The genetic architecture of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) reveals a complex landscape of risk alleles, with PSP being one of the most genetically tractable neurodegenerative disorders. Both conditions are classified as 4R tauopathies, sharing pathological features of tau filament accumulation, but they demonstrate distinct clinical phenotypes and genetic risk profiles.
This page compiles the current understanding of genetic risk factors for CBS and PSP, including genome-wide association study (GWAS) findings, candidate gene associations, and functional genomics insights that illuminate disease mechanisms.
flowchart TD
subgraph MAPT_H1
A["MAPT H1 Haplotype"] --> B4 ["R Tau Overproduction"]
B --> C["Altered Tau Splicing"]
end
subgraph ST ["X6"]
DSTX ["6 Risk Variant"] --> E["Vesicle Trafficking Defect"]
E --> F["Synaptic Dysfunction"]
end
subgraph MO ["BP"]
G["MOBP Risk Variant"] --> H["Myelin Instability"]
H --> I["Axonal Vulnerability"]
end
subgraph EIF2A ["K3"]
JEIF2AK ["3 Risk Variant"] --> K["ER Stress Response"]
K --> L["Unfolded Protein Response"]
L --> M["Apoptotic Signaling"]
end
C --> N4 ["R Tauopathy"]
F --> N
I --> N
M --> N
N --> O["PSP Pathology"]
N --> P["CBD Pathology"]
style A fill:#f3e5f5,stroke:#333
style D fill:#f3e5f5,stroke:#333
style G fill:#f3e5f5,stroke:#333
style J fill:#f3e5f5,stroke:#333
style O fill:#9f9,stroke:#333
style P fill:#9f9,stroke:#333
flowchart LR
A["MAPT H1"] --> B["4R Tau Overexpression"]
C["STX6"] --> D["Vesicle Trafficking Defect"]
E["MOBP"] --> F["Myelin Instability"]
G["EIF2AK3"] --> H["ER Stress / UPR"]
I["TRIM11"] --> J["Impaired Protein Degradation"]
K["DUSP10"] --> L["MAPK Dysregulation"]
B --> M["4R Tauopathy"]
D --> M
F --> M
H --> M
J --> M
L --> M
M --> N["PSP / CBD"]
The microtubule-associated protein tau gene (MAPT) on chromosome 17q21.31 represents the strongest and most consistent genetic risk factor for PSP. The H1 haplotype, comprising a ~500 kb inversion polymorphism, demonstrates a remarkably strong association with PSP risk.
Key Findings:
- H1 vs H2 frequency: PSP cases show H1 haplotype frequency >95% compared to ~78% in controls
- Odds ratio: H1 homozygosity confers OR ~5.5-8.0 for PSP risk (1)
- H1c subhaplotype: The H1c subhaplotype specifically associates with PSP, particularly with the Richardson's syndrome subtype (2)
The H1 haplotype encompasses multiple polymorphisms that influence MAPT expression and splicing. These variants affect:
- Tau isoform expression: H1 haplotype is associated with increased 4R tau expression
- Promoter activity: H1-specific SNPs increase transcriptional activity
- Splicing regulation: H1 variants alter exon 10 splicing, favoring 4R tau inclusion
| Variant | Population Frequency (PSP) | Odds Ratio | Functional Effect |
|---------|---------------------------|------------|-------------------|
| H1 haplotype (homozygous) | ~95% | 5.5-8.0 | Increased 4R tau expression |
| H1c subhaplotype | ~25% | 2.1 | Enhanced exon 10 inclusion |
| A allele of rs242557 | ~80% | 1.8 | Increased MAPT transcription |
While sporadic CBS shows modest MAPT associations, pathogenic MAPT mutations can cause familial CBS phenotypes:
- P301L: Classic FTDP-17 mutation, can present as CBS (11)
- N279K: Exon 10 splicing mutation causing 4R tau increase
- G389R: CBD-like phenotype with predominant cortical involvement
- R406W: Can present with CBS features including asymmetric rigidity
Large-scale GWAS meta-analyses have identified multiple genome-wide significant loci beyond MAPT (3)(4). The International PSP Genetics Consortium has defined the following as definitive PSP risk genes:
Located at 1q24.2, STX6 encodes a SNARE protein involved in intracellular vesicle trafficking.
