What you carry at this position in your DNA and what research says about it.
Schizophrenia and Immune Risk: 5/10 evidence, 8 publications.
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Sample genotype (not yours): C/C
Higher Schizophrenia Risk
Carrying two copies of the C allele is associated with an increased risk of developing schizophrenia. However, this genotype is linked to a lower risk of autoimmune conditions.
What this genotype means: Increased risk of schizophrenia; Lower risk of autoimmune disorders; Typical lean body mass.
Sample genotype (not yours): C/T
Slightly Higher Schizophrenia Risk
Carrying one copy of the T allele is linked to a slightly elevated risk of schizophrenia and a mild increase in autoimmune susceptibility.
What this genotype means: Slightly increased risk of schizophrenia; Slightly increased autoimmune risk; Slightly higher lean body mass potential.
Sample genotype (not yours): T/T
Typical Schizophrenia Risk but Higher Autoimmune Risk
Carrying two copies of the T allele provides protection against schizophrenia, but increases the risk of autoimmune conditions and supports higher lean body mass.
What this genotype means: Typical baseline risk of schizophrenia; Increased risk of autoimmune conditions; Higher lean body mass potential.
Gene function and biological role
Gene Function: The NOTCH4 gene encodes a member of the Notch family of transmembrane receptors, which play a critical role in cell-to-cell signaling and neurodevelopment. It is highly active in the central nervous system, regulating neuronal maturation, cell proliferation, and differentiation during brain development [1]. Because of its fundamental role in shaping brain circuitry, variations in this gene have been heavily studied in connection with psychiatric conditions [2]. Additionally, NOTCH4 is located within the major histocompatibility complex region on chromosome 6, a genetic zone tightly linked to immune system regulation [3]. This dual role positions the gene at a fascinating intersection between brain development and immune function.
Variant Impact: The rs3131296 variant is an intron variant located within the NOTCH4 gene. This genetic change does not directly alter the amino acid sequence of the Notch4 protein, but it is thought to influence gene expression or splice patterns during development [1]. It serves as a prominent genetic marker in genome-wide association studies, showing strong links to both psychiatric susceptibility and physical traits [2]. Interestingly, this variant is in strong linkage disequilibrium with classical human leukocyte antigen alleles, meaning it is inherited alongside specific immune system genes [4]. Consequently, this single genetic marker acts as a bridge connecting brain development patterns with immune system behavior.
Key Insight: This variant represents an evolutionary trade-off where the genetic sequence that protects against schizophrenia simultaneously increases the risk for certain autoimmune conditions like lupus.
Location: NOTCH4. Chromosome 6 · 6p21.32 · 32.2 Mb
Estimated prevalence by population
Global 80.1%; European 75.1%; African 82.6%; East Asian 93.5%; South Asian 81.8%; Americas 89.4%; Ashkenazi 85.2%; Finnish 78.0%; Middle Eastern 90.1%; Amish 85.8%.
Estimated CC genotype frequency.
Global 18.7%; European 23.1%; African 16.6%; East Asian 6.4%; South Asian 17.3%; Americas 10.3%; Ashkenazi 14.2%; Finnish 20.7%; Middle Eastern 9.7%; Amish 13.6%.
Estimated CT genotype frequency.
Global 1.2%; European 1.8%; African 0.8%; East Asian 0.1%; South Asian 0.9%; Americas 0.3%; Ashkenazi 0.6%; Finnish 1.4%; Middle Eastern 0.3%; Amish 0.5%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Neurology & Mental Health
Psychotic Disorders
Schizophrenia. Evidence: 5/10. Source: PMID 19571808. ~1.4x Higher Risk.
Immunity & Inflammation
Autoimmune Diseases
Autoimmune Disease Risk. Evidence: 3/10. Source: PMID 18204098. Lower Risk.
Lifestyle, Fitness & Aging
Muscle Strength & Power
Muscle Mass. Evidence: 6/10. Source: PMID 38538606. Typical Mass.
Showing effects for C/T genotype
Schizophrenia. Evidence: 5/10. Source: PMID 19571808. ~1.2x Higher Risk.
Autoimmune Disease Risk. Evidence: 3/10. Source: PMID 18204098. Slightly Higher Risk.
Muscle Mass. Evidence: 6/10. Source: PMID 38538606. Slightly Higher.
Showing effects for T/T genotype
Schizophrenia. Evidence: 5/10. Source: PMID 19571808. Typical Risk.
Autoimmune Disease Risk. Evidence: 3/10. Source: PMID 18204098. Higher Risk.
Muscle Mass. Evidence: 6/10. Source: PMID 38538606. Higher Mass.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Inheriting two copies of the C allele is associated with a moderately increased susceptibility to schizophrenia, estimated at approximately 1.4 times the baseline risk [1]. This association has been replicated across multiple genome-wide scans, particularly in European populations [2]. The biological mechanism is believed to involve altered Notch4 signaling during critical windows of brain development, which may affect neuronal connectivity [3]. On the positive side, this genotype is protective against several autoimmune disorders [4]. Because the C allele is not linked to the HLA-DRB1*03 immune variant, individuals with this genotype have a lower risk of developing conditions like systemic lupus erythematosus [4]. Additionally, this genotype is associated with typical lean body mass levels [5].
Increased risk of schizophrenia; Lower risk of autoimmune disorders; Typical lean body mass.
Sample genotype: CT (Heterozygous)
Having one copy of each allele represents an intermediate genetic profile for both psychiatric and autoimmune traits. This genotype is associated with a slightly elevated risk of schizophrenia, estimated at roughly 1.2 times the baseline [1]. This modest increase has been observed in several large-scale genetic analyses [2]. Simultaneously, carrying one T allele introduces a slight increase in the risk of autoimmune conditions, as the T allele is inherited alongside immune-modulating HLA variants [3]. This dual influence demonstrates how complex genetic regions can pull health risks in opposite directions. On a physical level, this genotype is also associated with a minor positive influence on lean body mass [4]. Overall, this represents a balanced genetic profile with subtle shifts in risk across different body systems.
Slightly increased risk of schizophrenia; Slightly increased autoimmune risk; Slightly higher lean body mass potential.
Sample genotype: TT (Homozygous)
Inheriting two copies of the T allele is highly favorable for mental health, as it is associated with a typical, non-elevated risk of developing schizophrenia [1]. This protective effect has been validated in major psychiatric genome-wide association studies [2]. However, this genotype presents a distinct biological trade-off. The T allele is in strong linkage disequilibrium with classical HLA variants, meaning it is inherited alongside genes that increase susceptibility to autoimmune diseases like systemic lupus erythematosus [3]. Additionally, recent genetic research associates the T allele with higher lean body mass, which can influence overall metabolic health and physical build [4]. This genotype perfectly illustrates evolutionary balancing, where a protective psychiatric profile comes with a more active immune system.
Typical baseline risk of schizophrenia; Increased risk of autoimmune conditions; Higher lean body mass potential.
Variants with shared genetic architecture
rs11191580 · NT5C2 Gene · Chr 10 · Blood Pressure and Brain
rs13107325 · SLC39A8 Gene · Chr 4 · Multisystem Health Trade-offs
rs13135092 · SLC39A8 Gene · Chr 4 · Mental Health and Addiction
Common variants conferring risk of schizophrenia.
Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX.
Search for schizophrenia susceptibility variants at the HLA-DRB1 locus among a British population.
New role of fat-free mass in cancer risk linked with genetic predisposition.
Content updated August 2026.
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