Update on ADHD genetics: A practitioner's perspective: Mise à jour sur la génétique du TDAH : le point de vue d’un praticien

Abstract

French

Background

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterized by early-onset inattention, hyperactivity, and impulsiveness. Affecting 5% to 10% of youth and persisting into adulthood in ∼6%, ADHD is frequently discussed in genetic terms by patients and their families, making it essential for clinicians to understand current genetic evidence.

Objective

To summarize contemporary genetic findings relevant to ADHD across the lifespan and provide practical guidance for clinicians on assessment, treatment, and psychoeducation.

Scope and methods

This focused narrative review integrates evidence from family and twin studies, genome-wide association studies (GWAS), copy number variants (CNVs), polygenic risk scores (PRS), and Mendelian randomization (MR), as well as pharmacogenetics and studies of gene–environment interplay.

Findings

ADHD is highly heritable (∼70%), comparable to other major neuropsychiatric conditions. GWAS reveals that thousands of common variants collectively contribute to risk (i.e., polygenic), though each has a small effect. Rare CNVs are more frequent in ADHD than controls and overlap with CNVs in autism. Genetic findings implicate neurodevelopmental pathways expressed in early brain and frontal cortical circuits. ADHD genetic risk correlates with cognitive traits, risk-taking behaviours, and multiple psychiatric and physical health outcomes. Gene–environment correlations and interactions influence risk and course. Pharmacogenetic evidence supports CYP2D6 genotyping for atomoxetine dosing; routine genetic testing for stimulant selection is not justified.

Clinical implications

There are no diagnostic genetic tests for ADHD. Assessment should prioritize functional impairment, developmental and family history, and comorbidity. Psychoeducation should emphasize modifiable risks and the interplay of genes and the environment. While genetic insights may eventually refine diagnosis and personalized care, current best practice relies on comprehensive clinical evaluation and multimodal management.

Conclusion

Genetic research confirms ADHD's neurodevelopmental basis, continuity across the lifespan, and overlap with other neurodevelopmental conditions of childhood. Clinicians can use these insights for counselling and risk monitoring while avoiding over-reliance on genetic testing outside targeted pharmacogenetic use.

Plain language summary

Update on ADHD Genetics: A Practitioner’s Perspective

Attention deficit/hyperactivity disorder (ADHD) is a common condition that usually begins in childhood and can continue into adulthood. It affects attention, activity level, and impulse control. About 5–10% of children are diagnosed with ADHD, and for some people, symptoms continue later in life. Because ADHD often appears in more than one family member, many people wonder how much genetics plays a role.

Research shows that genes do influence ADHD, but there is no single “ADHD gene.” Instead, many genes each contribute a very small amount to a person’s likelihood of developing ADHD. These genetic influences affect early brain development, supporting the idea that ADHD is a brain based condition. Some of the same genetic factors are also involved in other neurodevelopmental conditions, such as autism. Genetic risk linked to ADHD is also related to traits like attention, activity level, and risk taking, as well as some mental and physical health conditions.

Genes do not act alone. Environmental factors such as school demands, family environment, and life stress also play an important role in how ADHD develops and how much it affects daily life. Genetics can help explain why some people are more vulnerable than others, but it does not explain why ADHD diagnosis rates change over time or differ between communities.

There is currently no genetic test that can diagnose ADHD or determine which ADHD medication will work best for an individual. Diagnosis is made through clinical evaluation that focuses on symptoms, daily functioning, development, and family history. Genetic information can be helpful for understanding ADHD and discussing it with families, but care and treatment are still guided by careful assessment and personalized support, not by genetic testing.