- Lead SNP: rs1411478
- Odds ratio: 1.29 per risk allele (p = 2.4 × 10⁻¹²)
- Functional relevance: Altered endosomal trafficking and autophagy dysfunction
- Pathway involvement: Membrane trafficking, autophagosome-lysosome fusion
- Expression QTL: Risk allele associated with reduced STX6 expression in brain tissue (12)
Located at 3p22.2, MOBP is expressed in oligodendrocytes.
- Lead SNP: rs1768208
- Odds ratio: 1.25 per risk allele (p = 3.0 × 10⁻¹⁰)
- Functional relevance: Myelin integrity and oligodendrocyte function
- Pathway involvement: White matter integrity, myelin maintenance
- Expression: Highly expressed in white matter tracts affected in PSP
Located at 2p22.2, EIF2AK3 encodes PERK, a key sensor of endoplasmic reticulum stress.
- Lead SNP: rs7571971
- Odds ratio: 1.23 per risk allele (p = 4.8 × 10⁻⁹)
- Functional relevance: Unfolded protein response (UPR) dysregulation
- Pathway involvement: ER stress response, autophagy, tau phosphorylation
- PERK pathway: Chronic activation leads to translational repression and apoptosis (13)
Located at 12p12.1, SLCO1A2 encodes an organic anion transporter involved in drug uptake.
- Lead SNP: rs2075650
- Odds ratio: 1.22 per risk allele
- Functional relevance: May affect tau propagation between cells
- Pathway involvement: Cellular export/import of molecules
- Blood-brain barrier: Expressed at BBB, may transport tau species
Located at 1q41, DUSP10 encodes a MAPK phosphatase that regulates stress-activated protein kinases.
- Lead SNP: rs6692995
- Odds ratio: 1.18 per risk allele
- Functional relevance: MAPK signaling dysregulation, altered stress response
- Pathway involvement: JNK/p38 MAPK signaling, tau phosphorylation
- Stress response: Key regulator of cellular stress pathways
Located at 7q22.1, TRIM11 is involved in protein quality control.
- Lead SNP: rs9637318
- Odds ratio: 1.15 per risk allele
- Functional relevance: Impaired protein degradation pathways
- Pathway involvement: Ubiquitin-proteasome system, autophagy
- Tau degradation: Can ubiquitinate mutant tau for proteasomal degradation (14)
Recent meta-analyses have identified additional risk loci (15):
- Chromosome: 6q21
- Odds ratio: 1.14 per risk allele
- Function: Transcription factor involved in bone development and cell differentiation
- Brain expression: Expressed in neurons, potential role in neurodegeneration
- Chromosome: 10q26.3
- Odds ratio: 1.12 per risk allele
- Function: Mitophagy receptor
- Pathway: Mitochondrial quality control, apoptosis regulation
CBS demonstrates greater genetic heterogeneity than PSP, with multiple causative and risk genes identified. The genetics of CBS overlaps substantially with frontotemporal dementia (FTD) and progressive aphasia syndromes. Unlike PSP, which shows strong MAPT associations, CBS shows more diverse genetic causation.
LRRK2 mutations are a cause of familial Parkinson's disease and can present with CBS phenotypes.
- G2019S: Most common LRRK2 mutation, occasionally associated with CBS (16)
- R1441C/H/G: Parkin-linked mutations can present atypically
- Pathogenesis: Kinase hyperactivity leads to dopaminergic neuron dysfunction
- Therapeutic target: LRRK2 kinase inhibitors in clinical trials
GRN haploinsufficiency causes familial frontotemporal dementia with ubiquitin-positive inclusions.
- Frameshift/nonsense mutations: Cause progranulin deficiency
- CBS phenotype: Up to 10% of GRN mutation carriers develop CBS (17)
- Pathology: TDP-43 proteinopathy, not tauopathy
- Mechanism: Reduced progranulin leads to increased TDP-43 aggregation
The C9orf72 repeat expansion causes ALS-FTD spectrum disorders.
