Genetics of Attention Deficit Hyperactivity Disorder (ADHD)

Genetics of Attention Deficit Hyperactivity Disorder (ADHD) With a Slight Emphasis on Twin and Familial Studies

Abstract

Attention Deficit Hyperactivity Disorder (ADHD) is an impairing disorder that is considered to be one of the most heritable of all psychiatric disorders. Signs of this disorder include, but are not limited to, fidgetiness, interrupting, lack of focus, and trouble waiting their turn. Many individuals with this disorder, also exhibit other disorders as well. The presence of two or more conditions in an individual is called comorbidity.

The most common comorbid conditions include depression, learning disabilities, and in some smaller cases, autism spectrum disorder (ASD), and even some eating disorders. Because of this, Attention Hyperactive Deficit Disorder has been a focal point in a large amount of genetic research. Attention Hyperactive Deficit Disorder appears to be a disorder that is complex and has multiple genetic and environmental risk factors that can contribute to the measurable trait.

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At the same time, there is growing evidence that in a proportion of cases, individually rare variants such as copy number variants may play an important causal role; the more genetic risks, both common and rare, the more extreme the trait (4).

With increasing samples and advanced genetic methods, single nucleotide polymorphism (SNPs) and copy number variants (CNVs) conferring risk for Attention Hyperactive Deficit Disorder is being identified (4). However, further research needs to be performed before we can begin to understand the importance of these findings.

Non-behavioral markers of genetic risks known as endophenotypes could also play a role in parsing the phenotypic and genetic heterogeneity of Attention Hyperactive Deficit Disorder as they have in other complex disorders (4). As more studies of Attention Hyperactive Deficit Disorder are performed, the ability to have more precise diagnosis and the improvement in early detection will increase as a better understanding develops on the disease itself and how it works.

I am the only person in my family that has Attention Hyperactive Deficit Disorder and my mom had no idea what to do with me. I was antsy, never paying attention, and always doing something I wasn’t supposed to be doing. As I progressed through school, my outbursts increased to a peak around the 5th and 6th grade, then began to level out. I am not sure if it was because I finally understood how I was supposed to act, or if it was the whooping’s my mom was handing out like candy. Either way it went, my mom refused to keep me on medication. It made me a zombie, and caused me to just go through the motions of the day like a person who battles depression.

As an adult, I still have my moments when my Attention Hyperactive Deficit Disorder flares up. I cannot sit still for more than an hour in my classes, I have to utilize a stress ball during my tests and I also have to be doing at least two things at once to be fully “paying attention”. The research done in this paper brought a lot of loose ends together for both me and my mom, who I am sharing this paper with. It gave us a better understanding of how and why I acted the way I did.

When beginning my research, I discovered that the concept of Attention Deficit Hyperactivity Disorder (ADHD) as a clinical condition can be traced back to before the 20th century (5). It is also a common early-onset developmental disorder that is considered to be prevalent due to the fact that this disorder often continues into an individual’s adulthood.

Behaviors associated with Attention Hyperactive Deficit Disorder came from early “brain damage” that remained highly influential throughout much of the 20th century until family and twin studies unintentionally revealed that genetic risk factors could actually be a contribution to the disorder (5).

During the 21st century, technological advances and large-scale collaborative efforts have enabled direct and successful genetic investigations into neuropsychiatric disorders, including Attention Hyperactive Deficit Disorder (5).

ttention Hyperactive Deficit Disorder, however, cannot be explained by just genes by themselves. Sometimes environmental factors can also play a big role in the disorder. As my personal back story would suggest, Attention Hyperactive Deficit Disorder was only considered to be a behavioral issue for quite a long time. However, more recent genetic studies have highlighted its neurodevelopmental nature, and these findings have added to clinical arguments that Attention Hyperactive Deficit Disorder behaves as a neurodevelopmental disorder (5).