Keywords

ADHD genetics genetic testing practice guidance

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder defined by early onset, developmentally atypical and impairing restless, inattentive and impulsive traits. ADHD affects 2.5% to 5% of children and youth worldwide. Meta-analyses of longitudinal cohort studies have consistently shown that ADHD frequently persists beyond childhood. Approximately 15% to 20% of individuals diagnosed in childhood continue to meet full DSM diagnostic criteria in adulthood, while a substantially larger proportion (around 50-65%) continue to exhibit clinically significant and impairing ADHD symptoms, either at subthreshold or full diagnostic levels and accounts for considerable burden of disease.^1–3 The prevalence of ADHD is rising, particularly in adults.^4–6

Assessment and management of ADHD are complicated by the high prevalence of comorbid mental health disorders, which occur 4.5 to 8 times more frequently in individuals with ADHD. These include major depressive disorder, bipolar disorder, anxiety disorders, autism, and substance use disorders.⁷ Gaps in specialized services for children and adults with ADHD means that primary care physicians, clinical nurse practitioners, pediatricians, and generalist psychiatrists must increasingly bear the responsibility for comprehensive assessment, treatment, and patient education.⁸ Patients, practitioners and policy makers often want to know whether they will transmit or inherit ADHD, whether genetic testing can confirm the diagnosis or help guide treatment, and whether genetic factors explain secular trends in prevalence rates. This interest in genetics has grown alongside media coverage of genetic research and the availability of direct-to-consumer genetic tests.

This article synthesizes key genetic findings relevant to ADHD across the lifespan with a focus on what family doctors, pediatricians, clinical nurse practitioners and generalist psychiatrists need to know. We focus on the contribution of genetics to the understanding of ADHD's etiology, diagnosis and treatment, mental and physical health comorbidity, long-term care, and counselling and psychoeducation.

The genetic architecture of ADHD

ADHD is a complex, multifactorial neurodevelopmental condition arising from interactions among genetic susceptibility, variations in brain development and neural function,^9,10 environmental exposures,¹¹ cognitive impairments,¹² and immune and inflammatory risks.¹³ Traits such as inattentiveness, restlessness, and impulsiveness exist on a severity continuum in the general population. When these traits are frequent and impair daily life, they cross the threshold into an ADHD diagnosis.

Genetic factors play a major role in ADHD. Family studies show that first-degree relatives of individuals with ADHD are 4 to 5 times more likely to have the disorder than relatives of unaffected individuals.¹⁴ ADHD also shares familial risk with autism and conduct disorder.¹⁵ This risk is bidirectional: there is an increased likelihood of ADHD among relatives of individuals with autism.¹⁶ However, familial aggregation alone does not confirm a genetic basis.

Twin studies estimate heritability (h²) by comparing concordance in monozygotic (MZ) and dizygotic (DZ) twins. Across 38 studies, mean heritability is 74%,¹⁴ like autism (74%) and schizophrenia (77%), but lower than other traits such as height (90%).¹⁷ Estimates are consistent across ADHD traits and DSM diagnoses and are comparable in individuals with ADHD that persists into adulthood.¹⁴ Twin studies show that ADHD also shares genetic risks with autism, conduct disorder, depression, and schizophrenia.^18,19

Genome-wide association studies (GWAS) compare common variants in DNA (present in at least 5% of the population) across the genomes of ADHD and controls, to identify genetic variants associated with the disorder (risk loci). The largest ADHD GWAS to date (38,691 ADHD cases and 186,843 controls)¹⁷ identified 27 genome-wide significant risk loci mapping to 76 risk genes involved in neurodevelopmental processes. These genetic risks are often expressed in the frontal cortex or in neurons during early brain development. SNP heritability (proportion of variation in ADHD that SNPs explained) was significant (h²SNP = 0.14), but lower than estimates of heritability from twin studies (74%). “Missing heritability” may be identified using larger samples as has been the case with other mental and physical conditions, more precise genetic resolution (e.g., sequencing of an individual's entire genome), and increasingly homogeneous and better-defined samples. The results of the Demontis GWAS¹⁷ demonstrate that ADHD is highly polygenic: Over 7,000 common variants explain 90% of its SNP heritability. The polygenicity of ADHD is comparable to estimates for schizophrenia (8.5 K common variants), autism (9.9 K), and bipolar disorder (8.6 K).

Polygenic risk scores (PRS) summarize the combined effects of common genetic loci contributing to ADHD. Genetic correlation analyses also examine overlapping genetic risk, which occurs when the same genetic variants influence multiple phenotypes—a phenomenon known as pleiotropy. Researchers use these methods to assess shared genetic influences across traits and disorders. Mendelian randomization (MR) analysis uses GWAS data to estimate the causal relationships between ADHD genetic variants and other traits or disorders.