- Repeat >30: Pathological expansion
- CBS phenotype: Can present as CBS/ALS overlap (18)
- Pathology: TDP-43 proteinopathy with dipeptide repeat inclusions
- Mechanism: RNA foci formation and dipeptide repeat protein toxicity
¶ CHCHD10 (Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 10)
- Function: Mitochondrial protein involved in cristae organization
- CBS association: Rare cause of ALS-FTD spectrum
- Pathology: Mitochondrial dysfunction, TDP-43 pathology
- Function: Kinase involved in autophagy and inflammation
- CBS phenotype: Can present as FTD/ALS/CBS overlap
- Pathway: Autophagy regulation, interferon signaling
Sporadic CBS shows weaker genetic associations than PSP:
| Gene/Locus |
Odds Ratio |
Strength of Evidence |
| MAPT H1 |
1.5-2.0 |
Moderate |
| APOE ε4 |
1.8 |
Moderate |
| LRRK2 variants |
1.3-1.5 |
Weak-moderate |
| GRN variants |
1.2-1.4 |
Weak-moderate |
The APOE gene shows complex associations with tauopathies:
- APOE ε4: Associated with increased risk of AD, but complex relationship with PSP/CBS
- ε4 carriers: May have earlier age at onset in some studies (19)
- Neuroprotection hypothesis: ε2 allele may be protective
- Tau metabolism: APOE affects tau pathology and neuroinflammation
¶ Pathway Analysis and Enrichment
The PSP genetic risk genes converge on pathways relevant to tau pathogenesis:
- Tau metabolism: MAPT directly influences tau expression and splicing
- Protein quality control: TRIM11, EIF2AK3 involved in degradation pathways
- Cellular stress response: DUSP10, EIF2AK3 mediate stress signaling
- Post-translational modification: Kinases and phosphatases affecting tau phosphorylation
¶ Myelin and Oligodendrocyte Pathways
MOBP association suggests white matter integrity plays a role in PSP pathogenesis:
- Oligodendrocyte dysfunction may contribute to axonal degeneration
- Myelin abnormalities observed in PSP postmortem brain
- White matter tract degeneration is a key MRI finding in PSP (20)
¶ Vesicle Trafficking and Autophagy
STX6 and related genes implicate intracellular trafficking in PSP:
- Autophagy-lysosome pathway dysfunction
- Impaired protein clearance
- Potential for tau propagation via extracellular vesicles
- Lysosomal dysfunction contributes to tau aggregation
EIF2AK3 (PERK) links ER stress to neurodegeneration:
- Chronic ER stress in PSP brain
- Impaired UPR signaling
- Downstream effects on translation and autophagy
- PERK inhibition as potential therapeutic strategy
BNIP3 and related genes highlight mitochondrial involvement:
- Mitophagy impairment in PSP
- Accumulation of dysfunctional mitochondria
- Energy deficit contributing to neurodegeneration
- Mitochondrial therapeutics in development
Gene expression studies in PSP brain tissue reveal:
- Substantia nigra: Highest pathology burden, altered expression of stress response genes
- Globus pallidus: Affected in PSP, shows mitochondrial dysfunction signatures
- Superior frontal cortex: Cortical involvement, synaptic dysfunction genes
- Brainstem nuclei: Oculomotor circuit disruption, specific vulnerability
Single-cell studies reveal cell-type specific patterns:
- Oligodendrocytes: MOBP expression, white matter degeneration
- Microglia: Inflammatory gene expression, complement activation
- Neurons: Synaptic dysfunction, energy metabolism alterations
- Astrocytes: Reactive gliosis, potassium buffering dysfunction
Epigenetic changes contribute to PSP pathogenesis:
- MAPT methylation: Altered methylation patterns in PSP brain
- Global hypomethylation: Observed in PSP temporal cortex
- Gene-specific changes: EIF2AK3 and stress response genes
- H3K9me3: Altered in PSP, affects tau expression
- H3K27ac: Enhancer activity changes in disease state
- HDAC inhibitors: Potential therapeutic approach
While specific gene-environment interactions in CBS/PSP remain incompletely characterized, several factors may modify genetic risk:
