A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder

Joanna Martin,Elliott Rees,Grace Hosking,Michael J Owen,George Kirov,Michael O’Donovan,Megan Wadon,Kate Langley,Sharifah Shameem Agha,Anita Thapar

doi:10.1038/s41398-020-0821-y

Abstract

Recent case–control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD. Children with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200 kb) CNVs and identified those calls that were present in the proband and absent in both biological parents. In 305 parent–offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at four genomic loci (15q13.1–13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case–control ADHD studies. Our study complements ADHD case–control genomic analyses and demonstrates the need for larger parent–offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.

Highlights

Attention deficit hyperactivity disorder (ADHD) is a highly heritable (~70%), common and impairing neurodevelopmental disorder with a complex genetic architecture[1]
The rate of de novo copy number variants (CNVs) is highest in individuals with developmental delay/ intellectual disability (DD/ID), at ~10%15
We examined whether the loci disrupted by the de novo CNVs had previously been implicated in case–control common variant[2] and rare CNV studies[4,5,6] of ADHD

Summary

Introduction

Attention deficit hyperactivity disorder (ADHD) is a highly heritable (~70%), common and impairing neurodevelopmental disorder with a complex genetic architecture[1]. Individuals with ASD have a rate of de novo CNVs that is between three- and fivefold higher than in unaffected siblings or control individuals[13]. Individuals with simplex Tourette disorder have a similar rate of de novo CNVs to probands with ASD14 as do individuals with schizophrenia[7]. Of these neurodevelopmental disorders, the rate of de novo CNVs is highest in individuals with DD/ID, at ~10%15.

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Conclusion