The familial and highly heritable nature of ADHD has been known for several decades. More recently, technological advances and large-scale collaboration have allowed further investigation into the genetic basis of ADHD. In this selective and conceptual review, the author examined the genetic discoveries during the past 5 years, and considered their implications for the conceptualisation of ADHD and future clinical practice.
Genetic overlap between ADHD and neurodevelopmental disorders
ADHD shares similar traits with childhood developmental disorders, such as autism spectrum disorder (ASD) and intellectual disability; these traits include an early onset of disease, a steady clinical course and the presence of early neurocognitive deficits. Recent genetic studies have also revealed a strong genetic overlap between ADHD, ASD and intellectual disability.
Until the publication of the Diagnostic and Statistical Manual of Mental Disorders – 5th Edition, the diagnosis of ADHD was disallowed in the presence of ASD. The author stated that the change in the guidelines was a welcome change, and is an important focus for clinicians and service providers, who tend to be diagnosis-specific. Despite the genetic overlap between ADHD, ASD and intellectual disability, individuals with a lower IQ have historically been excluded from genetic studies of ADHD. The author emphasised the importance of including individuals with ADHD who have comorbid intellectual disability or ASD in such studies, to ensure that the studies are fully representative of the clinical population.
Genetic overlap between ADHD and neuropsychiatric disorders and other conditions
Recent genome-wide association studies (GWAS) have demonstrated that ADHD is associated with significant positive genetic correlations with a wide range of neuropsychiatric disorders, including schizophrenia, bipolar disorder, Tourette’s syndrome, anxiety disorder and major depressive disorder. Furthermore, GWAS have shown strong genetic overlap between ADHD and some physical conditions and traits, including lung cancer, insomnia and migraine. Genetic correlations have also been demonstrated with some social and environmental phenotypes, such as educational attainment and smoking behaviours.
Although these are important findings, the author stated that the observation of genetic overlap itself is no longer a novel observation. Thus, efforts should now focus on testing alternative hypotheses using methods that can distinguish causal relationships, different ADHD subtypes and misclassification from pleiotropy.
Conceptualising ADHD as a trait and category
Although ADHD is usefully conceptualised as a disorder in clinical practice, the condition can also be viewed as a trait. Consistent with previous twin and epidemiological studies, recent GWAS have suggested that ADHD lies at the extreme end of a continuously distributed dimension, akin to hypertension along the continuum of blood pressure.
The author stated that these findings highlight the importance of applying a developmental continuum to ADHD. If ADHD is a trait, akin to blood pressure, then public or population health-based samples and approaches should be integrated with traditional genetics research on patients. Longitudinal population cohorts are also attractive for developmentally informative genetic studies, because unlike patient registry data, they involve trait-based assessments. The author noted that the conceptualisation of ADHD as a trait and disorder is particularly relevant for clinicians, as they most frequently encounter subthreshold cases in clinical practice; the presence of an underlying continuum means that issues such as defining the boundary for impairment and treatment are not straightforward.
Genetic mutations and implication for testing
Recent genetic discoveries have demonstrated that ADHD is a highly polygenetic disorder. This means that its genetic architecture is explained by thousands of common gene variants, which have a small effect size, as well as by rare mutations, some of which have a much larger effect size.
Very large sample sizes are required to detect individual common gene variants using GWAS, and until recently, these have been lacking for ADHD. Although GWAS in ADHD are now becoming more frequent, some studies remain underpowered. For example, GWAS have not been able to confirm any of the candidate genes previously implicated in ADHD (e.g. dopaminergic genes); however, this evidence could emerge with larger GWAS samples. Recent genetic discoveries have also implicated rare genetic mutations, such as copy number variants and protein-truncating variants in ADHD, with significant overlap observed between ADHD and ASD.
Routine testing for rare mutations in ADHD is not currently recommended; however, guidelines for such testing in clinical settings have been expanded in many countries to include intellectual disability and, in the US, ASD. In the author’s opinion, the reducing costs of genetic testing and the increasing knowledge of the causality of different mutations will lead to the introduction of routine testing for ADHD within the next decade, particularly if some rare mutations are found to have treatment or prognostic implications. Due to the weak predictive power and smaller risk effects associated with common genetic variants, the author suggested that their clinical utility for predicting ADHD is less certain. Despite this, combining information on common genetic scores and family history may be helpful in stratifying individuals with ADHD for the purposes of treatment or prognosis (e.g. in identifying those at increased risk of future psychosis or in guiding treatment).
The author concluded that many novel genetic findings have emerged, and will continue to emerge, in the 21st century. In the author’s opinion, these genetic discoveries are of interest and relevance to a broad scientific field, including neuroscientists, developmental scientists and population epidemiologists, as well as clinicians. These findings may help to shape the next 5 years of research and clinical practice in ADHD.
Thapar A. Discoveries on the genetics of ADHD in the 21st century: new findings and their implications. Am J Psychiatry 2018; 175: 943-950.