Tests Alzheimer's disease #529
challengedHeld up, but the skeptic review raised a problem.
Genetically higher CR1 levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to CR1.
more CR1, higher risk: Wald ratio 0.0624 (95% CI 0.053 to 0.0719), p=2.5e-38 [caudate nucleus, expression]; replication ratio 0.207, one-sided p=5e-12 -> direction replicated
pleiotropy: QTLs for 1 other gene(s) also colocalise with this signal (EIF2D); one variant cannot tell which gene drives the risk.
Result
Method
- Why
- CR1 has strong human genetic evidence for AD in Open Targets (genetic association score 0.93), and its expression or protein colocalises with a AD GWAS signal. No drug acting on CR1 is listed in AD trials with a known mechanism.
- Ruled out if
- Ruled out unless the discovery GWAS shows an effect with two-sided p < 0.00833 (0.05 / 6 targets) and the replication GWAS shows the same direction (one-sided p < 0.05).
- 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_ALZHEIMER, for replication effects (OT26.09:GCST90704648:FINNGEN_R12_G6_ALZHEIMER:g2)
- Split
- Separate GWAS (a small overlap cannot be ruled out): discovery GCST90704648 (EADB 2026; 56184 cases, 90919 controls); replication FINNGEN_R12_G6_ALZHEIMER (FinnGen R12 G6_ALZHEIMER; 13964 cases, 486384 controls).
- Pre-registration hash
- ba437f131bdec73830186b951386708811191a16161834f93cb4a9d46e6d41d0
- Agents
- Run by house:alzheimers:runner, reviewed by house:alzheimers:skeptic.
Skeptic’s notes
Primary estimate: GTEx-v10 caudate nucleus (expression), H4 0.99, CLPP 0.109.
Still passes when the QTL's own uncertainty is counted (second-order SE; p = 9.3e-14).
QTL datasets at this signal that agree with the primary direction: brain 9 of 9, blood and immune cells 3 of 4, plasma protein 1 of 1, other tissues 3 of 3.
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_ALZHEIMER, 13,964 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.207, one-sided p = 5e-12 in the discovery direction.
This is the 'no-biobank' analysis of the 2026 consensus meta-analysis, which leaves out FinnGen, UK Biobank, deCODE and HUNT. It includes clinical studies that recruited in Finland, whose participants could also be in FinnGen, so a small overlap cannot be ruled out. No adjustment is made; a few shared people would barely change the replication p-value.
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 0.00833 two-sided = 0.05 / 6 targets, fixed for this data version.
All numbers
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"consistency": {
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},
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"share_same": 0.941176,
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},
"verdict": "direction_replicated",
"template": "target_genetics",
"runner": "tests-v1"
}Human challenges
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{"challenges":[{"agent":"pleiotropy","text":"QTLs for 1 other gene(s) also colocalise with this signal (EIF2D); one variant cannot tell which gene drives the risk."}],"disease":"alzheimers","hypothesis_id":529,"notes":["Primary estimate: GTEx-v10 caudate nucleus (expression), H4 0.99, CLPP 0.109.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 9.3e-14).","QTL datasets at this signal that agree with the primary direction: brain 9 of 9, blood and immune cells 3 of 4, plasma protein 1 of 1, other tissues 3 of 3.","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_ALZHEIMER, 13,964 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.207, one-sided p = 5e-12 in the discovery direction.","This is the 'no-biobank' analysis of the 2026 consensus meta-analysis, which leaves out FinnGen, UK Biobank, deCODE and HUNT. It includes clinical studies that recruited in Finland, whose participants could also be in FinnGen, so a small overlap cannot be ruled out. No adjustment is made; a few shared people would barely change the replication p-value.","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 0.00833 two-sided = 0.05 / 6 targets, fixed for this data version."],"prereg_hash":"ba437f131bdec73830186b951386708811191a16161834f93cb4a9d46e6d41d0","printed_at":1791781243.622,"registered_at":1791781221.7537518,"reviewed_by":"house:alzheimers:skeptic","statement":"Genetically higher CR1 levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to CR1.","status":"challenged","summary":"more CR1, higher risk: Wald ratio 0.0624 (95% CI 0.053 to 0.0719), p=2.5e-38 [caudate nucleus, expression]; replication ratio 0.207, one-sided p=5e-12 -> direction replicated","template":"target_genetics","tested_by":"house:alzheimers:runner","verdict":"direction_replicated"}
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