PRS analyses indicate substantial genetic overlap between ADHD and other mental health conditions (autism, major depressive disorder, schizophrenia, cannabis use disorder, alcohol use disorder, and risk of depression later in life^17–21), irritability, aggression and risk-taking behaviours (impulsiveness, smoking, early pregnancy), insomnia, academic attainment, and intelligence.^17,22 ADHD PRS is negatively associated with performance on working memory, facial memory, verbal, nonverbal, and spatial reasoning tasks, as well as standardized reading tests and measures of language ability.²³ ADHD PRS is linearly related to the likelihood of an ADHD diagnosis and the severity of ADHD traits, indicating that genetic risk for ADHD is quantitative in nature.²⁴ However, PRS explains only 4% of ADHD variation and is not diagnostic.^28–30 Accuracy declines in non-European ancestry groups given lack of diversity in the current GWAS , so PRS remains a research tool for now.

Rare copy number variants (CNVs) also contribute to ADHD.^25–29 CNVs are low-frequency (< 1% of the population) losses or gains of gene segments or genes which can contribute to ADHD by altering gene function and affecting brain structure³⁰ or neurotransmitter function.³¹ CNVs may be inherited or occur de novo (i.e., they only appear in the child but not the parents).^26,30,32 Inherited plus de novo CNVs occur in 9.4% of those with ADHD, 11.4% with autism, 10.8% with schizophrenia, and 5.6% with obsessive compulsive disorder.³³ Some CNVs amplify risk conferred by common genetic variants, whereas others may provide protection.²⁸ Many of the CNVs associated with ADHD also appear in other disorders such as autism and schizophrenia,³⁴ which indicates that susceptibility genes are shared across multiple mental health conditions.^19,35,36

Genetics of ADHD across the life span

Genetic factors influence the persistence of ADHD from childhood to adulthood. Family studies show that greater familial aggregation of ADHD predicts a higher likelihood that ADHD will persist.³⁷ Genetic studies indicate that ADHD diagnosed in childhood is genetically comparable to ADHD first diagnosed in adulthood, provided there is evidence of childhood onset. SNP heritability is similar across groups: persistent ADHD (h²_SNP = 0.29), first diagnosis in adulthood with childhood onset (h²_SNP = 0.27), and childhood-onset ADHD (h²_SNP = 0.24).^15,38 However, ADHD PRS are higher in children with persistent ADHD than in those with nonpersistent ADHD, suggesting a possible dose–response effect on persistence. These findings support the conclusion that childhood ADHD and ADHD first detected in adulthood with a childhood history are genetically comparable conditions and that the magnitude of genetic risk influences the disorder's course.^39,40

ADHD, physical health and risk factors

One of the most important findings of recent genetic research is the association of ADHD genetic risk and risk for physical illnesses and risk factors including elevated rate of mortality from natural and unnatural causes.⁴¹ PRS and genetic correlation analyses show a significant association between the genetic risk for ADHD and the genetic risk for body mass index (BMI), obesity, diabetes, migraines, mild cognitive impairment in mid-life and Alzheimer's disease in later life.^42–44 ADHD PRS is associated with younger age at first sexual intercourse, earlier age at time of first birth, increased risk-taking behaviour, smoking, younger age at mother's death and younger age at the time of mother's first birth and greater cognitive decline over 6 years in mid-life.^44–46

Studies using MR analyses support a causal relationship between ADHD genetic risk and increased risk of epilepsy, immune traits (e.g., rheumatoid arthritis), migraine, and cardiovascular disease (heart failure, cerebro- and peripheral vascular disease), obesity, and type 1 diabetes.^45,47–50 Education, BMI, tobacco use, and alcohol misuse significantly mediated these genetic effects.⁵¹

Genetic influences on treatment response

Stimulant medications (methylphenidate and amphetamines) are first-line treatments for ADHD, while nonstimulants (atomoxetine, clonidine, and guanfacine) are considered second-line options.⁵² These medications affect catecholamine signalling by inhibiting the reuptake of dopamine and norepinephrine.⁵³ Methylphenidate is metabolized by carboxylesterase 1 (CES1), and atomoxetine by CYP2D6. Both enzymes have multiple variants, resulting in different levels of activity.

