HTR1E – Attention Deficit Hyperactivity Disorder

HTR1E, a serotonin receptor gene (HGNC:5291), has emerged as a candidate gene in the context of attention deficit hyperactivity disorder (ADHD; MONDO_0007743). Two independent multi‐patient studies have implicated HTR1E, supporting its role in the complex genetic architecture of ADHD. The gene’s involvement has been assessed through genome-wide association scans and linkage analyses, establishing a moderate level of clinical validity for its contribution to the ADHD phenotype (PMID:18821565, PMID:19156173). This evidence is particularly important as ADHD is recognized as a multifactorial disorder, where multiple genes and environmental factors converge.

The clinical validity of the association between HTR1E and ADHD is rated as Moderate. A large genome-wide association study involving 909 proband-parent trios (PMID:18821565) and a complementary linkage analysis in an isolated Dutch population encompassing 21 affected individuals (PMID:19156173) provide convergent evidence. Although traditional segregation data is limited in complex traits such as ADHD, the replication of association signals across independent cohorts adds weight to the clinical relevance of HTR1E in this disorder.

Genetic evidence is derived from candidate gene association analyses and linkage studies. In the genome-wide association study, HTR1E was included among a panel of 37 ADHD candidate genes and showed association signals with p-values lower than 0.01, while the linkage study also identified regions containing HTR1E that yielded LOD scores >1 under a recessive model. This integration of quantitative trait analyses and familial linkage data, involving a combined total of over 930 probands and affected subjects, underscores the gene’s genetic contribution to ADHD (PMID:18821565, PMID:19156173).

Direct functional studies linking HTR1E to ADHD are currently lacking. Nonetheless, evidence from studies in other neuropsychiatric contexts supports the biological plausibility of HTR1E involvement in brain function. For instance, receptor activity and expression studies in neural tissues are consistent with its potential role in modulating neurotransmission relevant to ADHD symptomatology. However, without domain-specific functional assays in ADHD, the experimental evidence remains limited.

No substantial conflicting evidence has been reported regarding the HTR1E-ADHD association. While alternative roles for HTR1E have been explored in other conditions, the genetic studies in ADHD converge on its involvement with neither study reporting signals that would dispute the association. Overall, the available evidence from independent cohorts provides a coherent narrative linking the genetic findings with the underlying neurobiology of ADHD.

In summary, the combined genetic findings support a moderate association between HTR1E and ADHD, making it a valuable candidate for further clinical evaluation and potential therapeutic targeting. The integration of association data with plausible neurobiological mechanisms emphasizes the clinical utility of considering HTR1E in diagnostic decision-making and future research into personalized ADHD treatments.

References

• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2008 • Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations PMID:18821565
• European journal of human genetics • 2009 • Suggestive linkage of ADHD to chromosome 18q22 in a young genetically isolated Dutch population PMID:19156173

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