What you carry at this position in your DNA and what research says about it.
Multisystem Health Trade-offs: 10/10 evidence, 106 publications.
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Sample genotype (not yours): C/C
Typical Mental Health and Higher Blood Pressure Risk
Normal metal transporter activity maintains a standard risk of schizophrenia and osteoarthritis. However, it is linked to slightly higher blood pressure and elevated LDL cholesterol levels.
What this genotype means: Typical risk of schizophrenia; Higher blood pressure; Higher LDL cholesterol.
Sample genotype (not yours): C/T
Balanced Cardiovascular and Mental Health Profile
A single copy of the variant allele represents an intermediate physiological state. It offers a moderate reduction in blood pressure alongside a slight increase in schizophrenia and joint risks.
What this genotype means: Slightly lower blood pressure; Slightly increased schizophrenia risk; Slightly higher BMI.
Sample genotype (not yours): T/T
Lower Blood Pressure but Higher Schizophrenia Risk
Two copies of the variant allele significantly lower blood pressure and LDL cholesterol. However, they substantially increase the risk of schizophrenia, osteoarthritis, and elevated body mass index.
What this genotype means: Lower blood pressure; Increased schizophrenia risk; Increased osteoarthritis risk.
Gene function and biological role
Gene Function: The SLC39A8 gene encodes the ZIP8 metal transporter, which is responsible for moving essential trace minerals like manganese and zinc into cells [1]. These metals act as vital cofactors for numerous enzymes, particularly those involved in protein glycosylation and antioxidant defense [1]. Proper functioning of this transporter is crucial for maintaining the integrity of the intestinal barrier and supporting systemic metabolic health [2]. When ZIP8 activity is altered, it can disrupt cellular homeostasis across multiple organ systems, including the brain, liver, and kidneys [1].
Variant Impact: The rs13107325 variant is a missense mutation that changes the amino acid alanine to threonine at position 391 of the ZIP8 transporter [1]. This structural alteration reduces the accumulation of the transporter on the cell surface, leading to impaired manganese and zinc uptake [1]. Consequently, individuals carrying the variant allele exhibit significantly lower levels of manganese in their blood and tissues [2]. This localized deficiency impairs manganese-dependent enzymes in the Golgi apparatus, causing subtle changes in protein glycosylation that ripple across various physiological systems [2].
Read on the Left-Handedness page
Key Insight: This variant represents one of the most powerful evolutionary trade-offs in the human genome, where protection against high blood pressure comes at the cost of mental health and joint risks.
Location: SLC39A8. Chromosome 4 · 4q24 · 102.3 Mb
Origin Story: The threonine-producing T allele underwent rapid positive selection as modern humans migrated into Europe, likely because its blood pressure-lowering effects or immune alterations offered a survival advantage in colder climates.
Estimated prevalence by population
Global 91.4%; European 86.4%; African 97.5%; East Asian 99.9%; South Asian 99.0%; Americas 89.9%; Ashkenazi 77.5%; Finnish 98.1%; Middle Eastern 89.4%; Amish 97.6%.
Estimated CC genotype frequency.
Global 8.4%; European 13.1%; African 2.5%; East Asian 0.1%; South Asian 1.0%; Americas 9.9%; Ashkenazi 21.1%; Finnish 1.9%; Middle Eastern 10.3%; Amish 2.4%.
Estimated CT genotype frequency.
Global 0.3%; European 0.5%; African < 0.1%; East Asian < 0.1%; South Asian < 0.1%; Americas 0.3%; Ashkenazi 1.4%; Finnish < 0.1%; Middle Eastern 0.3%; Amish < 0.1%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Neurology & Mental Health
Psychotic Disorders
Schizophrenia. Evidence: 10/10. Source: PMID 35396580. Typical Risk.
Addiction & Reward
Alcohol Use Disorder. Evidence: 10/10. Source: PMID 30940813. Increased Risk.
Cardiovascular & Metabolic
Hypertension
Blood Pressure. Evidence: 10/10. Source: PMID 21909115. Increased Pressure.
Obesity & Body Composition
Body Mass Index. Evidence: 10/10. Source: PMID 25673413. Typical BMI.
Lipids & Cholesterol
LDL Cholesterol. Evidence: 10/10. Source: PMID 29507422. Higher LDL.
