An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

Abstract

Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

Recent developments in the genetics of attention‐deficit hyperactivity disorder

“…This was indeed found in one study looking at polygenic risk scores in cases with rare variants. In this study, patients with ADHD without rare variants had indeed higher polygenic risk scores, supporting the importance of rare variants in lowering the genetic threshold for penetrance of the phenotype …”

“…Further genome‐wide studies of childhood ADHD have investigated the overall burden with rare, large CNV in cases compared to healthy volunteers. They have provided some evidence of an overall enrichment of rare variants in childhood ADHD cases, which was, however, not replicated in another study …”

Genetics of ADHD: What Should the Clinician Know?

“…Further genome-wide studies on ADHD in childhood investigated the overall burden of rare, large CNVs in patients compared to healthy subjects. They provide some evidence of an accumulation of rare variants in childhood ADHD [40][41][42]. Nevertheless, there is no ADHD-specific CNV, but an increase in the total number of CNVs within ADHD patients ("high CNV burden") compared to the control group is observed.…”

Genetische Grundlagen der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung

“…Weitere genomweite Studien zur ADHS im Kindesalter untersuchten die Gesamtbelastung mit seltenen, großen CNVs in Patien-tenfällen im Vergleich zu gesunden Probanden. Sie lieferten einige Hinweise auf eine Gesamtanreicherung seltener Varianten bei ADHS im Kindesalter [38][39][40], die jedoch noch der Replikation harren. Bisher gibt es kein ADHS-spezifisches CNV, sondern man beobachtet einen Anstieg an der Gesamtzahl an CNVs innerhalb von ADHS-Patienten ("high CNV burden") im Vergleich zur Kontrollgruppe.…”