Bipolar & Schizophrenia Shared Risk and Your Genetics

Written by Scott Peeples, BS Biomedical Sciences · ExomeDNA Founder Reviewed by ExomeDNA Editorial Process Last reviewed: 2026-05-29

This page contains general information only. For personal health decisions, consult a qualified clinician.

Bipolar disorder and schizophrenia shared genetic risk describes a cluster of common genetic variants that independently raise population-level likelihood for both conditions — confirming that the two conditions share a portion of their heritable architecture. Genome-wide association studies published between 2010 and 2012 identified early loci near genes involved in synaptic plasticity, neuronal migration, and transsynaptic adhesion. Below: the specific genes most implicated and what research suggests about the shared biology connecting these two conditions.

What is bipolar and schizophrenia shared risk?

Bipolar disorder and schizophrenia shared genetic risk refers to the overlap in common DNA variants that contribute to heritable susceptibility for both bipolar disorder (ICD-10: F31) and schizophrenia (ICD-10: F20). Family and twin studies have long noted that relatives of people with schizophrenia face modestly elevated rates of bipolar disorder, and vice versa — an observation that genome-wide data have now partly explained at the molecular level. Both conditions are highly heritable, and a meaningful fraction of that heritability is attributable to variants shared across diagnostic boundaries. Recognizing this shared architecture does not change how either condition is experienced or treated, but it deepens understanding of the common biological pathways — particularly in synaptic signaling and brain circuit development — that underlie both.

The genetics behind bipolar and schizophrenia shared risk

The genetic architecture of both bipolar disorder and schizophrenia is highly polygenic: hundreds to thousands of common variants each contribute a small amount to overall risk, and no single gene determines outcome. The loci identified in early genome-wide meta-analyses point toward four converging biological themes: synaptic plasticity, transsynaptic adhesion, neuronal migration during brain development, and myelin integrity in white matter.

ARC (activity-regulated cytoskeleton-associated protein) is among the most biologically compelling genes implicated in this shared-risk landscape. ARC is an immediate-early gene — its transcription is triggered within minutes by neural activity — and its protein product regulates the endocytosis of AMPA-type glutamate receptors at the synapse. When a synapse is active, ARC coordinates the selective internalization and recycling of AMPA receptors, a process essential for the strengthening and weakening of synaptic connections that underlies learning and memory consolidation. Perhaps most remarkably, ARC protein self-assembles into virus-like capsid structures that can package ARC messenger RNA and transfer it between neurons via extracellular vesicles — a recently characterized mechanism for intercellular RNA communication unique among known synaptic proteins. Disruption of ARC function impairs the experience-dependent refinement of neural circuits, and ARC haploinsufficiency produces autism-like phenotypes in model systems. Common variants near the ARC locus have emerged in studies of both schizophrenia and bipolar disorder, consistent with a role for synaptic plasticity deficits in the shared biology of both conditions (Wang et al., 2010).[1]

ADAM23 encodes a catalytically inactive member of the ADAM (a disintegrin and metalloproteinase) family that is expressed in neurons. ADAM23 forms a transsynaptic complex with LGI1 (leucine-rich glioma-inactivated 1) spanning the synaptic cleft, and this complex organizes the localization of AMPA receptors at the postsynaptic density. The importance of this pathway is underscored by LGI1 autoimmune encephalitis: when the immune system generates antibodies against LGI1, the resulting disruption of the ADAM23-LGI1 complex produces prominent psychiatric features including psychosis, seizures, and memory disturbance — demonstrating that interference with this single molecular complex is sufficient to generate clinical presentations that overlap with both schizophrenia and mood disorders. Common ADAM23 variants identified in genome-wide association work may affect the stability or assembly of this transsynaptic complex, with downstream consequences for AMPA receptor organization relevant to both conditions (Curtis, 2011).[2]

