Schizophrenia: genes and variants

Genes linked to Schizophrenia

• MTHFR: Methylenetetrahydrofolate reductase (NADPH)

  It generates 5-methyltetrahydrofolate for remethylation of homocysteine to methionine, linking folate metabolism with methyl-group supply. Severe biallelic deficiency causes homocystinuria with neurologic and thrombotic complications, while common variants produce much smaller effects on homocysteine.

  2 disease-causing and 13 uncertain variants in MTHFR are linked to Schizophrenia.

• SHANK3: SH3 and multiple ankyrin repeat domains protein 3

  At excitatory synapses, it organizes glutamate receptors, signaling proteins, and the actin cytoskeleton. Haploinsufficiency causes Phelan-McDermid syndrome and is strongly associated with intellectual disability, severe speech impairment, and autism-related features.

  1 disease-causing and 1 uncertain variants in SHANK3 are linked to Schizophrenia.

• DRD2: D(2) dopamine receptor

  Its activation by dopamine modulates cyclic-AMP signaling and neuronal excitability in circuits governing movement, motivation, reward, and endocrine control. It is a major pharmacologic target of antipsychotic drugs and dopamine agonists, and rare variants can produce movement or neuropsychiatric phenotypes.

  0 disease-causing and 0 uncertain variants in DRD2 are linked to Schizophrenia.

• DRD4: D(4) dopamine receptor

  It modulates dopamine signaling in cortical and limbic circuits and influences cyclic-AMP production and neuronal excitability. Common repeat polymorphisms have been studied extensively for behavioral traits, although their individual effects are modest and not deterministic.

  0 disease-causing and 0 uncertain variants in DRD4 are linked to Schizophrenia.

• GRIN2A: Glutamate receptor ionotropic, NMDA 2A

  It helps determine the kinetics and signaling properties of NMDA receptors, particularly in cortical circuits involved in language and epilepsy. Pathogenic variants cause a spectrum of developmental epileptic encephalopathies and epilepsy-aphasia disorders.

  0 disease-causing and 0 uncertain variants in GRIN2A are linked to Schizophrenia.

• HTR2A: 5-hydroxytryptamine receptor 2A

  Its activation by serotonin engages Gq signaling in cortical, vascular, and other tissues and influences perception, mood, cognition, and smooth-muscle responses. It is a major target of many antipsychotic drugs and psychedelic compounds, while common genetic effects on behavior are generally modest.

  0 disease-causing and 0 uncertain variants in HTR2A are linked to Schizophrenia.

• HTR2C: 5-hydroxytryptamine receptor 2C

  Its serotonin-dependent signaling in hypothalamic and limbic circuits suppresses appetite and modulates mood, reward, and neuroendocrine function. Altered signaling can affect body weight and psychiatric drug responses, and the receptor is a pharmacologic target of several neuropsychiatric agents.

  0 disease-causing and 0 uncertain variants in HTR2C are linked to Schizophrenia.

• OPRM1: Mu-type opioid receptor

  A G protein-coupled receptor for endogenous opioids and medicines such as morphine and fentanyl. Its activation changes neuronal signaling involved in pain, reward, and respiratory control through inhibitory G protein pathways.

  0 disease-causing and 0 uncertain variants in OPRM1 are linked to Schizophrenia.

Weakly linked (only a few uncertain records): COMT and TH.

Known disease-causing variants in Schizophrenia

Same protein, different disease

• Homocystinuria due to methylene tetrahydrofolate reductase deficiency is also caused by MTHFR variants; they fall mostly in different places as the Schizophrenia variants (43 disease-causing).
• Neural tube defects, folate-sensitive is also caused by MTHFR variants; they fall mostly in different places as the Schizophrenia variants (19 disease-causing).
• Thrombophilia due to thrombin defect is also caused by MTHFR variants; they fall mostly in different places as the Schizophrenia variants (6 disease-causing).

Diseases related to Schizophrenia

• Parkinson disease, also linked to DRD2, DRD4, GRIN2A, HTR2A and 1 more
• Autism, also linked to DRD2, HTR2A and HTR2C
• Alzheimer disease, also linked to GRIN2A
• Landau-Kleffner syndrome, also linked to GRIN2A
• Homocystinuria due to methylene tetrahydrofolate reductase deficiency, also linked to MTHFR
• Neural tube defects, folate-sensitive, also linked to MTHFR
• Epilepsy, also linked to GRIN2A
• Thrombophilia due to thrombin defect, also linked to MTHFR
• Self-limited epilepsy with centrotemporal spikes, also linked to GRIN2A
• Dementia, also linked to GRIN2A
• Dystonic disorder, also linked to DRD2
• GRIN2A-related complex neurodevelopmental disorder, also linked to GRIN2A

Frequently asked questions

Which genes are linked to Schizophrenia?

In CATVariant, Schizophrenia is linked to 8 analyzed proteins: MTHFR (Methylenetetrahydrofolate reductase (NADPH)), SHANK3 (SH3 and multiple ankyrin repeat domains protein 3), DRD2 (D(2) dopamine receptor), DRD4 (D(4) dopamine receptor), GRIN2A (Glutamate receptor ionotropic, NMDA 2A), HTR2A (5-hydroxytryptamine receptor 2A) and 2 more.

How many genetic variants are linked to Schizophrenia?

31 variants: 3 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 15 are of uncertain significance or have conflicting reports.

Which uncertain variants in Schizophrenia look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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