Genetic research can contribute not only to the elucidation of neurobiological mechanisms but also to clinical questions such as the effect of operationalization or the genetic correlation with comorbid disorders. Patients with ADHD show high comorbidity with autism, obesity, bipolar disorder and depression, anxiety, and substance use disorder. This suggests common underlying risk gene variants. Genetic correlations provide insights how biologic mechanisms manifest in different but related disorders (pleiotropy). Here we look at why this is so.

Introduction

Understanding the difference between Heritability vs. Risk of having offspring with ADHD

Understanding that heritability is NOT equal to the genetic risk of your child being born with ADHD, but simply a measure of how much (in percentages) that the TRAITS associated with ADHD, can be traced back to their underlying, causal genetic origins.

This means, that 80% of the behaviors associated with persons with ADHD are NOT under the individual’s willpower or cognizant control, meaning that these behaviors are pre-programmed from Nature and is to be understood in the context of unconscious behavior, like breathing, sleeping and processing food into energy.

In others words, a heritability of 80% does NOT mean that if you have ADHD, then 80% of your children will be born with ADHD, but that the behavior associated with ADHD (hyperactivity, impulsivity, distractability, emotional dysregulation, and mind wandering) can be scientifically linked to the genetics that are shared by ALL persons with a clinical diagnosis of ADHD.

What this also means is, that merely 20% of the behaviors we often see in persons with ADHD is NOT genetically in origin, but is due to psychosocial, sociocultural, and intra-personal influences, that are within some degree of the individual’s cognizant willpower or control.

This unequivocally settles the debate of Nature vs. Nurture in the behaviors related to ADHD – it is NOT the parent’s style of upbringing, social status, or familial culture that creates these behaviors – they were delivered into the child’s genetics at the time of conception, long before parenting style ever had any influence – at all.

Therefore this ends the debate on whether a child is born with ADHD or if the child develops ADHD during childhood – it does NOT!

ADHD is a genetic, neurobiological neurodevelopmental disorder, and thereby something that you are born with and that you will die with – just like diabetes type I is – there is NO difference – period!

FACT: What is heritability?

The following definitions are carbon copy quotes from The U.S. National Library of Medicine – Genetics Home Reference, which is the scientific consensus of this topics, as proven by scientific evidence using the Scientific Method – or said in plain English – The Truth (as we know it today), and I will quote it in its entirety so not to leave any room for misconceptions or possible doubt concerning ADDspeaker’s agenda in this article. We have only one agenda – No BS, Just Science …

[…] Heritability is a measure of how well differences in people’s genes account for differences in their traits. Traits can include characteristics such as height, eye color, and intelligence, as well as disorders like schizophrenia and autism spectrum disorder. In scientific terms, heritability is a statistical concept (represented as h²) that describes how much of the variation in a given trait can be attributed to genetic variation. An estimate of the heritability of a trait is specific to one population in one environment, and it can change over time as circumstances change. […]

[…] Heritability estimates range from zero to one. A heritability close to zero indicates that almost all of the variability in a trait among people is due to environmental factors, with very little influence from genetic differences. Characteristics such as religion, language spoken, and political preference have a heritability of zero because they are not under genetic control. A heritability close to one indicates that almost all of the variability in a trait comes from genetic differences, with very little contribution from environmental factors. Many disorders that are caused by mutations in single genes, such as phenylketonuria (PKU), have high heritability. Most complex traits in people, such as intelligence and multifactorial diseases, have a heritability somewhere in the middle, suggesting that their variability is due to a combination of genetic and environmental factors. […]

[…] Heritability has historically been estimated from studies of twins. Identical twins have almost no differences in their DNA, while fraternal twins share, on average, 50 percent of their DNA. If a trait appears to be more similar in identical twins than in fraternal twins (when they were raised together in the same environment), genetic factors likely play an important role in determining that trait. By comparing a trait in identical twins versus fraternal twins, researchers can calculate an estimate of its heritability. […]

[…] Heritability can be difficult to understand, so there are many misconceptions about what it can and cannot tell us about a given trait:

• Heritability does not indicate what proportion of a trait is determined by genes and what proportion is determined by environment. So, a heritability of 0.7 does not mean that a trait is 70% caused by genetic factors; it means than 70% of the variability in the trait in a population is due to genetic differences among people.
• Knowing the heritability of a trait does not provide information about which genes or environmental influences are involved, or how important they are in determining the trait.
• Heritable is not the same as familial. A trait is described as familial if it is shared by members of a family. Traits can appear in families for many reasons in addition to genetics, such as similarities in lifestyle and environment. For example, the language that is spoken tends to be shared in families, but it has no genetic contribution and so is not heritable.
• Heritability does not give any information about how easy or difficult it is to change a trait. For example, hair color is a trait with high heritability, but it is very easy to change with dye.

