What you carry at this position in your DNA and what research says about it.
ADHD Medication Response: 6/10 evidence, 22 publications.
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Sample genotype (not yours): G/G
Optimal Response to ADHD Stimulants
Optimal therapeutic outcomes are common when treating ADHD with standard stimulants. A slightly higher susceptibility to certain depressive symptoms under stress may also be present.
What this genotype means: Better response to methylphenidate; Slightly higher risk of depressed mood.
Sample genotype (not yours): A/A
Reduced Response to ADHD Stimulants
Lower likelihoods of responding well to standard methylphenidate treatments are associated with this profile. Conversely, a protective effect against certain depressive symptoms may be present.
What this genotype means: Reduced response to methylphenidate; Lower risk of depressed mood.
Sample genotype (not yours): G/A
Favorable Response to ADHD Stimulants
Preserving a good therapeutic response to methylphenidate is typical for this profile. It represents a balanced genetic background with standard risks for mood and attention traits.
What this genotype means: Favorable response to methylphenidate; Typical risk for depressive symptoms.
Gene function and biological role
Gene Function: The SLC6A2 gene encodes the norepinephrine transporter, a protein responsible for clearing norepinephrine from the synaptic cleft back into neurons [1]. This transporter plays a critical role in regulating attention, arousal, and cognitive function in the prefrontal cortex [2]. By controlling the active duration of norepinephrine, it directly influences executive control and behavioral inhibition [2]. It also serves as the primary therapeutic target for several major ADHD medications and antidepressants [3]. Variations in this gene can alter transporter expression or efficiency, thereby affecting both natural neurochemistry and individual drug sensitivity [3].
Variant Impact: The rs5569 variant is a single nucleotide polymorphism located in exon 9 of the SLC6A2 gene, representing a synonymous G-to-A change at position 1287 [4]. Although it does not alter the encoded threonine amino acid, this silent mutation can influence mRNA stability or translation kinetics [4]. It is one of the most widely studied genetic variations in the norepinephrine system due to its high heterozygosity across populations [4]. Researchers have extensively evaluated this variant for its role in modulating susceptibility to psychiatric conditions and predicting treatment outcomes [5]. Its primary clinical relevance lies in its strong association with how patients respond to stimulant medications [6].
Key Insight: This variant is a silent mutation that does not change the final protein sequence, yet it significantly alters how the brain responds to first-line ADHD medications like Ritalin.
Location: SLC6A2. Chromosome 16 · 16q12.2 · 55.7 Mb
Estimated prevalence by population
Global 54.7%; European 44.3%; African 78.5%; East Asian 51.0%; South Asian 65.4%; Americas 44.7%; Ashkenazi 54.1%; Finnish 41.8%; Middle Eastern 49.1%; Amish 35.1%.
Estimated GG genotype frequency.
Global 37.2%; European 44.5%; African 20.2%; East Asian 40.8%; South Asian 30.9%; Americas 44.3%; Ashkenazi 38.9%; Finnish 45.7%; Middle Eastern 41.9%; Amish 48.3%.
Estimated GA genotype frequency.
Global 8.1%; European 11.2%; African 1.3%; East Asian 8.2%; South Asian 3.7%; Americas 11.0%; Ashkenazi 7.0%; Finnish 12.5%; Middle Eastern 9.0%; Amish 16.6%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Pharmacogenomics
Antidepressant & Psychiatric Drug Response
Methylphenidate Response. Evidence: 6/10. Source: PMID 29230023. Stronger Response.
Neurology & Mental Health
Mood Disorders
Depression. Evidence: 4/10. Source: PMID 18779921. Slightly Increased.
Showing effects for A/A genotype
Methylphenidate Response. Evidence: 6/10. Source: PMID 29230023. Poorer Response.
Depression. Evidence: 4/10. Source: PMID 18779921. Lower Risk.
Showing effects for G/A genotype
Depression. Evidence: 4/10. Source: PMID 18779921. Typical.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Norepinephrine transporter activity is highly efficient in individuals carrying two copies of the G allele. Clinical trials consistently demonstrate that children and adults with this genotype show significantly greater improvement in ADHD symptoms when treated with methylphenidate [1]. This optimal response is particularly evident in the reduction of hyperactive and impulsive behaviors [2]. However, this efficient transporter state has also been linked to a slightly increased risk of developing depressed mood or psychomotor retardation during major depressive episodes [3]. Antidepressant therapies targeting the norepinephrine system, such as nortriptyline, tend to be highly effective for this group [4]. Overall, this common genetic profile represents a highly responsive state to standard noradrenergic treatments.
Better response to methylphenidate; Slightly higher risk of depressed mood.
Sample genotype: AA (Homozygous)
Transporter dynamics are altered in individuals carrying two copies of the A allele, leading to differences in synaptic clearance. Clinical studies indicate that patients with this genotype are significantly less likely to experience optimal symptom relief from methylphenidate [1]. When treated with standard stimulants, they often show poorer improvement in both attention and hyperactive-impulsive scales [2]. However, this genetic profile appears to be protective against specific depressive symptoms, showing a lower risk of depressed mood and psychomotor retardation [3]. Alternative therapeutic strategies, such as non-stimulant medications or different classes of antidepressants, may be more effective if standard treatments fail [4]. Understanding this profile helps clinicians personalize behavioral and pharmacological interventions.
Reduced response to methylphenidate; Lower risk of depressed mood.
Sample genotype: GA (Heterozygous)
A single copy of the G allele generally maintains adequate norepinephrine transporter function. Individuals with this heterozygous profile show a favorable clinical response to methylphenidate, though it may be slightly less pronounced than in G/G homozygotes [1]. Standard ADHD therapies remain highly viable and effective options for managing attention and impulsivity [2]. In terms of mental health, this genotype is not strongly associated with elevated risks for major depressive disorder or severe depressive symptoms [3]. It represents the baseline genetic profile for noradrenergic system function across most populations [4]. Consequently, standard clinical guidelines and typical treatment pathways are highly appropriate for individuals with this genetic makeup.
Favorable response to methylphenidate; Typical risk for depressive symptoms.
Variants with shared genetic architecture
rs2242446 · SLC6A2 Gene · Chr 16 · Antidepressant Response
rs1611115 · DBH Gene · Chr 9 · Impulsivity and ADHD Risk
rs4570625 · TPH2 Gene · Chr 12 · Anxiety and Mood Regulation
Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD.
Association of norepinephrine transporter gene with methylphenidate response.
Pharmacogenetics of antidepressant response.
Content updated August 2026.
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