- Head trauma: May interact with tau pathway genes (21)
- Vascular risk factors: May modify disease expression
- Cognitive reserve: May modify age at onset
- Smoking: Complex relationship with neurodegeneration
- Physical activity: May modify risk in carriers
- Diet: Mediterranean diet may reduce risk
- Sleep: Glymphatic clearance affected in tauopathies
- PSP: MAPT H1 haplotype testing has limited clinical utility
- CBS: Genetic testing more relevant for familial cases
- Counseling: Important given complex inheritance patterns
- Panel testing: FTD/ALS gene panels often include CBS causes
- Pre-symptomatic testing: Generally not recommended
- Research contexts: Available through research programs
- Incidental findings: Need for careful counseling
Genetic findings inform therapeutic development:
- MAPT-targeted therapies: ASOs, small molecules targeting tau (22)
- Autophagy enhancers: Targeting STX6-associated pathways
- UPR modulators: EIF2AK3-based interventions
- Protein aggregation inhibitors: Based on TRIM11 biology
- Kinase inhibitors: LRRK2 inhibitors for LRRK2-associated cases
| Gene |
Association Strength |
Functional Evidence |
Pathway Relevance |
Overall Score |
| MAPT H1 |
★★★★★ |
★★★★★ |
★★★★★ |
A |
| STX6 |
★★★★☆ |
★★★☆☆ |
★★★★☆ |
B+ |
| MOBP |
★★★★☆ |
★★★☆☆ |
★★★☆☆ |
B |
| EIF2AK3 |
★★★★☆ |
★★★★☆ |
★★★★☆ |
B+ |
| DUSP10 |
★★★☆☆ |
★★☆☆☆ |
★★★☆☆ |
C+ |
| TRIM11 |
★★★☆☆ |
★★☆☆☆ |
★★★☆☆ |
C+ |
| RUNX2 |
★★★☆☆ |
★★☆☆☆ |
★★☆☆☆ |
C |
| BNIP3 |
★★★☆☆ |
★★☆☆☆ |
★★☆☆☆ |
C |
Scoring Rubric:
- A: Strong GWAS + functional validation + direct pathway relevance
- B+: Strong GWAS + some functional evidence
- B: Moderate GWAS signal + pathway relevance
- C+: Suggestive evidence + biological plausibility
- C: Preliminary evidence, needs validation
- MAPT Gene Page
- STX6 Gene Page
- EIF2AK3 Gene Page
- DUSP10 Gene Page
- TRIM11 Gene Page
- LRRK2 Gene Page
- GRN Protein Page
- C9orf72 Protein Page
- APOE Gene Page
- Tau Protein Page
- 4R Tauopathy Mechanisms
- Corticobasal Syndrome
- Corticobasal Degeneration
- PSP
- Progressive Supranuclear Palsy
Polygenic risk scores (PRS) aggregate the effects of multiple risk variants:
- Number of SNPs: Current PRS includes ~2,000-5,000 SNPs
- Prediction accuracy: Area under curve (AUC) ~0.7-0.75
- Validation: Independent cohort validation shows moderate predictive power
- Clinical utility: Not yet ready for clinical implementation
| Disease |
PRS AUC |
Top GWAS Hits |
| PSP |
0.72 |
MAPT, STX6, MOBP |
| CBD |
0.65 |
MAPT, GRN |
| AD |
0.85 |
APOE, CLU, PICALM |
| PD |
0.75 |
SNCA, LRRK2, GBA |
Transgenic and knock-in models help understand PSP genetics:
- MAPT transgenic mice: Express human MAPT with P301L mutation
- STX6 knockout mice: Autophagy deficits, behavioral changes
- EIF2AK3 models: ER stress, memory deficits
- Tau pathology: Variable across models
- Motor symptoms: Some models show gait abnormalities
- Cognitive deficits: Working memory impairments
Genetic factors may influence treatment response:
- Lithium response: Genetic modifiers of neuroprotection
- CoQ10 response: Mitochondrial genetic variants
- Tau immunotherapy: Genetic predictors of outcome
- Personalized medicine: Genetic stratification for clinical trials
- Biomarker development: Genetic predictors of progression
- Therapeutic development: Target validation using genetic data
- Sample size: PSP is rare, limiting GWAS power
- Population diversity: Most studies in European ancestry
- Phenotypic heterogeneity: Clinical subtypes vary genetically
- Functional validation: Many risk alleles lack functional evidence
- Multi-omics integration: Transcriptomics, proteomics, metabolomics
- Single-cell approaches: Cell-type specific genetic effects
- Diversity initiatives: Studies in non-European populations
- Longitudinal cohorts: Progression genetics
¶ Resources and Databases
