What you carry at this position in your DNA and what research says about it.
Mental Health Risk: 5/10 evidence, 54 publications.
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Sample genotype (not yours): G/G
Increased Schizophrenia Risk
Higher susceptibility to schizophrenia is associated with this genotype, particularly in females. It may also lead to a more favorable response to certain antidepressant medications.
What this genotype means: Increased risk of schizophrenia; Better response to duloxetine; Slightly reduced verbal memory performance.
Sample genotype (not yours): A/A
Typical Schizophrenia Risk
Typical baseline risk for schizophrenia and standard response to antidepressant therapies are associated with this genotype. There is a higher chance of experiencing drowsiness as a side effect of opioid medications.
What this genotype means: Typical baseline risk of schizophrenia; Standard response to antidepressant therapies; Higher likelihood of opioid-induced drowsiness.
Sample genotype (not yours): G/A
Slightly Increased Schizophrenia Risk
A moderately increased risk of schizophrenia and a better response to antidepressants are linked to this genotype. There is also an increased likelihood of experiencing drowsiness when taking opioid medications.
What this genotype means: Slightly increased risk of schizophrenia; Better response to duloxetine and bupropion; Higher likelihood of opioid-induced drowsiness.
Gene function and biological role
Gene Function: The ARVCF gene encodes a member of the catenin family, which plays a critical role in cell-to-cell adhesion and signaling. Located in the chromosomal region 22q11.2, this gene is highly expressed in the brain and cardiovascular system. Genetic variations in this region are frequently studied due to their proximity to the catechol-O-methyltransferase (COMT) gene, which regulates dopamine levels. Adhesion proteins like ARVCF are essential for maintaining synaptic structure and neural connectivity [1]. Disruptions in these pathways have been implicated in neurodevelopmental and psychiatric conditions [2].
Variant Impact: The rs165599 variant is a single nucleotide polymorphism located in the 3 prime untranslated region of the ARVCF gene, adjacent to the COMT gene. This genetic change influences the expression levels of COMT, thereby modulating dopamine clearance in the prefrontal cortex [3]. Because dopamine is a key neurotransmitter involved in cognition, mood, and pain perception, this variant has wide-ranging effects on mental health and drug response [4]. The G allele is associated with reduced COMT expression, leading to higher baseline dopamine levels in certain brain regions.
Key Insight: This variant sits in the ARVCF gene but directly influences the neighboring COMT gene, acting as a remote control for dopamine levels in the brain.
Location: COMT. Chromosome 22 · 22q11.21 · 20.0 Mb
Estimated prevalence by population
Global 22.0%; European 9.4%; African 46.9%; East Asian 25.1%; South Asian 18.7%; Americas 21.2%; Ashkenazi 15.3%; Finnish 11.1%; Middle Eastern 11.8%; Amish 4.1%.
Estimated GG genotype frequency.
Global 44.1%; European 42.5%; African 43.2%; East Asian 50.0%; South Asian 49.1%; Americas 49.7%; Ashkenazi 47.6%; Finnish 44.4%; Middle Eastern 45.1%; Amish 32.4%.
Estimated GA genotype frequency.
Global 33.9%; European 48.1%; African 9.9%; East Asian 24.9%; South Asian 32.2%; Americas 29.1%; Ashkenazi 37.0%; Finnish 44.6%; Middle Eastern 43.1%; Amish 63.4%.
Estimated AA genotype frequency.
Showing effects for G/G genotype
Neurology & Mental Health
Psychotic Disorders
Schizophrenia. Evidence: 5/10. Source: PMID 30165727. Increased Risk.
Memory, Learning & Attention
Verbal Memory. Evidence: 3/10. Source: PMID 28273278. Worse Verbal Memory.
Pharmacogenomics
Antidepressant & Psychiatric Drug Response
Antidepressant Response. Evidence: 5/10. Source: PMID 21788083. Stronger Response.
Pain Medication Response
Opioid Drowsiness. Evidence: 5/10. Source: PMID 38126330. Typical Response.
Showing effects for A/A genotype
Schizophrenia. Evidence: 5/10. Source: PMID 30165727. Typical Risk.
Verbal Memory. Evidence: 3/10. Source: PMID 28273278. Better Verbal Memory.
Antidepressant Response. Evidence: 5/10. Source: PMID 21788083. Typical Response.
Opioid Drowsiness. Evidence: 5/10. Source: PMID 38126330. Increased Drowsiness.
Showing effects for G/A genotype
Schizophrenia. Evidence: 5/10. Source: PMID 30165727. Slightly Increased.
Verbal Memory. Evidence: 3/10. Source: PMID 28273278. Typical.
What this genotype means for the people who carry it
Sample genotype: GG (Homozygous)
Dopamine regulation in the prefrontal cortex is altered in those with two copies of the G allele, resulting from lower COMT expression [1]. This alteration is linked to a higher risk of developing schizophrenia, with some studies showing a more pronounced effect in females [2]. However, this same biological mechanism appears to enhance the effectiveness of antidepressants like duloxetine, offering a better therapeutic response [3]. Individuals with this genotype may also experience typical sensitivity to opioid-induced drowsiness compared to those with the A allele [4]. Verbal memory and cognitive performance during certain mood phases can be slightly reduced [5]. Understanding these patterns helps researchers map how dopamine-related genes influence both psychiatric risk and treatment outcomes.
Increased risk of schizophrenia; Better response to duloxetine; Slightly reduced verbal memory performance.
Sample genotype: AA (Homozygous)
Higher COMT expression and more rapid dopamine clearance in the prefrontal cortex are characteristic of this genotype [1]. This efficient clearance is associated with a lower, typical risk of schizophrenia, acting as a protective factor compared to G allele carriers [2]. Standard responses to antidepressant medications like duloxetine are typically observed, without the enhanced efficacy seen in G carriers [3]. Opioid treatments are more likely to cause side effects such as drowsiness and fatigue [4]. Cognitive functions, particularly verbal memory and executive tasks, are often highly efficient due to optimal dopamine processing [5]. These findings demonstrate how the major allele maintains baseline mental health risks while influencing drug sensitivity.
Typical baseline risk of schizophrenia; Standard response to antidepressant therapies; Higher likelihood of opioid-induced drowsiness.
Sample genotype: GA (Heterozygous)
Carrying one copy of each allele results in intermediate COMT expression and moderate dopamine clearance rates in the brain [1]. This balance is associated with a slightly elevated risk of schizophrenia compared to the protective AA genotype [2]. On the therapeutic side, this genotype is linked to improved clinical responses to antidepressants such as duloxetine and bupropion [3]. When prescribed opioid medications, there is a higher probability of experiencing side effects like drowsiness [4]. Cognitive performance, including working memory and verbal fluency, generally falls within the typical range [5]. These diverse effects highlight how a single genetic variation can influence both psychiatric vulnerability and medication sensitivity.
Slightly increased risk of schizophrenia; Better response to duloxetine and bupropion; Higher likelihood of opioid-induced drowsiness.
Variants with shared genetic architecture
rs165722 · COMT Gene · Chr 22 · Opioid Nausea Risk
rs4633 · COMT Gene · Chr 22 · Endometrial Cancer Risk
rs4680 · COMT Gene · Chr 22 · Stress and Focus
Impact of interacting functional variants in COMT on regional gray matter volume in human brain.
Content updated August 2026.
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