ADAM19 (also known as meltrin beta) is a catalytically active metalloprotease expressed in the developing brain whose best-characterized substrate is neuregulin-1 (NRG1). ADAM19 cleaves the NRG1 ectodomain to release the soluble ligand that activates ErbB4 receptors. ErbB4 is expressed preferentially on parvalbumin-positive (PV+) GABAergic interneurons — the fast-spiking inhibitory cells whose synchronous firing coordinates gamma-band oscillations across cortical circuits. NRG1-ErbB4 signaling governs the maturation of these interneurons and regulates inhibitory synapse strength. Because PV+ interneurons set the excitatory/inhibitory (E/I) balance that underlies cognitive processing, variants in ADAM19 that alter NRG1 cleavage may affect the interneuron-dependent circuit dynamics implicated in the cognitive symptoms shared across schizophrenia and bipolar disorder (Bergen et al., 2012).[3]

ASTN2 encodes astrotactin 2, a neuronal surface protein that works together with ASTN1 to attach migrating neurons to radial glial fibers during cortical and cerebellar development. Proper radial migration is necessary for the laminar organization of the cortex; disruptions produce subtly misplaced neurons that may alter circuit connectivity throughout life. Copy number variants (CNVs) at the ASTN2 locus are significantly enriched across autism spectrum disorder, ADHD, schizophrenia, and bipolar disorder — placing ASTN2 among the most cross-diagnostic structural variant associations known. Beyond its migration role, ASTN2 also regulates the surface expression of synaptic proteins, providing a plausible mechanism linking a developmental migration gene to ongoing synaptic function in the mature brain (Wang et al., 2010).[1]

ABCD1 encodes the adrenoleukodystrophy protein, a peroxisomal ABC half-transporter responsible for importing very-long-chain fatty acids (VLCFAs) into the peroxisome for degradation. While loss-of-function mutations in ABCD1 cause X-linked adrenoleukodystrophy (a rare, severe demyelinating disease), common ABCD1 variants implicated in the bipolar-schizophrenia shared-risk signal are thought to affect peroxisomal VLCFA metabolism in white matter more subtly. White matter microstructure abnormalities — detected by diffusion tensor imaging — are among the most consistently replicated neuroimaging findings in both schizophrenia and bipolar disorder, and myelin integrity depends partly on peroxisomal lipid metabolism, providing a plausible mechanistic bridge (Bergen et al., 2012).[3]

ATP8A2 encodes a neuronal P4-ATPase phospholipid flippase that maintains membrane phospholipid asymmetry. Variants near this locus have appeared in early genome-wide association work on shared psychiatric risk (Wang et al., 2010).[1]

Genome-wide meta-analysis across multiple independent cohorts identified novel susceptibility loci including variants near ARC and ASTN2, highlighting synaptic plasticity pathways in schizophrenia risk.^[1]

A Swedish population genome-wide association study provided replication evidence for cross-diagnostic loci shared between schizophrenia and bipolar disorder, supporting greater etiological overlap than clinical frameworks alone suggest.^[3]

What the research says

Research base: Robust.

Genome-wide association studies of schizophrenia and bipolar disorder have progressed substantially since the first large collaborative meta-analyses were published. The early-era work by Wang et al. (2010)[1] and Bergen et al. (2012)[3] established a framework: that both conditions are highly polygenic, that many of their associated variants overlap, and that the implicated loci cluster around synaptic function, neuronal development, and white matter integrity. Curtis (2011)[2] extended this by explicitly examining case-case designs — comparing genetic profiles of people with schizophrenia against those with bipolar disorder — to identify markers that differentiate as well as markers that are shared, refining the landscape of shared versus disorder-specific genetic architecture.

The biological theme that unifies the ARC, ADAM23, ADAM19, and ASTN2 loci is consistent: genes that shape how neurons connect, signal, and refine their connections during development and throughout life appear in the shared genetic architecture of both conditions. This convergence supports a neurodevelopmental hypothesis for the shared risk: that both bipolar disorder and schizophrenia partially arise from subtle disruptions to synaptic organization and circuit maturation that originate during brain development but manifest clinically in adolescence and early adulthood, when those circuits are under greatest demand.