As previously stated, Attention Hyperactive Deficit Disorder is highly heritable. The heritability estimates are in the range of 60%-90%. The studies of twins have shown a strong genetic overlap with other child psychopathology, most prominently with behavioral problems such as conduct disorder (5).

Worldwide, the estimates of school-aged children that are diagnosed with Attention Hyperactive Deficit Disorder are between 5%-7%. This makes this disorder the most often used psychiatric classification that are assigned to children. Attention Hyperactive Deficit Disorder and other mental disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (3). The definition of Attention Hyperactive Deficit Disorder has changed over the years.

According to the authors of the fourth additionof American Psychiatric Association in 1994, these disorders are “valuable heuristic constructs” useful for research and practice but they are not “well-defined entities that describe nature exactly as it is. The fifth edition of the DSM however, lists the disorder as “neurodevelopmental” (3). In an influential consensus statement released in 2002, several opinion leaders claim there is no “substantial scientific disagreement over whether Attention Hyperactive Deficit Disorder is a real medical condition” (3).

Molecular studies show that genetics only has a small effect for individual genes that are associated with Attention Hyperactive Deficit Disorder. When aggravated, these genes account for only 10% of variances. The consensus statement says that the effect size (ES) of the association gene is unspecified. The practice of mentioning only associations has often been criticized (3). P-values are commonly used; however they are based on only average differences between groups. This indicates that the possibility of overlaps between these groups is greatly ignored. Unlike P-values, effect size (ES) allows understanding into the amount of overlap and present information dealing with the extent of a result.

Molecular genetics studies are also showing that the genetic architecture of Attention Hyperactive Deficit Disorder is more complex than it was once believed, and that it has multiple common and rare genetic variants involved(2). More recent molecular studies are beginning to use a method called Genomic-Relationship-Matrix Restricted Maximum Likelihood’.

This method was applied by the Genomic-wide Complex Trait Analysis software. It confirmed that common genetic variants can contribute to the estimates of heritability. Although, genome-wide association studies (GWAS) have not reported any significantly associated single nucleotide polymorphisms (SNPs) so far, these studies have been relatively small and underpowered for detecting individual loci significant at a genome-wide level, compared with genome-wide association studies of adult psychiatric conditions such as schizophrenia (2).

Sample heterogeneity and pseudo-controls used in trio-based analyses could also possibly have a role. An aggregate score (a ‘polygenic risk’ score) of common genetic variants was found to be, higher in Attention Hyperactive Deficit Disorder cases than in controls on average. For now, the power of this analysis is weak, though it is likely to improve with score alleles derived from future larger discovery genome-wide association study samples, as has been seen in genetic studies of other psychiatric conditions, including schizophrenia (2). There are several studies imply that a large amount of rare copy number variants (CNV’s) in some Attention Hyperactive Deficit Disorder cases compared with controls. Only a small portion of affected children have these large deletions or duplications, and only a few specific loci have been found to be significantly enriched in Attention Hyperactive Deficit Disorder cases relative to controls (2). However, there is also evidence that CVN’s that are in children with Attention Hyperactive Deficit Disorder are loaded in gene sets that are also enhanced for common variant associations.

The previous statement suggests that Attention Hyperactive Deficit Disorder both common and rare variants can disrupt biological pathways in Attention Hyperactive Deficit Disorder; in particular, the ones dealing with cholesterol homeostasis or central nervous system development. Pathway analysis of the top SNPs identified in Attention Hyperactive Deficit Disorder Genome-wide Association Studies has implicated a protein network related to neurite outgrowth, which also appears to be disrupted by several CNVs previously reported in Attention Hyperactive Deficit Disorder cases (2).

There have been about 2,800 publications on Attention Hyperactive Deficit Disorder and genetics with over 300 appearing in 2012-2013 alone (4). Most of these publications include many twin and family studies. There were 24 genome-wide association studies and 32 meta-analyses of genetic findings exploring the genetic architecture of Attention Hyperactive Deficit Disorder (4).