[…] If heritability provides such limited information, why do researchers study it? Heritability is of particular interest in understanding traits that are very complex with many contributing factors. Heritability can give initial clues as to the relative influences of “nature” (genetics) and “nurture” (environment) on complex traits, and it can give researchers a place to start teasing apart the factors that influence these traits. […]

What does the latest science say?

There are several ways to investigate the heritability of ADHD. A classical strategy makes use of twin studies, due to the possibility of assessing the genetic effect (heritability) of the disorder (Grimm et al, 2020).

According to a recent meta- analysis of twin studies, the heritability of ADHD is estimated at 77–88%. The magnitude is therefore similar to that of autism spectrum disorder (about 80%), bipolar disorder (about 75%), and schizophrenia (about 80%) (Grimm et al, 2020)

A recent meta-analysis in more than 17,000 cases showed a high overlap in genetic correlation between children and adults as well as continuous measures as well as categorical ADHD definition (Grimm et al, 2020).

There, genetic factors influencing ADHD persistence in adults (6532 patients with ADHD and 15,874 healthy controls) and early childhood ADHD (10,617 children with ADHD and 16,537 healthy controls) were compared (Grimm et al, 2020).

A comparison of the data sets showed a high genetic correlation (r = 0.81) between early childhood and adult ADHD arguing that these are indeed covering the same clinical phenotype (Grimm et al, 2020).

An additional meta-analysis of ADHD over the entire life span in children and adults revealed nine genes significantly associated with ADHD over the life span (Grimm et al, 2020)..

This underscores how GWAS can contribute to clinical questions about differences between childhood and adult manifestations of ADHD (Grimm et al, 2020).

Are ID, Autism, ADHD, Schizophrenia, and Bipolar Disorder – actually a single Spectrum Disorder, and not as we now believe, specific and individual mental disorders?

The hypothesis of a genetic neurodevelopmental continuum

Over the past decade, evidence has been accumulating that childhood neurodevelopmental disorders such as ID, ASD, and ADHD share specific genetic risk alleles with each other, as well as with psychiatric disorders, particularly schizophrenia (Morris-Rosendahl et al., 2020).

Copy number variants (CNVs) associated with Intellectual Disability (ID) were significantly enriched in patients with schizophrenia, supporting the view that many additional ID-related variants also confer risk to schizophrenia, but at reduced penetrance (Morris-Rosendahl et al., 2020).

This has led authors to propose the model of a neurodevelopmental continuum, in which neurodevelopmental disorders, including schizophrenia, are seen as representing the diverse range of outcomes that follow from disrupted or deviant brain development (Morris-Rosendahl et al., 2020).

Thus, childhood neurodevelopmental disorders (ID, ASD, ADHD) and adult psychiatric disorders (including both bipolar disorder [BPD] and schizophrenia) could better be conceptualized as lying on an etiological and neurodevelopmental continuum, rather than being defined as discrete entities (Morris-Rosendahl et al., 2020).

The model is based on emerging evidence for shared genetic and environmental risk factors and predicts that there are likely overlapping pathogenic mechanisms (Morris-Rosendahl et al., 2020).

The authors have taken this model one step further and have proposed the neurodevelopmental gradient hypothesis, in which disorders are graded according to the severity of neurodevelopmental impairment (Morris-Rosendahl et al., 2020).

Contributing features to this grading are age of onset relative to the typical age of onset for each of the disorders, the severity of associated cognitive impairment and the persistence of functional impairment (Morris-Rosendahl et al., 2020).

Although this model may appear to be a gross oversimplification of the diagnostic conundrum, it posits that the degree of neurodevelopmental impairment is currently the most recognizable of these features and makes clear predictions about the relative importance of the most damaging classes of rare genetic variants (Morris-Rosendahl et al., 2020).

In support of this hypothesis, Girirajan et al24 have shown that the burden of DNA CNVs is positively correlated with the severity of childhood neurodevelopmental disorders, being greater in ID than in ASD, and greater in ASD with ID than in those children without ID (Morris-Rosendahl et al., 2020).