It is important to note that the common variants identified in genome-wide association studies each carry very small individual effect sizes. No single variant, and no single gene, determines whether someone will develop either condition. Genetic risk is probabilistic and polygenically distributed; most people who carry any given risk variant, or even many of them, will not be affected with either condition. Environmental factors, life experiences, access to care, and many other influences shape outcomes alongside genetics.

For information on how ExomeDNA assesses the research basis for each trait result, visit our methodology page.

How bipolar and schizophrenia shared risk affects you

Bipolar disorder and schizophrenia are both treatable conditions, and many people live meaningful, productive lives with appropriate support and treatment. The genetic risk captured by an ExomeDNA result reflects common-variant associations established in genome-wide research — it is not a health assessment and does not predict whether any individual will develop either condition.

Understanding shared genetic architecture can be useful in several ways. It helps explain why family members of someone with schizophrenia may have elevated rates of bipolar disorder, and vice versa — not because the same condition runs in families, but because the shared genetic substrate can manifest differently depending on other factors. It also illustrates why some medications (certain atypical antipsychotics, for example) have demonstrated efficacy in both conditions: if the two share underlying circuit-level disruptions, it is plausible that interventions targeting those circuits benefit both.

From a lived-experience perspective, the genes implicated here point toward synaptic plasticity — the brain's ability to strengthen and weaken connections in response to experience. ARC's role in AMPA receptor endocytosis, ADAM23's organization of the postsynaptic density, and ASTN2's guidance of neurons into their proper cortical positions are all part of the molecular machinery that allows the brain to adapt. When any part of that machinery is subtly altered, the result may not be a single, predictable clinical outcome but rather a broadened vulnerability to stress, disrupted sleep, or other precipitants — vulnerabilities that, with appropriate awareness and support, can be managed.

Working with your bipolar and schizophrenia shared risk result

If your ExomeDNA result indicates elevated shared risk for bipolar disorder and schizophrenia, the following evidence-informed strategies are relevant to discuss with a qualified clinician or mental health professional.

1. Monitor mood and energy patterns consistently. Keeping a mood diary or using a structured tracking app supports early identification of mood episodes. Early recognition is associated with better treatment outcomes in both bipolar disorder and schizophrenia-spectrum conditions (Bergen et al., 2012).[3]
2. Minimize cannabis use. Regular cannabis use, particularly high-THC products and use beginning in adolescence, is robustly associated with elevated risk for psychosis and mood instability in people with genetic vulnerability. This is one of the most modifiable environmental risk factors in the shared-risk landscape.
3. Prioritize sleep regularity. Both bipolar disorder and schizophrenia are characterized by sleep architecture disruption, and irregular sleep schedules can destabilize mood and cognition. Consistent sleep-wake timing supports the circadian regulation that synaptic plasticity — including ARC-mediated consolidation — depends upon.
4. Manage acute stress proactively. The NRG1-ErbB4 axis implicated through ADAM19 is sensitive to stress-induced changes in GABAergic interneuron function. Structured stress management practices (exercise, mindfulness, social support networks) reduce chronic stress load.
5. Maintain medication adherence if prescribed. For individuals who have been assessed with either condition, medication adherence is the single most evidence-supported factor in reducing relapse risk. Genetic information does not change this evidence base.
6. Build a social support network. Strong social connection is protective across mental health conditions and is particularly relevant for conditions affecting cognition and mood. Maintaining relationships provides both practical support and early-warning capacity for symptom changes.
7. Discuss family history with a mental health professional. Given the shared genetic substrate, knowing which conditions appear in close relatives can help a clinician contextualize risk and support early monitoring or intervention.

