is there a difference in genetic architecture?

In a recent study posted to the medRxiv* preprint server, researchers investigated whether individuals diagnosed with attention-deficit hyperactivity disorder (ADHD) during childhood differed from those who were diagnosed during adulthood in terms of unique and shared genetic and functional architectures.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

ADHD, a neurodevelopmental condition, presents with persistent inattention, hyperactivity, and impulsivity. The condition may be diagnosed at any age; however, symptoms must begin prior to 12 years of age. The age at attention-deficit hyperactivity disorder diagnosis remains unclear, and effective treatment approaches are often trial-and-error.

Understanding pathways, symptoms, and comorbidities specific to adulthood- and childhood-diagnosed ADHD subtypes could improve treatment outcomes and identify therapies effective for specific groups.

About the study

In the present study, researchers investigated the disparities in genomic associations between ADHD identified in adulthood and childhood in terms of psychiatric, behavioral, health, and cognitive outcomes.

Stratified genomic structural equation modeling (SEM) as well as transcriptomic SEM (T-SEM), were applied to detect gene expression patterns and functional annotations related to genomic risk divergence or sharing across ADHD subgroups, as well as to investigate whether the age at attention-deficit hyperactivity disorder diagnosis could demarcate etiological limits and clinical differences at varying levels of analysis.

The genetic overlap between ADHD identified in childhood and adulthood was compared with cognitive, psychiatric, behavioral, social, drug misuse, and health outcome phenotypes.

The most well-powered and publicly accessible genome-wide association study with unrelated European participants was chosen for each trait. The researchers investigated whether distinct kinds of genomic variations (such as evolutionarily conserved variants) or gene expression patterns are connected to genetic risk uniqueness or sharing across subgroups at the genetic and functional levels.

The ADHD genome-wide association studies (GWAS) for ADHD diagnoses were collected from previously published original research that comprised 38,303, 14,878, and 6,961 Danish controls, pediatric ADHD patients, and adult ADHD patients, respectively.

Persistent ADHD (1,473 instances) was removed from the study because it reflected individuals who received a diagnosis before the age of 18 who continued to exhibit symptoms during adulthood. To ensure a constant reference point across subgroups, the same controls were employed for all subgroups of ADHD GWAS. The International Classification of Disorders, Tenth Version (ICD-10) criteria were used to get the ADHD diagnosis.

Results and discussion

The study found that ADHD diagnosed in adulthood exhibited a larger negative genetic correlation (rg) with educational attainment, non-cognitive skills, and age at the initial sexual intercourse compared to childhood-diagnosed ADHD.

Additionally, adulthood-identified ADHD had a larger positive genetic correlation with loneliness, suicidal behavior, major depressive disorder (MDD), and an internalizing factor based on ANX, PTSD, and MDD.

The study discovered a combination of convergent and divergent genetic markers in adults and children with ADHD. The key distinctions were seen in cognitive and internalizing results. The data indicated that ADHD identified in adulthood had a genetic overlap, notably with the non-cognitive elements that contribute to academic achievement.

Adult-diagnosed ADHD may incur a higher likelihood of misdiagnosis than in children, perhaps due to overlapping symptoms, like restlessness and anxiety issues, in the internalizing area. Following-up models that included an internalizing component explained the greater genomic overlapping between ADHD diagnosed in adulthood and two internalizing correlates: suicidal behavior and loneliness.

Controlling for shared variation with internalizing, ADHD diagnosed in childhood had a significantly larger connection between ADHD and autism spectrum disorder (ASD) compared to ADHD identified in adulthood.

The genetic connection between adulthood-diagnosed and autism spectrum disorder was predicted to be around 0.0, indicating that when shared genetic variation with internalizing is removed, neurodevelopmental signals identified in the adulthood-identified ADHD GWAS are considerably attenuated or missing.

Follow-up models exploring the relationship between chronic ADHD and internalizing provided evidence supporting findings against the misdiagnosis hypothesis.

Internalizing problems may have a significant influence on ADHD persistence into adulthood. Internalizing overlaps with ADHD diagnosed in adulthood might be explained by gender variations in symptomatology and the age at ADHD diagnosis.

Three annotations and 22 genes with significant relationships with genomic risk sharing across ADHD subtypes were discovered using stratified SEM and T-SEM analysis, of which 15 genes were linked to the univariate transcriptome-wide association study (TWAS) of ADHD in children or adults, while 11 were linked to the general ADHD TWAS.

The top five genes have previously been associated with ADHD symptoms. The ADHD genes CTC-498M16.4 and LINC02060 are linked, whereas the Mediator Complex Subunit 8 (MED8) gene is linked to schizophrenia susceptibility.

In cases of ADHD, Lysine Demethylase 4A (KDM4A) is linked to disruptive behavior problems. Artemin (ARTN) promotes TWAS of general ADHD survival, growth, differentiation, and methylation and is linked to schizophrenia and ADHD. CRIM1 (cysteine-rich transmembrane BMP regulator 1) and DNM1 (dynamin 1) showed significant divergence, with greater relationships with ADHD diagnosed at minor and major ages, respectively.

Conclusion

Overall, the study findings showed genetic similarities between ADHD and internalizing disorders and clinical correlates compared to childhood-diagnosed ADHD. This highlights the importance of distinguishing subgroups within the disorder class. Future studies should explore the association between gender differences and the age of ADHD diagnosis for alternate interpretations.

There are limitations to the application of these findings given the study was only carried out on Europeans. Expanding sample sizes to include underrepresented populations is crucial for understanding ADHD and its association with other diseases.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.