Kirov et al have shown that the burden of large, rare CNVs implicated in neurodevelopmental disorders is greater in cases with developmental delay, autism, or congenital malformations, than in schizophrenia (Morris-Rosendahl et al., 2020).

The enrichment of rare mutations appears to be correlated with the degree of cognitive impairment both across and within diagnostic groups, but pathogenic CNVs and rare coding variants are found in ASD and schizophrenia, without gross cognitive impairment (Morris-Rosendahl et al., 2020).

Pathogenic CNVs are also found in individuals with subtle impairments of cognition but who do not have psychiatric diagnosis (Morris-Rosendahl et al., 2020).

Neurodevelopmental disorders are associated with reduced fecundity.26 One can postulate then, that genetic variants that confer a high risk for those disorders should be rare in the population due to negative selection (Morris-Rosendahl et al., 2020).

The frequency of such variants in the population should be a function of that selection pressure and the rate of replacement due to new, or de novo mutation. The increased rate of de novo variants in most neurodevelopmental disorders, supports this postulation (Morris-Rosendahl et al., 2020).

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes (the Deciphering Developmental Disorders Study [DDDS], 2017) (Morris-Rosendahl et al., 2020).

In a large whole-exome sequencing study of 4293 families with individuals with developmental disorders and meta-analysis of data with another 3287 individuals with similar disorders, the DDDS identified 94 genes enriched for damaging de novo mutations (DNMs). The authors estimated that 42% of the cohort carried pathogenic DNMs in coding sequences, and approximately half disrupt gene function, with the remainder resulting in altered function. They concluded that de novo mutations account for approximately half of the genetic architecture of severe developmental disorders and more than 40% in intellectual disability (Morris-Rosendahl et al., 2020).

Conclusion

In general, the genetic disposition plays a major role in the pathogenesis of ADHD (Grimm et al, 2020).

On the one hand, knowledge and public discussion about this can counteract stigmatization of patients (Grimm et al, 2020).

Genetic causes are now accepted by many affected patients and their relatives as an explanatory model (Grimm et al, 2020).

An increase in knowledge of genetics and neurobiology will not replace the physician’s intuition in diagnosing and treating the individual patient (Grimm et al, 2020).

Psychiatric genetics will not change the art of clinical medicine, i.e., the way physician and patient communicate about mental health, but it will provide a useful tool for a more personalized medicine (Grimm et al, 2020).

The historic use of categorical diagnoses and classifications has failed NDDs in that the boundaries between disorders are not clear and comorbidity is common (Morris-Rosendahl et al., 2020).

The neurodevelopmental continuum underscores the need for new and flexible approaches to diagnosis and patient stratification, and the high degree of pleiotropy suggests that therapeutic approaches may be fruitful across diagnostic boundaries (Morris-Rosendahl et al., 2020).

The rate of disease gene identification has accelerated dramatically over the past decade and with whole-exome and genome sequencing becoming increasingly routine practice, the genotype-first approach will likely soon spread beyond autism and developmental delay to include genes and CNVs associated with other psychiatric disorders (Morris-Rosendahl et al., 2020).

This surge in technological development to generate large datasets has been accompanied by increasing sophistication in the statistical methods used for data analysis (Morris-Rosendahl et al., 2020).

While genetically informed targeted therapies are the ultimate goal of precision medicine, there are substantial clinical and psychosocial benefits to the genotype-first approach (Morris-Rosendahl et al., 2020).

For families, this will translate into better diagnosis and counseling, and the formation of patient-driven support groups. Family groups associated with specific genetic subtypes can be mobilized to support one another, share experiences, and work closely with clinicians and researchers to enrol participants for research projects, to provide valuable phenotypic data and to place them in the front line for potential clinical trials (Morris-Rosendahl et al., 2020).

References

Grimm, O., Kranz, T. M., & Reif, A. (2020). Genetics of ADHD: What Should the Clinician Know?. Current psychiatry reports, 22(4), 18. https://doi.org/10.1007/s11920-020-1141-x

Morris-Rosendahl, D. J., & Crocq, M. A. (2020). Neurodevelopmental disorders-the history and future of a diagnostic concept. Dialogues in clinical neuroscience, 22(1), 65-72. https://doi.org/10.31887/DCNS.2020.22.1/macrocq

The U.S. National Library of Medicine – Genetics Home Reference
https://ghr.nlm.nih.gov/primer/inheritance/heritability (Accessed August 19, 2020)