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DRD4 48bp multiallelic variants as age-population-specific biomarkers in Attention-Deficit/Hyperactivity Disorder

DRD4 48bp multiallelic variants as age-population-specific biomarkers in Attention-Deficit/Hyperactivity Disorder
DRD4 48bp multiallelic variants as age-population-specific biomarkers in Attention-Deficit/Hyperactivity Disorder
The identification of biomarkers to support the diagnosis and prediction of treatment response for attention-deficit/hyperactivity disorder (ADHD) is still a challenge. Our previous works highlighted the DRD4 (dopamine receptor D4) as the best potential genetic marker for childhood diagnosis and methylphenidate (MPH) response. Here, we aimed to provide additional evidence on biomarkers for ADHD diagnosis and treatment response, by using more specific approaches such as meta-analytic and bioinformatics tools. Via meta-analytic approaches including over 3000 cases and 16,000 controls, we demonstrated that, among the different variants studied in DRD4 gene, the 48-base pair, Variable Tandem Repeat Polymorphism, VNTR in exon 3 showed an age/population-specificity and an allelic heterogeneity. In particular, the 7R/“long” allele was identified as an ADHD risk factor in European-Caucasian populations (d = 1.31, 95%CI: 1.17–1.47, Z = 4.70/d = 1.36, 95%CI: 1.20–1.55, Z = 4.78, respectively), also, from the results of last meta-analysis, linked to the poor MPH efficacy. The 4R/“short” allele was a protective factor in European-Caucasian and South American populations (d = 0.83, 95%CI: 0.75–0.92, Z = 3.58), and was also associated to positive MPH response. These results refer to children with ADHD. No evidence of such associations was detected for adults with persistent ADHD (data from the last meta-analysis). Moreover, we found evidence that the 4R allele leads to higher receptor expression and increased sensitivity to dopamine, as compared with the 7R allele (d = 1.20, 95%CI: 0.71–1.69, Z = 4.81), and this is consistent with the ADHD protection/susceptibility effects of the respective alleles. Using bioinformatics tools, based on the latest genome-wide association (GWAS) meta-analysis of the Psychiatry Genomic Consortium (PGC), we demonstrated that the 48 bp VNTR is not in Linkage Disequilibrium with the DRD4 SNPs (Single Nucleotide Polymorphisms), which were not found to be associated with ADHD. Moreover, a DRD4 expression down regulation was found in ADHD specific brain regions (Putamen, Z score = −3.02, P = 0.00252). Overall, our results suggest that DRD4 48 bp VNTR variants should be considered as biomarkers to support the diagnosis of ADHD and to predict MPH response, although the accuracy of such a biomarker remains to be further elucidated.
Bonvicini, Cristian
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Cortese, Samuele
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Maj, Carlo
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Baune, Bernhard T.
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Faraone, Stephen
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Scassellati, Catia
f9ab9687-5dc1-41cd-b2bb-8d473bde3fc7
Bonvicini, Cristian
8e33237a-81f3-4324-9ee6-7707a36d9b80
Cortese, Samuele
53d4bf2c-4e0e-4c77-9385-218350560fdb
Maj, Carlo
a68229c5-f24e-415f-8b25-adc6d98c3da1
Baune, Bernhard T.
fa44425d-1578-4d53-8e8c-604e44a9af9b
Faraone, Stephen
19b748ae-7a78-4be2-9c00-695f9e7a97ee
Scassellati, Catia
f9ab9687-5dc1-41cd-b2bb-8d473bde3fc7

Bonvicini, Cristian, Cortese, Samuele, Maj, Carlo, Baune, Bernhard T., Faraone, Stephen and Scassellati, Catia (2020) DRD4 48bp multiallelic variants as age-population-specific biomarkers in Attention-Deficit/Hyperactivity Disorder. Translational Psychiatry, 10 (1), [70]. (doi:10.1038/s41398-020-0755-4).

Record type: Article

Abstract

The identification of biomarkers to support the diagnosis and prediction of treatment response for attention-deficit/hyperactivity disorder (ADHD) is still a challenge. Our previous works highlighted the DRD4 (dopamine receptor D4) as the best potential genetic marker for childhood diagnosis and methylphenidate (MPH) response. Here, we aimed to provide additional evidence on biomarkers for ADHD diagnosis and treatment response, by using more specific approaches such as meta-analytic and bioinformatics tools. Via meta-analytic approaches including over 3000 cases and 16,000 controls, we demonstrated that, among the different variants studied in DRD4 gene, the 48-base pair, Variable Tandem Repeat Polymorphism, VNTR in exon 3 showed an age/population-specificity and an allelic heterogeneity. In particular, the 7R/“long” allele was identified as an ADHD risk factor in European-Caucasian populations (d = 1.31, 95%CI: 1.17–1.47, Z = 4.70/d = 1.36, 95%CI: 1.20–1.55, Z = 4.78, respectively), also, from the results of last meta-analysis, linked to the poor MPH efficacy. The 4R/“short” allele was a protective factor in European-Caucasian and South American populations (d = 0.83, 95%CI: 0.75–0.92, Z = 3.58), and was also associated to positive MPH response. These results refer to children with ADHD. No evidence of such associations was detected for adults with persistent ADHD (data from the last meta-analysis). Moreover, we found evidence that the 4R allele leads to higher receptor expression and increased sensitivity to dopamine, as compared with the 7R allele (d = 1.20, 95%CI: 0.71–1.69, Z = 4.81), and this is consistent with the ADHD protection/susceptibility effects of the respective alleles. Using bioinformatics tools, based on the latest genome-wide association (GWAS) meta-analysis of the Psychiatry Genomic Consortium (PGC), we demonstrated that the 48 bp VNTR is not in Linkage Disequilibrium with the DRD4 SNPs (Single Nucleotide Polymorphisms), which were not found to be associated with ADHD. Moreover, a DRD4 expression down regulation was found in ADHD specific brain regions (Putamen, Z score = −3.02, P = 0.00252). Overall, our results suggest that DRD4 48 bp VNTR variants should be considered as biomarkers to support the diagnosis of ADHD and to predict MPH response, although the accuracy of such a biomarker remains to be further elucidated.

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DRD4 ADHD_Rev_CLEAN VERSION_II - Accepted Manuscript
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Accepted/In Press date: 20 December 2019
e-pub ahead of print date: 19 February 2020

Identifiers

Local EPrints ID: 436817
URI: http://eprints.soton.ac.uk/id/eprint/436817
PURE UUID: 1ea96f32-e309-48bd-959f-c93bb7254f1c
ORCID for Samuele Cortese: ORCID iD orcid.org/0000-0001-5877-8075

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Date deposited: 10 Jan 2020 17:31
Last modified: 28 Apr 2022 05:30

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Contributors

Author: Cristian Bonvicini
Author: Samuele Cortese ORCID iD
Author: Carlo Maj
Author: Bernhard T. Baune
Author: Stephen Faraone
Author: Catia Scassellati

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