Related traits and genes

The shared-risk architecture connecting bipolar disorder and schizophrenia sits within a broader landscape of overlapping psychiatric and neurological genetic associations. Related ExomeDNA traits and genes worth exploring:

• Schizophrenia genetic risk — disorder-specific loci including CACNA1C and CSMD1, for a deeper look at the schizophrenia-specific genetic signal
• Bipolar disorder genetic risk — the bipolar-predominant portion of the shared architecture, including TRANK1 and immune-related loci
• ADHD and autism shared risk — a parallel cross-diagnostic shared-risk signal, with ASTN2 copy number variants appearing in both landscapes
• Anxiety genetic risk — overlapping pathways via GABAergic interneuron function and stress-response circuitry
• Sleep chronotype — circadian gene variants relevant to mood and cognitive stability across psychiatric conditions

ARC — synaptic plasticity, AMPA receptor endocytosis, inter-neuronal mRNA transfer via extracellular vesicles ADAM23 — transsynaptic AMPA receptor organization via the LGI1-ADAM23 complex ASTN2 — neuronal migration and radial glial attachment during cortical development

Frequently asked questions

Does having elevated shared risk mean I will develop bipolar disorder or schizophrenia? No. Elevated shared risk reflects a population-level statistical association between certain common genetic variants and the likelihood of either condition — it is not a prediction for any individual. The vast majority of people who carry these variants do not develop either condition. Many factors beyond genetics shape whether and how psychiatric symptoms develop.

Why do bipolar disorder and schizophrenia share genetic risk factors? Genetic studies have established that both conditions are highly polygenic and that a meaningful fraction of their heritable architecture overlaps. The shared loci cluster around synaptic plasticity genes (such as ARC), transsynaptic adhesion proteins (such as ADAM23), and neuronal migration factors (such as ASTN2) — suggesting both conditions partially arise from disruptions to the same brain-circuit-building processes, even though their clinical presentations differ substantially.

What is ARC, and why does it matter for psychiatric conditions? ARC (activity-regulated cytoskeleton-associated protein) is an immediate-early gene whose protein product regulates AMPA receptor recycling at synapses — a process central to how synapses strengthen and weaken in response to experience. ARC also assembles into capsid-like structures that transfer RNA between neurons. Disruption of ARC function impairs the circuit refinement that underlies healthy cognition and mood regulation, making it a plausible contributor to the synaptic plasticity deficits observed in both schizophrenia and bipolar disorder.

Can genetic risk for these conditions be reduced by lifestyle changes? Genetic variants themselves cannot be changed. However, several environmental and lifestyle factors are known to modulate risk in people with genetic vulnerability. Avoiding regular cannabis use (particularly high-THC products), maintaining consistent sleep schedules, managing chronic stress, and building social support are all evidence-informed strategies relevant to this shared-risk context.

Is this result the same as being told I have either condition? No. ExomeDNA genetic results reflect population-level research associations between genetic variants and health traits. They are not assessments and cannot confirm or rule out any condition. A qualified clinician or psychiatrist is the appropriate resource for mental health or family history concerns.

How does this result differ from separate schizophrenia or bipolar disorder risk results? This result specifically captures the genetic variants that are shared between both conditions — variants that appear at elevated frequency in people with either condition relative to those without. Separate results for schizophrenia or bipolar disorder emphasize disorder-specific loci (for example, calcium channel variants like CACNA1C in schizophrenia, or immune-related loci like TRANK1 in bipolar disorder). Together, the shared and disorder-specific results paint a more complete picture of the polygenic architecture underlying each condition.

References

1. Wang KS et al. (2010). A genome-wide meta-analysis identifies novel loci associated with schizophrenia. PMID: 20889312.
2. Curtis D (2011). Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes. PMID: 21057379.
3. Bergen SE et al. (2012). Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. PMID: 22688191.

Data sources:

• GWAS Catalog (NHGRI-EBI, accessed 2026-05-29)
• Open Targets Platform (CC0 1.0, accessed 2026-05-29)
• ClinVar (NCBI, accessed 2026-05-29) — entries at 2-star review status or above
• ClinGen Gene-Disease Validity (CC0 1.0, accessed 2026-05-29)

ExomeDNA genetic results are for wellness and educational purposes only. Consult a clinician for personalized health guidance.