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 downregulation 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.
Highlights
Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder, characterized byThe severity level and presentation of ADHD changes over the lifespan, with adult patients displaying less obvious symptoms of hyperactivity and impulsivity5.Bonvicini et al Translational Psychiatry (2020)10:70changes in structural brain abnormalities from childhood to adulthood with ADHD have been reported6, suggesting potential differential causes for the onset and persistence of the disorder7.ADHD aetiology is not yet completely understood.Despite evidence that environmental factors play a significant role, genetic studies support a strong genetic contribution
Meta-analysis DRD4 polymorphisms in children with ADHD 48 bp VNTR polymorphism The PRISMA flow chart is in Supplementary Fig. S1
As associations were observed for the SLC6A3 gene7,55 where allelic variants showed differential effects in children and adults with ADHD, these findings suggest that DRD4 and SLC6A3 are among those genes that account for developmental variations with differential effects across the lifespan
Summary
Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder, characterized byThe severity level and presentation of ADHD changes over the lifespan, with adult patients displaying less obvious symptoms of hyperactivity and impulsivity5.Bonvicini et al Translational Psychiatry (2020)10:70changes in structural brain abnormalities from childhood to adulthood with ADHD have been reported, suggesting potential differential causes for the onset and persistence of the disorder7.ADHD aetiology is not yet completely understood.Despite evidence that environmental factors (e.g., maternal smoking, low birth weight, and prematurity) play a significant role, genetic studies support a strong genetic contribution. Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder, characterized by. The severity level and presentation of ADHD changes over the lifespan, with adult patients displaying less obvious symptoms of hyperactivity and impulsivity. Changes in structural brain abnormalities from childhood to adulthood with ADHD have been reported, suggesting potential differential causes for the onset and persistence of the disorder. Despite evidence that environmental factors (e.g., maternal smoking, low birth weight, and prematurity) play a significant role, genetic studies support a strong genetic contribution. The most recent and largest genome-wide association (GWAS) meta-analysis from the Psychiatric Genomics Consortium (PGC) identified common single-nucleotide (SNPs) variants, surpassing genome-wide significance in 12 independent loci, providing important new insights into the neurobiology of childhood ADHD. Additional insight comes from the studies on the crucial role played by rare variants
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