These studies give support to the idea of genetic influences on Attention Hyperactive Deficit Disorder. There are a few reasons why Attention Hyperactive Deficit Disorder tends to be a controversial disorder.  It has a very high prevalence which varies widely from 2–3 % to 10 % depending on the assessment measures that are used, the population one is studying, and the specific diagnostic criteria and thresholds that are applied; such as a criteria for pervasiveness of symptoms and impairment (4). The diagnosis is applied to those at the extreme of a continuously distributed trait without a clear-cut and universally agreed threshold (4). Attention Hyperactive Deficit Disorder is also measured indirectly using teachers and parents as informers of behavior and not within an actual laboratory (there are no know biomarkers or tests for Attention Hyperactive Deficit Disorder).

With parents and teachers being informants, disagreements can be common between them. Any child can act one way at home and then a completely different way at school. Also, all the informants’ information was completely subjective. This could be because of situational specificity or a mere measurement error. Many individuals that are diagnosed with Attention Hyperactive Deficit Disorder can also exhibit other disorders (comorbidity). This raises awareness to the possibility that Attention Hyperactive Deficit Disorder could be a non-specific consequence or epiphenomenon of other disorders rather than a specific disorder (4).

The most common comorbid conditions include conduct disorder, anxiety disorders, depression, learning disabilities, and, in some smaller cases, autism spectrum disorder (ASD), bipolar disorder and even eating disorders. In a few instances, Attention Hyperactive Deficit Disorder presents in the context of a neurodevelopmental disorder such as one of the rare deletion syndromes like velo-cardio-facial syndrome (VCF, 22q11 deletion) (4). Many biological, social and psychological factors link traumatic brain injury, prematurity, low birth weight, and psychosocial adversity can increase the risk for Attention Hyperactive Deficit Disorder. Current treatments for Attention Hyperactive Deficit Disorder are even considered controversial because they may have limited long-term benefit.

In conclusion, genetics is not the only thing that contributes to Attention Deficit Hyperactivity Disorder. Environmental factors can also play a role. Current reports in the genetics of Attention Deficit Hyperactive Disorder are not conclusive. Presently, the reported research findings are not directly applicable in clinical practice for adult Attention Deficit Hyperactive Disorder which could be a goal for the near future. Studies are also not comprehended the same from person to person.

Also different researchers can also interpret their findings differently as well. Teachers and parents are the first to realize the signs of a child with Attention Deficit Hyperactive Disorder. However, because children do not always act the same both at home and school, it is difficult to pin down what it is the child is actually doing or if they are showing the signs of the disorder. The family physician will take both the patent and the teachers’ testimonies into account and draw a conclusion from there. As more twin and familial studies are being conducted, a better understanding of the disorder and its contributions also increases.

Resources

1. Dresler, T., Barth, B., Ethofer, T., Lesch, K.P., Ehlis, A.C., Fallgatter, A. Imaging genetics in adult attention-deficit/hyperactivity disorder (ADHD): a way towards pathophysiological understanding? Borderline Personality Disorder and Emotion Dysregulation. 2014 1: 6. https://doi.org/10.1186/2051-6673-1-6
2. Martin, J., O'Donovan, M. C., Thapar, A., Langley, K., & Williams, N. The relative contribution of common and rare genetic variants to ADHD. Transl Psychiatry. 2015 DOI 10.1038/tp.2015.5
3. Meerman, S., Batstra, L., Hoekstra, R., & Grietens, H., Academic textbooks on ADHD genetics: balanced or biased? International Journal of Qualitative Studies on Health and Well-being 12:sup11305590 2017 DOI: 10.1080/17482631.2017.1305590
4. Schachar, R. Genetics of Attention Deficit Hyperactivity Disorder (ADHD): Recent Updates and Future Prospects. Curr Dev Disord Rep 1: 41. 2014 DOI 10.1007/s40474-013-004-0
5. Thapar Anita. Discoveries on the Genetics of ADHD in the 21st Century: New Findings and Their Implications. American Journal of Psychiatry 2018 175:10, 943-950.