Genetics of attention-deficit/hyperactivity disorder: an update

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting children, adolescents, and adults. The prevalence is estimated at 5 to 7% of school-aged children and 2.5 to 5% of adults. The phenotype is complex and heterogeneous, presenting variable clinical features, developmental course, and outcome. The genetic susceptibility to ADHD is attributed to both common and rare variants from a broad range of genes related mainly to neurotransmission and neurodevelopment pathways. However, it has been difficult to identify the genetic risk variants that account for the high heritability of this disorder. In this paper, we present recent findings from molecular genetics studies on both child and adult ADHD. Challenges and future directions for ADHD genetic studies are reviewed and discussed.

KEYWORDS:

• ADHD
• CNVs
• genetics
• GWAS
• pathway analysis
• polygenic risk score analysis
• susceptibility

Financial & competing interests disclosure

MH Hutz receives support from Brazilian government institutions (CNPq, FINEP and CAPES). LA Rohde has been a member of the speakers’ bureau/advisory board and/or acted as a consultant for Eli-Lilly, Janssen-Cilag, Novartis and Shire in the last three years. He receives authorship royalties from Oxford Press and ArtMed. He has also received travel awards from Shire for his participation in the 2014 American Psychiatric Association meeting and in the 2015 World Federation of ADHD meeting. The ADHD and Juvenile Bipolar Disorder Outpatient chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Eli-Lilly, Janssen-Cilag, Novartis, and Shire. He also receives research support from Brazilian government institutions (CNPq, FAPERGS, HCPA and CAPES). GC Akutagaya-Martins has a post-doctoral fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico- CNPq-Brazil. The work was supported by Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior, Brazil. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• ADHD is a common neurodevelopmental disorder affecting 5–7% of school-aged children and 2.5–5% of adults.

• Genetics has a key role in ADHD etiology, with an estimated heritability of around 76%.

• To date, published genome-wide association studies (GWASs) did not identify significant risk loci but presented some promising genes, such as CDH13 and, more recently, FBOX33.

• Pathway analyses based on GWAS support a role for pathways involved in neurodevelopment and, more recently, ubiquitin-proteasome, immune, and inflammatory pathways.

• Polygenic score analysis demonstrates that common variants of very small effect are associated with ADHD in both clinical and general population samples.

• CNV studies demonstrate that, alongside common genetic variants, rare variants play a role in ADHD etiology.

• Cross-disorder analysis supports a role for calcium channel signaling pathway in the etiology of different psychiatric diseases, including ADHD.

• Dimensional approaches, in both clinical ADHD and ADHD traits in the general population, gene x gene and gene x environment studies, and exome sequencing are promising strategies in future ADHD research.