Organ Systems
Bone, Joint & Connective Tissue Health
Osteoarthritis. Evidence: 10/10. Source: PMID 34450027. Typical Risk.
Showing effects for C/T genotype
Schizophrenia. Evidence: 10/10. Source: PMID 35396580. Slightly Increased.
Alcohol Use Disorder. Evidence: 10/10. Source: PMID 30940813. Slightly Lower.
Blood Pressure. Evidence: 10/10. Source: PMID 21909115. Slightly Lower.
Body Mass Index. Evidence: 10/10. Source: PMID 25673413. Slightly Higher.
LDL Cholesterol. Evidence: 10/10. Source: PMID 29507422. Slightly Lower.
Osteoarthritis. Evidence: 10/10. Source: PMID 34450027. Slightly Increased.
Showing effects for T/T genotype
Schizophrenia. Evidence: 10/10. Source: PMID 35396580. ~1.18x Increased Risk.
Alcohol Use Disorder. Evidence: 10/10. Source: PMID 30940813. Lower Risk.
Blood Pressure. Evidence: 10/10. Source: PMID 21909115. Lower Pressure.
Body Mass Index. Evidence: 10/10. Source: PMID 25673413. Higher BMI.
LDL Cholesterol. Evidence: 10/10. Source: PMID 29507422. Lower LDL.
Osteoarthritis. Evidence: 10/10. Source: PMID 34450027. ~1.09x Increased Risk.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Possessing two copies of the common C allele ensures normal functioning of the ZIP8 metal transporter, maintaining typical cellular manganese and zinc levels [1]. This optimal metal transport supports healthy protein glycosylation and protects against joint cartilage degradation [1]. Consequently, this profile is associated with a lower risk of developing schizophrenia and osteoarthritis compared to variant carriers. On the other hand, normal transporter activity is consistently linked to higher systolic and diastolic blood pressure [2]. It also correlates with higher levels of LDL and total cholesterol, which are key cardiovascular risk factors [3]. Additionally, this genotype is associated with a slightly increased susceptibility to alcohol use disorder and higher overall alcohol consumption [4].
Typical risk of schizophrenia; Higher blood pressure; Higher LDL cholesterol.
Sample genotype: CT (Heterozygous)
Possessing one copy of the threonine-encoding T allele moderately reduces the efficiency of cellular manganese and zinc transport [1]. This slight reduction in transporter activity leads to intermediate systemic manganese levels [1]. As a result, cardiovascular markers show a favorable trend, including slightly lower blood pressure and reduced LDL cholesterol levels. Conversely, the mild cellular manganese deficiency gently elevates the risk of joint issues like osteoarthritis and metabolic changes like higher body mass index. There is also a small, incremental increase in the risk of developing schizophrenia [2]. This balanced profile highlights the evolutionary trade-offs maintained by this highly pleiotropic genetic variant [1].
Slightly lower blood pressure; Slightly increased schizophrenia risk; Slightly higher BMI.
Sample genotype: TT (Homozygous)
Two copies of the T allele severely limit the ZIP8 transporter's ability to import manganese and zinc into cells [1]. This profound cellular deficiency impairs critical manganese-dependent enzymes, leading to altered protein glycosylation [1]. The systemic effects of this transport deficit are highly diverse, offering a significant reduction in both systolic and diastolic blood pressure [2]. It also leads to lower circulating levels of LDL and total cholesterol, which are protective against certain cardiovascular issues [3]. However, these benefits are offset by a notable increase in the risk of schizophrenia [4]. Furthermore, the lack of cellular manganese accelerates cartilage wear, raising the risk of osteoarthritis [5]. It is also linked to a higher body mass index and an increased likelihood of acid reflux.
Lower blood pressure; Increased schizophrenia risk; Increased osteoarthritis risk.
Variants with shared genetic architecture
rs13135092 · SLC39A8 Gene · Chr 4 · Mental Health and Addiction
rs11191580 · NT5C2 Gene · Chr 10 · Blood Pressure and Brain
rs4129585 · TSNARE1 Gene · Chr 8 · Schizophrenia Risk
Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease.
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
A large electronic-health-record-based genome-wide study of serum lipids.
Mapping genomic loci implicates genes and synaptic biology in schizophrenia.
Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
Content updated August 2026.
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