The Predictive Power of Attention-Deficit Hyperactivity Disorder (ADHD) Genetic Risk Factors

Issues regarding disorganization and hyperactivity are large burdens on the pediatric population, and the severity of these behavioral disorders, called attention-deficit hyperactivity disorder (ADHD), falls on the slow-developing treatments that are unable to fully solve the symptoms of those affected. Limiting factors include the heterogeneous responses that many patients have in response to pharmacological treatments, the range of comorbid symptoms and conditions associated with ADHD, and the intricacies of the environmental and genetic interactions involved. Since ADHD has a strong genetic component with up to 80% heritability for the condition, epigenetic and genetic studies offer valuable insight into how future treatments could tackle the issue. In particular, the studies reveal how genes might provide indicators for patients’ response to medication, their symptomatology, and unique risks for comorbidities. This paper outlines the current pharmacological and cognitive treatments for ADHD, discusses their limitations, and offers an overview of present genetic risk factors to analyze how they may provide insights for detection, prevention, and responses to treatment.

impulsiveness. Children and adults can display these symptoms di erently.
Hyperactivity and impulsiveness tend to be traits shown more in children while inattentiveness is more persistent in adults 3 . For example, children can exhibit hyperactivity by not being able to sit still. Adults on the other hand can show signs of inattention by not being able to sit through long activities or interrupting people's sentences while they talk.

Causes of ADHD
The causes and the risk factors of ADHD are unknown to this day.
However, it is believed that genetics plays a very important role in the development of ADHD in individuals 4 . ADHD tends to run in the family, transmitted through genes inherited from one's parents 5 . Recent analysis of twin studies demonstrates 80% heritability for the condition, though no speci c genes have been linked to ADHD 6 . Along with genetics, some risk factors include brain injury, exposure to environmental risks during pregnancy or at a young age, alcohol or tobacco use during pregnancy, premature delivery, or low birth weight 4 .

Diagnosis of ADHD
Currently, there are no convenient or de nitive ways to diagnose ADHD.
Children can get diagnosed with ADHD by a pediatrician, adult psychiatrist, or quali ed healthcare professional with training in ADHD 7 . A physical examination is run to make sure the symptoms relayed are not caused by something other than ADHD. Then, an interview can be Berkeley Pharma Tech Journal of Medicine | 60 conducted with the child and parent. To be diagnosed with ADHD, multiple symptoms must be displayed. Additionally, the patient must experience these symptoms for over six months and before the age of twelve 7 . This process can be di erent for adults, though specialists will ask the adult about symptoms that they have. However, an adult will not get a con rmed diagnosis unless they a rm that symptoms were present in childhood 7 . All of these diagnostic tests mainly involve speaking to a specialist or doctor because no blood or invasive tests can diagnose ADHD 8 .

Current Treatments
The most popular treatments of ADHD include the use of medical was the rst FDA approved non-stimulant medication for ADHD with Clonidine, Guanfacine, and Qelbree following not soon after 9 .
Non-stimulants have fewer side e ects, but side e ects like nervousness, sleep problems, fatigue, upset stomach, dizziness, or a dry mouth can still happen 9 . Although it seems like non-stimulants are a good option of treatment, it can be less reliable as 20-30% of people with ADHD have stated that it does not work for them 9 .
Another option for treatment for ADHD is cognitive behavioral therapy, also known as CBT. CBT is a short-term psychotherapy that focuses on changing a person's negative perspective of themselves 11 . This could mean changing the way one thinks about themself and their potential. The way CBT works is that each session identi es situations where a lack of organization creates problems in a person's everyday life 11 . Therefore, these sessions help the person develop coping skills to deal with challenges and obligations. These sessions can also include time for relaxation and meditation as well. There is a recent study that shows the positive e ect of CBT through a randomized controlled trial 12 . The study primarily focused on determining how a treatment called Accessing Campus Connections and Empowering Student Success (ACCESS), a CBT program, a ects 250 college students with ADHD over a course of two semesters. The study assessed primary characteristics associated with ADHD such as executive functioning, depression, and anxiety. The results of the study show that CBT reduced these common ADHD symptoms. Furthermore, a learning curve growth of students was modeled and it showed improvements compared to groups not in the ACCESS participants. There were no ascertained changes seen in depression and anxiety with correlations for lower chances in worsening depression and anxiety symptoms. Therefore, it provides concrete evidence for ACCESS being used as treatment for college students with ADHD 12 .
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Genes of Interest
As discussed earlier, genes play a primary role in the cause of ADHD.
Currently, no studies have identi ed a speci c gene that causes ADHD. Part of the di culty lies in the complexity of the phenotypes and relatively small e ects of genetic variants 13 . This section will lay out and discuss the di erent genes of interest that could possibly relate to the cause of ADHD.
Gene of Interest Function in the Body Relation to ADHD  There are some in vivo studies that have correlated NRXN1 with ADHD.
For instance, researchers conducted one study to evaluate the protective e ect and potential mechanism of NRXN1 on learning and memory in ADHD rats 15 . The methods involved grouping the four-week-old rats into two categories: spontaneously hypertensive rats (SHRs) and normal Sprague Dawley (SD) rats. These groups of rats were tested by using a Morris water maze on a learning and memory test. Moreover, qPCR and western blots were used to analyze the expression levels of NRXN1 at mRNA and protein levels. It was concluded that the overexpression and interference of NRXN1 played a role in impairing the ability of the rats to learn and memorize things in both the SHRs and SD rats 15 . However, in the experiment, a portion of the SD rats were given treatments with methylphenidate (MPH) during the trails. This was shown to make an improvement in the performance of the treated SD rats. The change in NRXN1 in the rats led to a change in other synapse-related genes including PSD95, SYN1, GAP43, and NLGN1 genes. Therefore, it can be concluded that NRXN1 de ciency is associated with the expression of synapse-related genes and ADHD pathogenesis and can be a potential therapeutic target for ADHD treatment 15 .

Gene of Interest 2: Dopamine receptor 3 (DRD3)
Another gene of interest is in the dopamine receptor family, which encodes dopamine receptors D1, D2, D3, D4, and D5 16 . Dopamine receptors as a family are used in everyday function. It a ects the brain as it is able to control and process emotions and movement of the body 17  diseases such as Schizophrenia and Tremor. These mutations can be caused by Ser-9-Gly, a nucleotide polymorphism in DRD318. Ser-9-Gly has a C allele in it which encodes glycine and a T allele which encodes serine 13 .
There are quite a few in vitro studies that have tried to correlate DRD3 mutations with ADHD, but not a lot of them have been successful 18 .
However, there is a DRD3 gene and ADHD pharmco-behavioral genetic study that links the two together 13  In a recent study, heterozygous genotypes rs12708954 genotypes showed greater side e ects during treatment than normal genotypes. Similarly, in rs3785143 genotypes, side e ects in heterozygous carriers have been reported more frequently than WT carriers. In only one pilot study, rs3785143 T allele carriers reported a loss of appetite and irritability during ATX treatment 22 . This gene polymorphism implies that ADHD genetic risk factors not only in uence its symptomatology, but also modulate the e ectiveness of stimulant treatment such as ATX on the patient's response.

Future Investigations
ADHD is a heritable condition, although the inheritance, or rather the likelihood of the disease being passed onto the next generation, is complex. Multiple in vivo studies have demonstrated the link between these genes and ADHD. While all of this is known, there is still a lot to learn in this area.
There is a lack of clinical trials and testing which is essential to determine whether or not these genes can be successfully mutated and provide signi cant improvements to patients with ADHD.
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