rs6323 — MAOA R297R

X-linked monoamine oxidase A variant affecting enzyme activity and neurotransmitter breakdown

Strong Risk Factor

Details

Gene: MAOA
Chromosome: X
Risk allele: T
Protein change: p.Arg297=
Consequence: Synonymous
Inheritance: X Linked
Clinical: Risk Factor
Evidence: Strong
Chip coverage: v3 v4

Population Frequency

71%

29%

50%

42%

Ancestry Frequencies

east_asian

48%

south_asian

35%

latino

32%

european

29%

african

20%

External

SNPedia ClinVar dbSNP

The MAOA R297R Variant — A Silent Mutation with Loud Effects

Monoamine oxidase A (MAOA) is a mitochondrial enzyme responsible for breaking down neurotransmitters including serotonin, dopamine, norepinephrine, and epinephrine¹¹ serotonin, dopamine, norepinephrine, and epinephrine
These are key chemical messengers that regulate mood, motivation, stress response, and emotional regulation. The rs6323 variant, despite being synonymous (meaning it doesn't change the amino acid sequence at position 297), significantly affects how efficiently this enzyme works. This is a classic example of how ²² DNA changes don't need to alter protein structure to have meaningful biological effects — they can influence gene expression, mRNA stability, or protein folding.

The variant exists in two forms: G, which produces higher MAOA activity, and T, which produces lower activity³³ G, which produces higher MAOA activity, and T, which produces lower activity
The G allele encodes the high-activity form while T encodes the low-activity form. Because MAOA is located on the X chromosome, males (who have only one X) express whichever version they inherit, while females (with two X chromosomes) can have varying combinations. About 29% of Europeans carry the T (lower activity) allele, with higher frequencies in East Asian populations (~48%).

The Mechanism

MAOA requires flavin adenine dinucleotide (FAD) as a covalently attached cofactor⁴⁴ flavin adenine dinucleotide (FAD) as a covalently attached cofactor
FAD is derived from riboflavin (vitamin B2) and is permanently bound to the MAOA enzyme. The R297R variant affects enzyme activity through mechanisms that remain incompletely understood but likely involve mRNA stability or protein folding efficiency rather than direct catalytic changes. Studies show the G allele is associated with 2-10 times higher MAOA expression compared to the T allele⁵⁵ Studies show the G allele is associated with 2-10 times higher MAOA expression compared to the T allele
This translates to faster breakdown of monoamine neurotransmitters.

Lower MAOA activity (T allele) leads to slower breakdown of serotonin, dopamine, and norepinephrine, resulting in higher baseline levels of these neurotransmitters. Conversely, higher activity (G allele) means faster degradation and potentially lower neurotransmitter availability, though the body often compensates through feedback mechanisms and altered receptor sensitivity⁶⁶ feedback mechanisms and altered receptor sensitivity
The relationship between MAOA activity and mood is complex and influenced by environmental factors.

The Evidence

The rs6323 variant has been extensively studied in psychiatric and behavioral contexts. A study of major depressive disorder found that patients with the highest-activity G or GG genotypes had significantly lower placebo response⁷⁷ A study of major depressive disorder found that patients with the highest-activity G or GG genotypes had significantly lower placebo response
PMID: 19593178. This suggests they may be less responsive to psychological interventions alone.

In Korean children, the TT genotype was protective against ADHD in girls with an odds ratio of 0.31⁸⁸ In Korean children, the TT genotype was protective against ADHD in girls with an odds ratio of 0.31
PMID: 29782859. Park et al., 2018. Journal of Korean Medical Science. However, results vary by sex and population, with some studies showing opposite effects in males versus females.

Research on aggression has linked the low-activity variants to increased impulsivity and reactive aggression, particularly in individuals who experienced childhood adversity⁹⁹ Research on aggression has linked the low-activity variants to increased impulsivity and reactive aggression, particularly in individuals who experienced childhood adversity
The gene-environment interaction is crucial — the variant alone doesn't determine behavior. The so-called "warrior gene" association has been sensationalized in media but represents a modest effect size in scientific studies¹⁰¹⁰ "warrior gene" association has been sensationalized in media but represents a modest effect size in scientific studies
The variant contributes to behavioral tendencies but doesn't determine outcomes.

Evidence level is strong based on consistent replication across multiple populations, though effect sizes are generally modest and highly context-dependent.

