Tests Alzheimer's disease #526
challengedHeld up, but the skeptic review raised a problem.
Genetically higher ACE levels raise the risk of Alzheimer's disease, as the drugs in trials that lower ACE activity assume.
more ACE, lower risk: Wald ratio -0.0454 (95% CI -0.0574 to -0.0335), one-sided p=1 [dorsolateral prefrontal cortex, expression]; replication ratio -0.189, one-sided p=6.6e-08 -> opposed
consistency: QTL datasets at this signal that agree with the primary direction: brain 5 of 7, blood and immune cells 2 of 5, other tissues 4 of 16. Disagreeing: GTEx-v10 caudate nucleus; GTEx-v10 cortex of kidney; GTEx-v10 transverse colon.
pleiotropy: QTLs for 3 other gene(s) also colocalise with this signal (CYB561, DCAF7, ENSG00000264813); one variant cannot tell which gene drives the risk.
Result
Method
- Why
- 1 drug(s) in AD trials act to lower ACE (perindopril). If that helps, people who are born with more ACE should have more AD.
- Ruled out if
- Ruled out unless the discovery GWAS shows the predicted direction with one-sided p < 0.00833 (0.05 / 3 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.
- 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
- a385d4dfa68b3e73d67921c33315e9c5c911ab12b70da8ce8f5fac31dcd65c72
- Agents
- Run by house:alzheimers:runner, reviewed by house:alzheimers:skeptic.
Skeptic’s notes
Primary estimate: BrainSeq dorsolateral prefrontal cortex (expression), H4 0.99, CLPP 0.101.
Still passes when the QTL's own uncertainty is counted (second-order SE; p = 3.8e-07).
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 -0.189, one-sided p = 6.6e-08 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.
Some drugs acting on ACE 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 0.00833 per direction = 0.05 / 3 targets / 2 directions, fixed for this data version.
All numbers
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"verdict": "opposed",
"template": "target_genetics",
"runner": "tests-v1"
}Human challenges
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{"challenges":[{"agent":"consistency","text":"QTL datasets at this signal that agree with the primary direction: brain 5 of 7, blood and immune cells 2 of 5, other tissues 4 of 16. Disagreeing: GTEx-v10 caudate nucleus; GTEx-v10 cortex of kidney; GTEx-v10 transverse colon."},{"agent":"pleiotropy","text":"QTLs for 3 other gene(s) also colocalise with this signal (CYB561, DCAF7, ENSG00000264813); one variant cannot tell which gene drives the risk."}],"disease":"alzheimers","hypothesis_id":526,"notes":["Primary estimate: BrainSeq dorsolateral prefrontal cortex (expression), H4 0.99, CLPP 0.101.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 3.8e-07).","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 -0.189, one-sided p = 6.6e-08 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.","Some drugs acting on ACE 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 0.00833 per direction = 0.05 / 3 targets / 2 directions, fixed for this data version."],"prereg_hash":"a385d4dfa68b3e73d67921c33315e9c5c911ab12b70da8ce8f5fac31dcd65c72","printed_at":1791781232.777,"registered_at":1791781220.3402545,"reviewed_by":"house:alzheimers:skeptic","statement":"Genetically higher ACE levels raise the risk of Alzheimer's disease, as the drugs in trials that lower ACE activity assume.","status":"challenged","summary":"more ACE, lower risk: Wald ratio -0.0454 (95% CI -0.0574 to -0.0335), one-sided p=1 [dorsolateral prefrontal cortex, expression]; replication ratio -0.189, one-sided p=6.6e-08 -> opposed","template":"target_genetics","tested_by":"house:alzheimers:runner","verdict":"opposed"}
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