Genetically higher SNCA levels raise the risk of Parkinson's disease, as the drugs in trials that lower SNCA activity assume.

more SNCA, higher risk: Wald ratio 0.775 (95% CI 0.633 to 0.918), one-sided p=8.5e-27 [dorsolateral prefrontal cortex, expression]; replication ratio 0.23, one-sided p=3e-07 (adjusted for shared participants) -> supported replicated

consistency: QTL datasets at this signal that agree with the primary direction: brain 3 of 3, blood and immune cells 0 of 2, other tissues 0 of 1. Disagreeing: Cytoimmgen CD4-positive, alpha-beta T cell; GTEx-v10 blood; Schwartzentruber_2018 sensory neuron.

consistency: 1 other GWAS signal(s) near SNCA colocalise with SNCA QTLs in the opposite direction, so the gene-level direction is not settled.

Human genetics and drug targets (Mendelian randomization). Pre-registered 12 Oct 2026, receipt #503.

Method

Why: 1 drug(s) in PD trials act to lower SNCA (cinpanemab, prasinezumab). If that helps, people who are born with more SNCA should have more PD.
Ruled out if: Ruled out unless the discovery GWAS shows the predicted direction with one-sided p < 0.025 (0.05 / 1 targets, split between the two directions) and the replication GWAS agrees (one-sided p < 0.05). A significant effect the other way counts as 'opposed': genetics then says the trials push the target the wrong way. The discovery GWAS includes 1,587 cases and 94,096 controls who are also in the replication GWAS, so the replication test is conditioned on those participants' own z-score at the variant (from their public summary statistics) to remove the correlation they create.
Data: Open Targets Platform 26.09: GWAS credible sets (SuSiE fine-mapping), cis eQTL / sc-eQTL / pQTL colocalisation (eQTL Catalogue, GTEx, UKB-PPP), drug mechanisms of action (ChEMBL); FinnGen R12 full summary statistics, endpoint G6_PARKINSON, for replication effects (OT26.09:GCST90275127:FINNGEN_R12_G6_PARKINSON:g2)
Split: Overlapping GWAS: discovery GCST90275127 (Kim JJ 2023; 42792 cases, 568693 controls); replication FINNGEN_R12_G6_PARKINSON (FinnGen R12 G6_PARKINSON; 5861 cases, 494487 controls), which contains the 1,587 cases and 94,096 controls the discovery GWAS took from FinnGen release 4. The replication test is conditioned on those participants' own result, so it rests on the others.
Pre-registration hash: 67d52e1b51c5a5630f94e2d6bf24369647a95077b0d21bb44b32a046d8647192
Agents: Run by house:parkinsons:runner, reviewed by house:parkinsons:skeptic.

Skeptic’s notes

Primary estimate: GTEx-v10 dorsolateral prefrontal cortex (expression), H4 1.00, CLPP 0.194.

About the discovery GWAS: Its European data are Nalls 2019 without 23andMe (15,056 clinical cases and 18,618 UK Biobank proxy cases, people with a parent with Parkinson's) plus FinnGen release 4. Proxy cases dilute effect sizes but not their direction. Source: Kim et al. 2024, Table 1.

Still passes when the QTL's own uncertainty is counted (second-order SE; p = 6.6e-12).

A single variant cannot separate an effect through this gene from pleiotropy or linkage. Colocalisation makes a shared causal variant likely but does not prove the gene is causal.

Replication in FinnGen R12 (G6_PARKINSON, 5,861 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.23, one-sided p = 3e-07 in the discovery direction. This p-value is conditioned on the z-score of the FinnGen part of the discovery GWAS at this variant (3.65; correlation 0.52 from the shared participants), so it rests on the FinnGen participants who are not in the discovery GWAS. Unadjusted, one-sided p = 3.6e-10.

Kim 2023 includes FinnGen release 4 (1,587 cases, 94,096 controls), and all of them are also in FinnGen R12. Shared participants make the two z-scores correlated even with no true effect, so the replication test above is conditioned on the shared part's own result (from its public summary statistics), counting every shared person.

Some drugs acting on SNCA may be in trials for symptoms (for example agitation, sleep or mood) rather than to change the disease; genetics speaks to disease risk, not symptoms.

Targets were analysed because the GWAS has a signal there, so the discovery p-value mostly restates that signal. The new information is the direction and whether a second GWAS agrees.

GWAS effect sizes come on different scales in different studies; directions and p-values are compared, not sizes.

Threshold 0.025 per direction = 0.05 / 1 targets / 2 directions, fixed for this data version.

All numbers

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    "other_signals": [
      {
        "gwas_set": "3420def52485b3d81945946829dded6e",
        "direction": -1,
        "votes": -2
      }
    ]
  },
  "verdict": "supported_replicated",
  "template": "target_genetics",
  "runner": "tests-v1"
}

LLM reviewer

A language model (claude-opus-5-5) was shown this test, its quotes and the skeptic's notes, and asked what a domain expert would question. Each note had to quote the material it was shown; notes that did not were dropped. These notes do not change the verdict, the status or the receipt.

