NET1 and Attention Deficit‑Hyperactivity Disorder

NET1 (HGNC:14592) has been investigated as a candidate gene for attention‑deficit hyperactivity disorder (ADHD) (MONDO_0007743). Early studies focused on the role of the norepinephrine transporter in attentional systems and the potential impact of its genetic variability on ADHD pathogenesis (PMID:11920844).

In an initial family‑based study involving 122 families and 155 ADHD probands (PMID:11920844), analysis of several polymorphisms and a screening for known coding variants (e.g. c.296C>T (p.Thr99Ile)) did not reveal significant biased transmission or enrichment compared to controls. This finding challenged a major role for NET1 in ADHD susceptibility.

A subsequent study examined 163 ADHD probands together with 192 parents and 129 healthy controls and provided support for the association between NET1 and ADHD. In this investigation, transmission disequilibrium testing (TDT) identified significant association of two NET1 single nucleotide polymorphisms (SNPs) with ADHD (PMID:15717291), despite the involvement of another candidate gene, DRD1, in the same analysis.

Further evidence comes from a high‑density SNP screen in a Chinese Han population that included 182 ADHD cases and 184 controls. Although several candidate genes were analyzed, NET1 exhibited one or more SNPs with nominal P‑values (PMID:18180757), suggesting limited but supportive genetic evidence.

A reported coding change, formatted here as c.296C>T (p.Thr99Ile), was identified in one of the studies but was found at a similar frequency in controls (approximately 1.8% vs 2.2%), thereby limiting its diagnostic utility. The overall genetic evidence derives from candidate gene analyses with modest statistical significance and an absence of robust segregation data.

Functional investigations of NET1 have primarily focused on oncogenic processes, as illustrated in studies on chronic myelogenous leukemia and gastric cancer. These experiments, while valuable for understanding NET1 biology, do not provide direct functional support for a pathogenic role in ADHD. Integration of the genetic and experimental evidence therefore suggests that the current clinical validity for NET1 in ADHD is limited, underscoring the need for further investigation before clinical implementation.

Key Take‑home sentence: Although NET1 has been evaluated in multiple genetic studies of ADHD, the conflicting and modest findings currently limit its clinical utility as a diagnostic marker for the disorder.

References

• American journal of medical genetics • 2002 • The norepinephrine transporter gene and attention‑deficit hyperactivity disorder PMID:11920844
• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2005 • Support for association between ADHD and two candidate genes: NET1 and DRD1 PMID:15717291
• Molecular psychiatry • 2009 • A high‑density single‑nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population PMID:18180757

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