic stem cell transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic hematopoietic stem cell transplantation, a pretransplant DNA specimen is recommended for testing.

 

This test does not detect polymorphisms other than the exon 3 variable number tandem repeat (VNTR).

 

The dopamine receptor D4 gene (DRD4) VNTR alleles are not correlated with the variability of antipsychotic drug response; this test should not be ordered for that purpose.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Ding Y, Chi H-C, Grady D, et al: Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci U S A 2002;99(1):309-314

2. Online Inheritance in Man. Accessed July 2018 at http://omim.org/entry/126452

3. Kustanovich V, Ishii J, Crawford L, et al: Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5. Mol Psychiatry 2004;9(7):711-717

4. Hamarman S, Fossella J, Ulger C, et al: Dopamine receptor 4 (DRD4) 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study. J Child Adolesc Psychopharmacol 2004;14(4):564-574

5. Myer NM, Boland JR, and Faraone SV: Pharmacogenetics Predictors of Methylphenidate Efficacy in Childhood ADHD. Mol Psychiatry 2017, doi: 10.1038/mp.2017.234

Special Instructions Library of PDFs including pertinent information and forms related to the test