Major. Cinpanemab and prasinezumab are antibodies against extracellular, aggregated alpha-synuclein protein. They do not lower SNCA gene expression. A lifelong, genetically higher level of brain SNCA mRNA is therefore a weak proxy for what these drugs do, so a supported direction says little about whether antibody clearance of aggregates helps. Refers to: “1 drug(s) in PD trials act to lower SNCA (cinpanemab, prasinezumab)”
Major. The primary instrument is bulk expression in dorsolateral prefrontal cortex, not substantia nigra or dopaminergic neurons where PD degeneration starts. The one neuronal dataset (sensory neuron) disagrees, so the direction in disease-relevant cells is not established. Refers to: “Primary estimate: GTEx-v10 dorsolateral prefrontal cortex (expression), H4 1.00, CLPP 0.194.”
Minor. The H4 is 1.00 but the CLPP is only 0.194. This means the specific variant used for the Wald ratio is unlikely to be the shared causal variant. SNCA has several independent regulatory signals, so a single-variant ratio at this locus may mix effects of different haplotypes. Refers to: “1 other GWAS signal(s) near SNCA colocalise with SNCA QTLs in the opposite direction, so the gene-level direction is not settled.”
Minor. The material is internally inconsistent. It counts '1 drug' but names two, and it cites the discovery GWAS as both Kim 2023 and Kim et al. 2024. These discrepancies raise doubt about whether the multiplicity count and the shared-participant adjustment were applied to the correct study. Refers to: “Kim 2023 includes FinnGen release 4 (1,587 cases, 94,096 controls)”

Human challenges

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Receipt #503

Printed when the review finished, 12 Oct 2026, 04:56 UTC. Its hash covers the text below and the hash of the receipt before it, so changing either one would break the chain.

Hash: 9234567eefbf74144df4f1ff301493c76361bb44f56812e743c13fb7b9930f62
Previous: c23084cab0958dece0c2af5bd5d6c8c6bb3b0f08a06f180cd10a3c222b6ab260

{"challenges":[{"agent":"consistency","text":"QTL datasets at this signal that agree with the primary direction: brain 3 of 3, blood and immune cells 0 of 2, other tissues 0 of 1. Disagreeing: Cytoimmgen CD4-positive, alpha-beta T cell; GTEx-v10 blood; Schwartzentruber_2018 sensory neuron."},{"agent":"consistency","text":"1 other GWAS signal(s) near SNCA colocalise with SNCA QTLs in the opposite direction, so the gene-level direction is not settled."}],"disease":"parkinsons","hypothesis_id":504,"notes":["Primary estimate: GTEx-v10 dorsolateral prefrontal cortex (expression), H4 1.00, CLPP 0.194.","About the discovery GWAS: Its European data are Nalls 2019 without 23andMe (15,056 clinical cases and 18,618 UK Biobank proxy cases, people with a parent with Parkinson's) plus FinnGen release 4. Proxy cases dilute effect sizes but not their direction. Source: Kim et al. 2024, Table 1.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 6.6e-12).","A single variant cannot separate an effect through this gene from pleiotropy or linkage. Colocalisation makes a shared causal variant likely but does not prove the gene is causal.","Replication in FinnGen R12 (G6_PARKINSON, 5,861 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.23, one-sided p = 3e-07 in the discovery direction. This p-value is conditioned on the z-score of the FinnGen part of the discovery GWAS at this variant (3.65; correlation 0.52 from the shared participants), so it rests on the FinnGen participants who are not in the discovery GWAS. Unadjusted, one-sided p = 3.6e-10.","Kim 2023 includes FinnGen release 4 (1,587 cases, 94,096 controls), and all of them are also in FinnGen R12. Shared participants make the two z-scores correlated even with no true effect, so the replication test above is conditioned on the shared part's own result (from its public summary statistics), counting every shared person.","Some drugs acting on SNCA may be in trials for symptoms (for example agitation, sleep or mood) rather than to change the disease; genetics speaks to disease risk, not symptoms.","Targets were analysed because the GWAS has a signal there, so the discovery p-value mostly restates that signal. The new information is the direction and whether a second GWAS agrees.","GWAS effect sizes come on different scales in different studies; directions and p-values are compared, not sizes.","Threshold 0.025 per direction = 0.05 / 1 targets / 2 directions, fixed for this data version."],"prereg_hash":"67d52e1b51c5a5630f94e2d6bf24369647a95077b0d21bb44b32a046d8647192","printed_at":1791780996.492,"registered_at":1791780980.926735,"reviewed_by":"house:parkinsons:skeptic","statement":"Genetically higher SNCA levels raise the risk of Parkinson's disease, as the drugs in trials that lower SNCA activity assume.","status":"challenged","summary":"more SNCA, higher risk: Wald ratio 0.775 (95% CI 0.633 to 0.918), one-sided p=8.5e-27 [dorsolateral prefrontal cortex, expression]; replication ratio 0.23, one-sided p=3e-07 (adjusted for shared participants) -> supported replicated","template":"target_genetics","tested_by":"house:parkinsons:runner","verdict":"supported_replicated"}

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