There is growing interest in predicting treatment responses based on genetics. Although ADHD medications are generally effective, up to 35% of patients do not respond adequately, require switching from stimulants to nonstimulants, or experience significant adverse drug effects (ADEs) leading to discontinuation.^54,55 Many ADEs are troublesome and can undermine treatment adherence. Other ADEs involve cardiovascular effects,⁵⁶ dyskinetic movements, growth suppression⁵⁷ and in rare instances, psychosis⁵⁸ which can have serious long-term consequences.

Genetic factors influence synthesis, transport, metabolism, and receptor activity of monoamines such as dopamine and norepinephrine, making them promising markers for predicting clinical benefits or ADEs.⁵⁹ For example, individuals with a particular genetic variant (rs71647871) may experience up to 2.5-fold higher effective exposure to methylphenidate compared to those without the variant. Higher polygenic liability for mood or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities increase the risk of discontinuing stimulant treatment and switching to nonstimulants.⁵⁴ Nevertheless, the sensitivity and specificity of current genetic testing is insufficient to support genetic testing for selecting one stimulant over another or determining optimal stimulant dosing for ADHD treatment.^59,60

Genetic variation in CYP2D6 affects the conversion of atomoxetine into its metabolite, 4-hydroxyatomoxetine. Lower CYP2D6 activity increases effective exposure to atomoxetine and the risk of side effects, while higher activity has the opposite effect.⁵⁸ For this reason, CYP2D6 testing before treatment can be beneficial and is advised in several clinical practice guidelines which recommend that individuals with absent CYP2D6 activity (poor metabolizers) start with the standard initial dose but require increased monitoring and are less likely to require dose increases. If adverse effects occur, dose reductions are suggested for poor and intermediate metabolizers. Ultra-rapid metabolizers require monitoring for effectiveness. According to the FDA label, poor metabolizers should not exceed 1.2 mg/kg/day, while others may reach up to 1.4 mg/kg/day.^61,62 CYP2D6 genetic testing is widely available and can guide therapy when treatment does not achieve the desired clinical response.⁶³

Genetic testing

Except for testing for metabolic genes related to atomoxetine treatment, there are no established indications for genetic testing in ADHD. Clinical microarray (or consultation from clinical genetics) might be considered for ADHD assessment when the patient presents with comorbid autism or intellectual deficiency or displays dysmorphic features (e.g., hypertelorism, syndactyly), congenital malformations (e.g., cleft palate, tetralogy of Fallot, polydactyly), abnormal head size (± 2 standard deviation (SD) for age, sex, ethnicity), unexplained growth abnormalities (± 2 SD for age, sex, ethnicity), prenatal growth restriction, failure to thrive, or short stature. Assessment should involve screening of these issues. Genetic testing might be useful when family history is consistent with Mendelian inheritance (disorder appears in pedigrees according to dominant, recessive, or X-linked inheritance) or when a person presents with medical comorbidities that are not expected in ADHD (sensory-neuronal hearing loss, vision impairment, renal disease, epilepsy, ataxia, and neuromotor deficits) (Carter et al., 2023).

Environmental influences on ADHD

Twin studies show that about 25% of the variance in ADHD is attributable to shared environmental effects (likely to affect everyone in the family), gene–environment interactions, and nonshared environmental factors (likely to affect individuals in the family differently). A range of individual environmental risk factors predict ADHD symptom severity and the likelihood of diagnosis. Exposure to small particulate matter, nitrogen dioxide, or cigarette smoke may exert neurobiological effects during gestation and throughout development, increasing ADHD risk.⁶⁴ Psychosocial factors, such as adverse parenting practices, are also associated with ADHD.¹¹

Genetic and environmental factors can act independently but often have additive effects on mental health,⁶⁵ or they may exert correlated effects. For example, parents’ genetic risk for ADHD increases the likelihood of smoking or inconsistent parenting, which in turn creates environmental exposures that compound transmitted genetic risks.^66,67 Similarly, ADHD in a child may evoke negative environmental responses, such as inconsistent parenting, which are more likely if the parent also has ADHD or ADHD traits. Genetic and environmental risks can interact so that similar environmental influences have a greater impact on genetically predisposed individuals, and genetic effects are more pronounced among those exposed to environmental risk.⁶⁸ Emerging evidence suggests that some environmental influences may operate through epigenetic mechanisms that alter gene expression rather than DNA sequence.⁶⁹

Guidance for translating ADHD genetics into clinical practice

ADHD is a clinical—not genetic—diagnosis.