Practical Implications

For those with lower MAOA activity (T allele carriers), higher baseline neurotransmitter levels can manifest as emotional intensity, stress sensitivity, or difficulty with emotional regulation. Riboflavin is essential for MAOA function as the precursor to FAD¹¹¹¹ Riboflavin is essential for MAOA function as the precursor to FAD
Adequate B2 status supports optimal enzyme activity. Some individuals with slow MAOA variants report benefits from riboflavin supplementation (100-400 mg daily)¹²¹² riboflavin supplementation (100-400 mg daily)
This supports FAD synthesis and may help normalize enzyme activity.

MAOA activity naturally increases with age and in response to oxidative stress¹³¹³ MAOA activity naturally increases with age and in response to oxidative stress
This means someone with genetically low activity might find symptoms moderate over time. Higher activity variants (G allele) may benefit from ensuring adequate precursors for neurotransmitter synthesis.

For treatment response, antidepressant choice may be influenced by MAOA genotype, though this isn't yet standard clinical practice¹⁴¹⁴ antidepressant choice may be influenced by MAOA genotype, though this isn't yet standard clinical practice
SSRIs work by different mechanisms than MAO inhibitors and may have variable effectiveness. MAO inhibitors are typically reserved for treatment-resistant depression.

Interactions

rs6323 interacts with rs1137070, another functional MAOA variant¹⁵¹⁵ rs1137070, another functional MAOA variant
Together these define MAOA haplotypes with different activity levels. The uVNTR (variable number tandem repeat) in the MAOA promoter is perhaps the most well-known MAOA variant and works in combination with rs6323 to determine overall enzyme activity. Compound heterozygosity or multiple low-activity alleles across these variants can result in markedly reduced MAOA activity¹⁶¹⁶ Compound heterozygosity or multiple low-activity alleles across these variants can result in markedly reduced MAOA activity
This may increase susceptibility to mood and behavioral regulation challenges.

MAOA activity also influences the metabolism of tyramine, a dietary amine found in aged cheeses, fermented foods, and red wine¹⁷¹⁷ the metabolism of tyramine, a dietary amine found in aged cheeses, fermented foods, and red wine
Low MAOA activity can increase sensitivity to tyramine and risk of hypertensive reactions when combined with MAO-inhibiting medications.

Nutrient Interactions

riboflavin increased_need

niacin increased_need

Genotype Interpretations

What each possible genotype means for this variant:

G “High Activity” Normal

Higher MAOA enzyme activity with faster neurotransmitter breakdown

You have the G allele, associated with higher MAOA enzyme activity. This means you break down serotonin, dopamine, and norepinephrine more rapidly. About 71% of European males have this version. Higher activity is generally considered the "typical" or reference form, though it's associated with faster depletion of neurotransmitters under stress and may influence antidepressant response.

GG “High Activity” Normal

Both copies produce high MAOA activity with rapid neurotransmitter breakdown

You have two copies of the G allele, associated with high MAOA enzyme activity. You break down serotonin, dopamine, and norepinephrine rapidly. About 50% of European females have this genotype. Higher activity is generally considered typical, though it may influence mood regulation and antidepressant response.

GT “Intermediate Activity” Intermediate

Mixed MAOA activity with one high and one low activity allele

You have one G (high activity) and one T (low activity) allele. Due to X-chromosome inactivation, females are mosaics with different cells expressing either the G or T version | This creates intermediate overall activity with tissue-specific variation. About 42% of European females share this genotype. Your MAOA activity falls between the two homozygous forms, and the specific pattern varies by tissue.

T “Low Activity” Reduced Caution

Lower MAOA enzyme activity leading to slower neurotransmitter breakdown

You have the T allele, associated with lower MAOA enzyme activity — approximately 2-10 times less than the G variant. This means you break down serotonin, dopamine, and norepinephrine more slowly, resulting in higher baseline levels of these neurotransmitters. About 29% of European males share this variant. While this can provide emotional resilience in some contexts, it may also increase sensitivity to stress and emotional intensity.

TT “Low Activity” Reduced Caution

Both copies produce low MAOA activity with slower neurotransmitter breakdown

You have two copies of the T allele, associated with significantly reduced MAOA enzyme activity. You break down serotonin, dopamine, and norepinephrine more slowly, resulting in higher baseline neurotransmitter levels. About 8% of European females have this genotype. While this can provide emotional depth and resilience, it may also increase sensitivity to stress and emotional reactivity.