What you carry at this position in your DNA and what research says about it.
Bipolar and Treatment Response: 8/10 evidence, 23 publications.
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Sample genotype (not yours): A/A
Earlier Bipolar Onset and Poorer Treatment Response
This genotype is associated with an earlier age of onset for bipolar symptoms and a reduced response to lithium therapy. It is linked to typical cholesterol levels and a baseline risk of insomnia.
What this genotype means: Earlier onset of bipolar disorder symptoms; Reduced therapeutic response to lithium; Lower baseline cholesterol levels.
Sample genotype (not yours): A/G
Later Bipolar Onset and Better Lithium Response
This genotype is linked to a delayed onset of bipolar symptoms and an improved response to lithium treatment. It may also slightly increase cholesterol levels.
What this genotype means: Later onset of bipolar disorder symptoms; Improved response to lithium therapy; Slightly elevated cholesterol levels.
Sample genotype (not yours): G/G
Better Treatment Response but Higher Cholesterol Risk
This genotype offers the best response to lithium and certain antidepressants, but it increases the risk of high cholesterol and insomnia.
What this genotype means: Optimized response to lithium and antidepressants; Later onset of bipolar symptoms; Higher LDL and total cholesterol levels.
Gene function and biological role
Gene Function: The GSK3B gene encodes glycogen synthase kinase 3 beta, a multifunctional enzyme involved in energy metabolism, neuronal cell development, and body clock regulation. It plays a critical role in the brain by regulating the stability of key proteins involved in signaling pathways. This enzyme is also a primary cellular target of lithium, a common mood-stabilizing medication used to manage bipolar disorder [1]. Variations in this gene can alter its expression levels, thereby influencing how the brain responds to mood stabilizers and antidepressants [2].
Variant Impact: The rs334558 variant is located in the promoter region of the GSK3B gene, where it directly influences transcriptional activity. The G allele is associated with reduced promoter activity and lower expression of the kinase compared to the A allele [2]. Because GSK3B activity affects neuronal signaling and drug binding, this expression difference impacts psychiatric drug efficacy [1]. It also influences downstream metabolic pathways, affecting circulating lipid levels.
Key Insight: The same genetic variant that helps delay the onset of bipolar disorder and improves response to lithium also increases the risk of high cholesterol and severe insomnia.
Location: GSK3B. Chromosome 3 · 3q13.33 · 120.1 Mb
Estimated prevalence by population
Global 28.7%; European 42.0%; African 2.1%; East Asian 14.5%; South Asian 19.6%; Americas 38.7%; Ashkenazi 35.7%; Finnish 39.9%; Middle Eastern 30.4%; Amish 55.7%.
Estimated AA genotype frequency.
Global 40.3%; European 45.6%; African 24.9%; East Asian 47.2%; South Asian 49.3%; Americas 47.0%; Ashkenazi 48.1%; Finnish 46.5%; Middle Eastern 49.5%; Amish 37.9%.
Estimated AG genotype frequency.
Global 30.9%; European 12.4%; African 73.0%; East Asian 38.3%; South Asian 31.0%; Americas 14.3%; Ashkenazi 16.2%; Finnish 13.6%; Middle Eastern 20.2%; Amish 6.4%.
Estimated GG genotype frequency.
Showing effects for A/A genotype
Neurology & Mental Health
Mood Disorders
Bipolar Disorder Onset. Evidence: 4/10. Source: PMID 23021822. Earlier Onset.
Sleep & Circadian Rhythm
Insomnia. Evidence: 6/10. Typical Risk.
Pharmacogenomics
Antiepileptic & Mood-Stabilizer Response
Lithium Response. Evidence: 4/10. Source: PMID 23021822. Poorer Response.
Antidepressant & Psychiatric Drug Response
Antidepressant Response. Evidence: 5/10. Source: PMID 18195729. Typical Response.
Cardiovascular & Metabolic
Lipids & Cholesterol
Cholesterol Levels. Evidence: 8/10. Source: PMID 34594039. Typical Levels.
Showing effects for A/G genotype
Bipolar Disorder Onset. Evidence: 4/10. Source: PMID 23021822. Later Onset.
Insomnia. Evidence: 6/10. Slightly Higher Risk.
Lithium Response. Evidence: 4/10. Source: PMID 23021822. Stronger Response.
Cholesterol Levels. Evidence: 8/10. Source: PMID 34594039. Slightly Higher.
Showing effects for G/G genotype
Insomnia. Evidence: 6/10. Higher Risk.
Antidepressant Response. Evidence: 5/10. Source: PMID 18195729. Stronger Response.
Cholesterol Levels. Evidence: 8/10. Source: PMID 34594039. Higher Levels.
What this genotype means for the people who carry it
Sample genotype: AA (Homozygous)
Having two copies of the A allele leads to higher promoter activity and increased expression of the GSK3B enzyme. In clinical studies, this higher activity is associated with developing bipolar disorder symptoms at an earlier age [1]. Furthermore, individuals with this genotype show a significantly lower rate of remission when treated with lithium, which works by inhibiting this kinase [2]. On the positive side, this genotype is associated with lower levels of LDL and total cholesterol compared to G allele carriers [3]. It is also linked to a typical baseline risk of developing severe insomnia during depressive episodes.
Earlier onset of bipolar disorder symptoms; Reduced therapeutic response to lithium; Lower baseline cholesterol levels.
Sample genotype: AG (Heterozygous)
Carrying one copy of the G allele reduces GSK3B promoter activity, resulting in moderate enzyme expression. This reduction is clinically protective, delaying the age at which bipolar disorder symptoms typically manifest [1]. It also enhances the brain's sensitivity to lithium therapy, leading to higher rates of treatment response and remission [2]. While this genotype provides notable psychiatric benefits, it is associated with a slight increase in LDL and total cholesterol levels [3]. There is also a marginally higher risk of experiencing severe insomnia during depressive episodes compared to the A/A genotype.
Later onset of bipolar disorder symptoms; Improved response to lithium therapy; Slightly elevated cholesterol levels.
Sample genotype: GG (Homozygous)
Having two copies of the G allele results in the lowest promoter activity and lowest expression of the GSK3B enzyme. This low-expression state is highly favorable for psychiatric treatments, correlating with the best response to lithium and SSRI antidepressants like fluoxetine and citalopram [1] [2]. It is also associated with a delayed onset of bipolar disorder symptoms [3]. However, this genotype presents a metabolic trade-off, as it is linked to significantly higher levels of LDL and total cholesterol [4]. Additionally, it is associated with an increased risk of severe insomnia during depressive episodes.
Optimized response to lithium and antidepressants; Later onset of bipolar symptoms; Higher LDL and total cholesterol levels; Increased risk of severe insomnia.
Variants with shared genetic architecture
rs6438552 · GSK3B Gene · Chr 3 · Brain Health and Lithium Response
rs13135092 · SLC39A8 Gene · Chr 4 · Mental Health and Addiction
rs7773004 · HIST1H3G Gene · Chr 6 · Varicose Veins
A cross-population atlas of genetic associations for 220 human phenotypes.
Content updated August 2026.
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