Genetic Influences on ADHD II: Unpacking the Inattentive Subtype

It may be worth reading the first instalment where I cover the broader link between the dopamine receptor genetic variants and ADHD.

However, since my diagnosis and research I've come to the conclusion that the Inattentive Subtype has only recently seen some heightened attention.

This has contributed in part to the perception that there is a revival of ADHD diagnosis that some find unsettling, yet at the same time acknowledges that a broader section of the undiagnosed were overlooked due to a lack of appreciation for the subtlety in the IA subtype. It is also credited for the increased recognition of ADHD amongst women.

Let's face it, the pervasive myth that ADHD was a rambunctious boy's affliction permeated even the professional class, the notion that Hyperactivity was the hallmark of ADHD (that a distinction was made between ADD and ADHD seems of little import). The silent daydreamers got by, either because their interests intersected with a love of learning supported by a structured environment, or society didn't expect too much of them within an educational context. The latter betrayed women during a darker time when their presence in classrooms was tolerated as a interlude before a career in the secretarial pool.

My own unrecognised struggles with IA and the role it played in my endeavours has certainly given me a little added bias to focus in on IA, and whether the genetic variants perhaps give insight into why this subtype is different.

Genetic Variants Associated with the Inattentive Subtype of ADHD

While the DRD4 gene, particularly the 7-repeat allele, has been more strongly linked to hyperactive and impulsive symptoms, other genetic variants have been implicated in the inattentive presentation of ADHD. Below are key genes and their associated variants that research has suggested may play a role in the inattentive subtype:

1. Dopamine Transporter Gene (DAT1 or SLC6A3)

• 40-bp VNTR in the 3' Untranslated Region (UTR)
  • 10-Repeat Allele (10R)
    • Description: The DAT1 gene encodes the dopamine transporter responsible for reuptake of dopamine from the synaptic cleft.
    • Association with Inattentive ADHD:
      • Some studies have found that the 10R allele is associated with the inattentive subtype.
      • Mechanism: Variations may affect dopamine availability in brain regions critical for attention regulation.

2. Dopamine Receptor D2 Gene (DRD2)

• TaqIA Polymorphism (rs1800497)
  • A1 Allele
    • Association with Inattentive Symptoms:
      • Linked to reduced D2 receptor density, affecting dopaminergic signalling related to attention.
      • Some research indicates a connection with inattentive symptoms, although findings are mixed.

3. Dopamine Beta-Hydroxylase Gene (DBH)

• -1021 C/T Polymorphism
  • Description: DBH converts dopamine to norepinephrine.
  • Association with Inattention:
    • The T allele has been associated with lower enzyme activity and increased dopamine levels.
    • May contribute to attention deficits due to imbalance between dopamine and norepinephrine.

4. Norepinephrine Transporter Gene (NET1 or SLC6A2)

• Variations Affecting Norepinephrine Reuptake
  • Association with Inattentive ADHD:
    • Altered norepinephrine transport can impact attention and arousal systems.
    • Some studies suggest NET1 variants are linked to inattentive symptoms.

5. Alpha-2A Adrenergic Receptor Gene (ADRA2A)

• -1291 C/G Polymorphism
  • Association with Inattention:
    • The G allele has been associated with differences in receptor expression.
    • Medications targeting alpha-2A receptors (e.g., guanfacine) are effective for inattentive symptoms, suggesting a genetic link.

6. Cholinergic Receptor Nicotinic Alpha 4 Subunit Gene (CHRNA4)

• Variants Affecting Nicotinic Receptors
  • Association with Cognitive Functions:
    • CHRNA4 is involved in cholinergic neurotransmission critical for attention and memory.
    • Certain polymorphisms have been linked to attentional deficits.

7. Catechol-O-Methyltransferase Gene (COMT)

• Val158Met Polymorphism (rs4680)
  • Met Allele
    • Association with Inattentive Symptoms:
      • The Met allele results in decreased COMT activity, leading to higher dopamine levels in the prefrontal cortex.
      • May affect executive functions like working memory and attention control.

