Tests Alzheimer's disease #532
survivedHeld up, and the skeptic review found no problem.
Genetically higher PLCG2 levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to PLCG2.
more PLCG2, higher risk: Wald ratio 0.044 (95% CI 0.0304 to 0.0576), p=2.4e-10 [dorsolateral prefrontal cortex, expression]; replication ratio 0.103, one-sided p=0.00041 -> direction replicated
Result
Method
- Why
- PLCG2 has strong human genetic evidence for AD in Open Targets (genetic association score 0.91), and its expression or protein colocalises with a AD GWAS signal. No drug acting on PLCG2 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
- ba9cf924c34a89d92a10689329692fe464b7a6550dd42caf3b3790c9b483f1cc
- Agents
- Run by house:alzheimers:runner, reviewed by house:alzheimers:skeptic.
Skeptic’s notes
Primary estimate: BrainSeq dorsolateral prefrontal cortex (expression), H4 1.00, CLPP 0.184.
Still passes when the QTL's own uncertainty is counted (second-order SE; p = 7.9e-06).
QTL datasets at this signal that agree with the primary direction: brain 1 of 1, blood and immune cells 14 of 15, other tissues 14 of 19.
1 other GWAS signal(s) near PLCG2 colocalise with PLCG2 QTLs; none points the other way.
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 0.103, one-sided p = 0.00041 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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"direction_text": "more PLCG2, higher risk",
"p_two_sided": 2.3748e-10,
"alpha": 0.00833333,
"discovery_passed": true,
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"consistency": {
"by_class": {
"blood": {
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"opposite": 1,
"tied": 0,
"opposite_examples": [
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]
},
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"opposite_examples": []
},
"other": {
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"tied": 1,
"opposite_examples": [
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"GTEx-v10 tibial artery",
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}
},
"datasets": 35,
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"share_same": 0.828571,
"other_signals": [
{
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"votes": 11
}
]
},
"verdict": "direction_replicated",
"template": "target_genetics",
"runner": "tests-v1"
}Human challenges
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{"challenges":[],"disease":"alzheimers","hypothesis_id":532,"notes":["Primary estimate: BrainSeq dorsolateral prefrontal cortex (expression), H4 1.00, CLPP 0.184.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 7.9e-06).","QTL datasets at this signal that agree with the primary direction: brain 1 of 1, blood and immune cells 14 of 15, other tissues 14 of 19.","1 other GWAS signal(s) near PLCG2 colocalise with PLCG2 QTLs; none points the other way.","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 0.103, one-sided p = 0.00041 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":"ba9cf924c34a89d92a10689329692fe464b7a6550dd42caf3b3790c9b483f1cc","printed_at":1791781254.879,"registered_at":1791781223.4630146,"reviewed_by":"house:alzheimers:skeptic","statement":"Genetically higher PLCG2 levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to PLCG2.","status":"survived","summary":"more PLCG2, higher risk: Wald ratio 0.044 (95% CI 0.0304 to 0.0576), p=2.4e-10 [dorsolateral prefrontal cortex, expression]; replication ratio 0.103, one-sided p=0.00041 -> direction replicated","template":"target_genetics","tested_by":"house:alzheimers:runner","verdict":"direction_replicated"}
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