There is no genetic “test” to diagnose ADHD or distinguish it from other mental health conditions.⁷⁰

Genetic risks that have been identified to date account for a small proportion of variation in ADHD only.

Direct-to-consumer genetic tests do not aid diagnosis.⁷⁰

Aside from testing for metabolic genes related to atomoxetine treatment, there are no established indications for genetic testing in routine ADHD assessment.

Consider clinical microarray or genetics consultation when comorbid autism, intellectual disability, or dysmorphic features are present.

Follow clinical guidelines for assessing attention, activity, self-regulation, and associated impairments.^72-74

Obtain a multigenerational family history.

The high heritability of ADHD means that there is a high likelihood that there will be multiple affected individuals in the patient's family.

Familial aggregation can strain family relations.

Transdiagnostic genetic sharing means family history may reveal relatives with autism or traits linked to ADHD, such as risk-taking or learning difficulties.

Highlight the importance of mental health and well-being of all family members.

Preassessment screening forms reviewed during evaluation efficiently capture family history.

Review mental and physical health comprehensively.

ADHD shares risks with other mental, academic, and physical conditions.

Assess comorbidities and risk behaviours at baseline and follow-up.

Treat concurrent mental health conditions when possible; refer complex cases (e.g., suspected bipolar disorder, schizophrenia) to specialists and collaborate with family physicians for physical health concerns.

Encourage open discussion to improve outcomes, empower families, and alleviate guilt.

Explain ADHD as a neurodevelopmental disorder—not laziness or poor parenting.

Stress that ADHD is highly heritable but not deterministic: many at-risk individuals never develop it.

Address modifiable non-genetic risks.

Ask parents what they believe causes their child's difficulties to start dialog.

Families often hold deterministic views (e.g., “They’ll turn out like their uncle”).

A detailed family history facilitates discussion of genetic influences and related health risks.

Genes increase risk but do not dictate outcomes.

Environment, experiences, and lifestyle matter.

Nothing is anyone's fault, and genetics do not define potential.

While practitioners cannot reduce genetic risk, interventions can mitigate environmental risk and build resilience—through medication, exercise, healthy diet, reduced media exposure, educational support, skill development, and positive parenting.

Shared genetic risks might explain ADHD's frequent comorbidities.

This knowledge informs psychoeducation and health monitoring, especially given associations with immune disorders, cardiovascular disease, cognitive decline, and premature mortality.

Genetic and environmental risks interact in a “dose-dependent” manner: more combined risks lead to greater ADHD severity.

Finally, address ethical issues, including privacy and stigma.

Explain that genetic information obtained through family history or genetic testing is confidential, shared only with consent, and used to guide care—not to label or limit.

Sometimes genetic insights can be used to benefit family members.

Conclusion

This focused review summarizes key findings from genetic studies of ADHD for general practitioners, pediatricians, clinical nurse practitioners, and psychiatrists. It is not a complete guide to the assessment, treatment, or management of ADHD in either children or adults.

Family, twin, and molecular genetic studies provide unambiguous evidence that genetic factors contribute to ADHD across the lifespan. Genetic risks in adult ADHD that have persisted from childhood are comparable to those in childhood ADHD, and the magnitude of genetic risks predicts persistence lending credence to the validity of the diagnosis and the importance of family history. Like other mental health disorders, ADHD is highly polygenic. We can explain only a modest proportion of variation in ADHD using common variants (10-20%) and rare variants (∼10%). We will identify more variants with larger samples and increasing precision in genetic analysis.