8. Synaptosomal-Associated Protein 25 kDa (SNAP25)

• MnlI and DdeI Polymorphisms
  • Association with ADHD Subtypes:
    • Variants in SNAP25 have been linked to differences in neurotransmitter release.
    • Some studies find associations with inattention more than hyperactivity.

9. Latrophilin 3 Gene (LPHN3)

• rs6551665 Polymorphism
  • Association with Inattentive Symptoms:
    • LPHN3 is involved in synaptic adhesion and neurotransmission.
    • Variants have been associated with ADHD susceptibility and treatment response, particularly inattention.

10. Glutamate Receptor Metabotropic 7 Gene (GRM7)

• Variants Affecting Glutamate Signaling
  • Association with Cognitive Processes:
    • Glutamatergic neurotransmission plays a role in attention and learning.
    • GRM7 polymorphisms may contribute to inattentive symptoms.

Understanding the Genetic Profile

• Polygenic Nature of ADHD: ADHD is highly polygenic, meaning it involves many genes each contributing a small effect. The inattentive subtype likely results from the combined influence of multiple genetic variants.
• Gene-Gene Interactions: The interplay between different genes may influence the severity and presentation of inattentive symptoms.
• Environmental Influences: Gene-environment interactions are crucial, as environmental factors can modulate gene expression and impact symptom manifestation.

Clinical Implications

Diagnostic Considerations

• Biomarkers: Identifying genetic markers associated with inattentive symptoms can aid in developing biomarkers for more precise diagnoses.
• Subtype-Specific Interventions: Understanding genetic differences between ADHD subtypes may lead to tailored treatments targeting specific neurotransmitter systems.

Treatment Approaches

• Medication Selection:
  • Norepinephrine Reuptake Inhibitors: Medications like atomoxetine target norepinephrine and are effective for inattentive symptoms.
  • Alpha-2A Adrenergic Agonists: Guanfacine and clonidine can improve attention by modulating noradrenergic pathways.
• Personalized Medicine:
  • Genetic profiling could inform medication choices and dosages, improving efficacy and reducing side effects.
  • Early identification of genetic risk may allow for interventions that mitigate symptom development.

Research Findings and Limitations

• Consistency of Findings: While associations have been found, results are sometimes inconsistent across studies due to factors like small sample sizes, population heterogeneity, and methodological differences.
• Need for Replication: Further research with larger, diverse cohorts is necessary to confirm associations and clarify the role of specific genes.
• Complexity of ADHD Genetics: The multifactorial nature of ADHD requires comprehensive studies that consider multiple genes and their interactions with environmental factors.

Conclusion

While the DRD4 gene is more prominently associated with hyperactive and impulsive symptoms in ADHD, research indicates that other genetic variants may be linked to the inattentive subtype. Genes involved in dopamine and norepinephrine pathways, such as DAT1, DRD2, DBH, NET1, and ADRA2A, have been implicated in attentional regulation deficits characteristic of the inattentive presentation.

Understanding these genetic associations enhances our comprehension of ADHD's heterogeneity and can inform more targeted and effective treatment strategies. Ongoing research is essential to validate these findings and translate them into clinical practice, ultimately improving outcomes for individuals with the inattentive subtype of ADHD.

Let me be clear, the genetic underpinnings of ADHD is only a small piece of the complicated puzzle, and may only offer us a brief glimpse into the foundation of who we could become. It is our interaction with our environment and societal conditions that further shape how we express who we are - some of these are outside of our control (though not always outside of our influence), but by being better informed we can make better choices.

Of course the rabbit  hole would not be complete if I didn't have at least some genetic data of my own. In my early days DNA analysis had just gone mainstream locally and I'd forked out for the medicine efficacy assessment as a side interest. It would be quite illuminating that a diagnosis made in rehab now had, at least in part, some validation of some genetic markers being present - my own specific to the IA subtype being:

• ADRA2A (C-1291G C/G)
• ANKK1/DRD2 (Taq1A C/T)
• COMT (Val158Met A/A)