- International PSP Genetics Consortium: Shared data resources
- Frontotemporal Dementia Variation Project: Genotype-phenotype correlations
- Genome Aggregation Database (gnomAD): Population frequencies
- GWAS Catalog: Published associations
- International PSP Genetics Consortium (IPSG): Primary resource
- Genetic Frontotemporal dementia Initiative (GENFI): FTD genetics
- ALS Sequencing Consortium: C9orf72 and related genes
PSP and PD share some genetic susceptibility factors but differ significantly:
| Gene |
PSP |
PD |
Shared? |
| LRRK2 |
Minor role |
Major cause |
Yes |
| GBA |
Weak |
Strong risk |
Yes |
| SNCA |
No |
Major cause |
No |
| MAPT |
Strong |
No |
No |
| STX6 |
Strong |
No |
No |
AD and PSP both involve protein aggregation but have distinct genetic architectures:
- APOE ε4: Strong AD risk, weak/none in PSP
- MAPT: Strong PSP risk, modest AD risk
- TREM2: Strong AD risk, limited in PSP
- CLU, PICALM: AD-specific, not PSP
CBD shows genetic overlap with both PSP and FTD:
- MAPT: Risk in both, stronger in PSP
- GRN: CBD risk, not PSP
- C9orf72: Both can have CBS phenotypes
- TMEM106B: Modifies FTD/CBD, not PSP
Genetic variants affecting white matter:
- MOBP: Myelin integrity, DTI changes
- STX6: Vesicle trafficking in oligodendrocytes
- Genetic imaging: GWAS of MRI traits in progress
Genotype-phenotype correlations:
- MAPT H1: Midbrain atrophy severity
- APOE: Cortical thinning patterns
- Genetic predictors: Regional vulnerability
Brain eQTLs inform functional mechanisms:
- STX6 eQTL: Risk allele reduces expression
- EIF2AK3 eQTL: Altered stress response
- MOBP eQTL: Myelin gene regulation
- MAPT methylation: H1 haplotype affects methylation
- Disease-specific changes: PSP vs. controls
- Tau isoforms: 4R:3R ratio alterations
- STX6 protein: Reduced in PSP brain
- UPR markers: Elevated in affected regions
Whole-exome sequencing reveals rare variants:
- TREM2 variants: Possible PSP risk (23)
- OPTN: Autophagy gene, rare variants
- VCP: Inclusion body myopathy with FTD
- Deletions: Rare large deletions in MAPT region
- Duplications: MAPT duplications cause FTD
- Clinical significance: Variable penetrance
- Common variants: Limited role in PSP
- Somatic mutations: Accumulate in affected brain regions
- Heteroplasmy: Variable across tissues
- Trial design: Enriching for genetic subtypes
- Biomarker endpoints: Genetic modifiers of response
- Patient selection: Precision medicine approaches
- Genetic evidence: Supporting therapeutic targets
- Mendelian randomization: Causal inference
- Drug repurposing: Genetic evidence for existing drugs
- 1994: MAPT mutations cause FTDP-17
- 2004: H1 haplotype association with PSP
- 2011: First large-scale GWAS (Hoglinger et al.)
- 2015: STX6, MOBP, EIF2AK3 identified
- 2019: Expanded GWAS meta-analysis
- 2021: New risk loci (RUNX2, BNIP3)
- John Hardy: MAPT mutations, tau hypothesis
- Gerard Schellenberg: MAPT haplotype discovery
- Günter Höglinger: GWAS leadership
- Irene Litvan: Clinical characterization
¶ Disease and Clinical Phenotype Context
- Progressive Supranuclear Palsy (PSP)
- Corticobasal Degeneration (CBD)
- Primary Age-Related Tauopathy (PART)
- Corticobasal Syndrome
- Tauopathy
- Cortisol-Tau Pathway
- Gut-Brain Axis in Tauopathy
- Microglial Neuroinflammation
- NLRP3 Inflammasome
- CBS/PSP Genetic Architecture
¶ Genetics and Molecular Risk
¶ Biomarkers and Imaging
- Tau PET in CBS/PSP
- MRI Atrophy Patterns in CBS/PSP
- DTI White Matter in CBS/PSP
- PSP Biomarkers
- Plasma p-tau217
- CSF p-tau181
- CSF p-tau231
¶ Therapeutic and Management Pages
- CBS/PSP Treatment Rankings
- CBS/PSP Daily Action Plan
- CBS/PSP Rehabilitation Guide
- CBS/PSP Clinical Trials Guide
- Melatonin for Tauopathy
- Lithium for Tauopathy
- Rapamycin for Tauopathy
- Methylene Blue for Tauopathy
- TUDCA/UDCA for Neurodegeneration
- Photobiomodulation for Neurodegeneration
¶ Vulnerable Cell Types and Circuits