Identified genetic risks are involved in brain function, supporting the conclusion that ADHD is a neurodevelopmental disorder. This understanding can help reduce stigma but also raise concerns about genetic determinism and the potential for inducing helplessness among affected individuals. Psychoeducation should emphasize factors within patients’ and families’ control, such as diet, exercise, and the quality of family relationships.

Individual genetic variants are only modestly associated with response to ADHD medications. Current clinical practice guidelines do not recommend pharmacogenetic testing with the possible exception of CYP2D6 testing for atomoxetine treatment. Family history of drug response, as a proxy for genetic effects, can be a useful starting point for predicting medication response. As research advances, genetic markers may become part of diagnostic algorithms or treatment selection tools, but these markers are likely to include other types of information beyond genetic variation. Overlap between ADHD genetic risks and those of other mental and physical health conditions could lead to new insights about mechanisms and repurposing of drugs.

Genetic research into ADHD and other mental health disorders is shaping the future of psychiatric nosology and clinical practice. Genetic risks associated with ADHD correlate quantitatively with attention, activity, and impulsivity, supporting the view that ADHD is less a discrete entity with sharp clinical boundaries than the extreme end of ADHD-related traits widely distributed in the general population. Genetic factors explain why some individuals are more vulnerable than others, but differences in prevalence rates across places or time are driven primarily by diagnostic practices (thresholds, awareness, help-seeking, and access to services), social context, and environmental demands (school quality and structure; workplace demands), rather than by population genetics, which are likely relatively stable. Genetic risk constrains prevalence estimates to a plausible range but cannot determine their exact level. Temporal changes in prevalence have occurred far more rapidly than population-level genetic evolution and are overwhelmingly nongenetic in origin.

Genetic factors contribute to understanding ADHD's persistence. Family history of ADHD is one of the most robust predictors of persistence. Consistent with this, PRS for ADHD modestly predict symptom persistence and diagnostic continuity from childhood into adolescence and adulthood. Higher ADHD PRS is associated with greater childhood severity and an increased likelihood of persistent ADHD, although PRS explains only a small proportion of variance and lacks clinical utility for individual-level prediction. Clinically, individuals with persistent ADHD show higher mean PRS than those whose ADHD remits, despite substantial overlap between groups. PRS evidence also supports continuity between childhood- and adult-diagnosed ADHD, as adults with persistent childhood-onset ADHD show elevated PRS, whereas individuals with apparent adult-onset ADHD generally do not.³⁹

Shared genetic risks for common mental illnesses suggest a conceptual model in which disorders such as ADHD result from both general transdiagnostic genetic vulnerability and a more specific set of genetic and other risk factors that shape a particular disorder. Currently, there is no sharp demarcation between affected and unaffected individuals, meaning that many people will have symptoms and impairment that just meet diagnostic criteria, while others fall just short. Monitoring severity and impairment over time is necessary to reduce overdiagnosis and to guide treatment decisions in the context of uncertain diagnosis.

ADHD genetics is an active area of research with potential to reveal novel mechanistic insights and new treatments that will improve patient care. We need far more research into combinations of risk markers (genetic, environmental, neuropsychological, clinical) and the role of environmental influences on gene function (epigenetics). There is a critical need to broaden the ethnic diversity of study populations to enhance equity and improve the potential for discovering causal genes.^71,72 Larger study samples and more precise genetic analyses, such as whole-genome sequencing, will clarify the full extent of genetic contributions to ADHD. Promising leads regarding specific genetic risks and pathways may eventually result in improved diagnostics and treatment options.

Genetic considerations are essential for adequate assessment and patient care, even in the absence of genetic testing. Translating genetic findings into clinical practice is a new frontier and ripe for research. Mental health practitioners of the future will benefit from additional training in genetics to understand and incorporate new methods and findings into practice. Practitioners who grasp these developments will be better prepared to integrate genetic data into clinical care.

Footnotes

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Canadian Institutes of Health Research, Ontario Brain Institute (Grant Nos. PJT-159462; PJT-165876; MOP-106573; MOP–93696 and, IDS-Il-02).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ORCID iDs

Russell Schachar

Jennifer Crosbie

Paul D. Arnold

Christie L. Burton

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