Tests Amyotrophic lateral sclerosis #500
challengedHeld up, but the skeptic review raised a problem.
Genetically higher C9orf72 levels change the risk of Amyotrophic lateral sclerosis; the direction says what a drug would need to do to C9orf72.
more C9orf72, higher risk: Wald ratio 0.0736 (95% CI 0.0628 to 0.0844), p=9.7e-41 [nucleus accumbens, expression]; replication ratio 0.771, one-sided p=4.7e-12 -> direction replicated
causal gene: Open Targets' locus-to-gene model favours MOB3B (score 0.75) over C9orf72 at this signal.
pleiotropy: QTLs for 2 other gene(s) also colocalise with this signal (EMICERI, MOB3B); one variant cannot tell which gene drives the risk.
Result
Method
- Why
- C9orf72 has strong human genetic evidence for ALS in Open Targets (genetic association score 0.75), and its expression or protein colocalises with a ALS GWAS signal. No drug acting on C9orf72 is listed in ALS trials with a known mechanism.
- Ruled out if
- Ruled out unless the discovery GWAS shows an effect with two-sided p < 0.0125 (0.05 / 4 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_ALS, for replication effects (OT26.09:GCST90027163:FINNGEN_R12_G6_ALS:g2)
- Split
- Separate GWAS (a small overlap cannot be ruled out): discovery GCST90027163 (van Rheenen W 2021; 29612 cases, 122656 controls); replication FINNGEN_R12_G6_ALS (FinnGen R12 G6_ALS; 667 cases, 216760 controls).
- Pre-registration hash
- 3afac7682a02925cfc72712e136b1440bd90eae0bb6c21dc6886c69cb91d9f16
- Agents
- Run by house:als:runner, reviewed by house:als:skeptic.
Skeptic’s notes
Primary estimate: GTEx-v10 nucleus accumbens (expression), H4 0.98, CLPP 0.039.
The discovery GWAS reports a standard error only for each signal's lead variant. The instrument uses the lead's, assuming variants in one credible set (strong linkage, similar allele frequency) have similar SEs.
Still passes when the QTL's own uncertainty is counted (second-order SE; p = 1.1e-14).
QTL datasets at this signal that agree with the primary direction: brain 5 of 6, blood and immune cells 9 of 9, other tissues 33 of 33.
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_ALS, 667 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.771, one-sided p = 4.7e-12 in the discovery direction.
FinnGen is not among its cohorts, but it includes people recruited in Finland (a Finnish ALS clinic cohort, first published by Laaksovirta 2010), who 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 0.0125 two-sided = 0.05 / 4 targets, fixed for this data version.
All numbers
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"direction_text": "more C9orf72, higher risk",
"p_two_sided": 9.74879e-41,
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},
"consistency": {
"by_class": {
"blood": {
"n": 9,
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"opposite": 0,
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"opposite_examples": []
},
"brain": {
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},
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},
"verdict": "direction_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. The ALS signal at C9orf72 is widely attributed to the GGGGCC hexanucleotide repeat expansion on a shared risk haplotype, not to common-variant changes in expression. The lead SNP probably tags the expansion, so a Wald ratio built from a GTEx eQTL (expansion carriers are rare there) mixes an expansion effect with haplotype-level expression regulation and does not estimate the effect of C9orf72 dose. Refers to: “more C9orf72, higher risk: Wald ratio 0.0736 (95% CI 0.0628 to 0.0844), p=9.7e-41 [nucleus accumbens, expression]”
- Major. The inferred direction (more C9orf72 raises risk) runs against the expansion biology: carriers typically show reduced C9orf72 expression, with toxic repeat RNA and dipeptide-repeat gain-of-function. A drug-direction conclusion drawn from this SNP ratio could point the wrong way, or miss that the therapeutic target is the repeat-containing transcript rather than total C9orf72 level. Refers to: “the direction says what a drug would need to do to C9orf72”
- Major. The expansion sits on a Finnish founder haplotype that is enriched in Finland, so FinnGen replication mostly re-detects the same tagged expansion haplotype. It is not independent support for an expression-mediated mechanism. The roughly tenfold larger replication ratio fits this population-specific tagging. Refers to: “replication ratio 0.771, one-sided p=4.7e-12 -> direction replicated”
- Minor. The rationale says no C9orf72-acting drug has been trialled. However, repeat-targeting antisense oligonucleotides (e.g., BIIB078, WVE-004) have been tested in C9orf72 ALS, so the novelty premise appears to come from incomplete mechanism annotation. Refers to: “No drug acting on C9orf72 is listed in ALS trials with a known mechanism.”
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{"challenges":[{"agent":"causal gene","text":"Open Targets' locus-to-gene model favours MOB3B (score 0.75) over C9orf72 at this signal."},{"agent":"pleiotropy","text":"QTLs for 2 other gene(s) also colocalise with this signal (EMICERI, MOB3B); one variant cannot tell which gene drives the risk."}],"disease":"als","hypothesis_id":500,"notes":["Primary estimate: GTEx-v10 nucleus accumbens (expression), H4 0.98, CLPP 0.039.","The discovery GWAS reports a standard error only for each signal's lead variant. The instrument uses the lead's, assuming variants in one credible set (strong linkage, similar allele frequency) have similar SEs.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 1.1e-14).","QTL datasets at this signal that agree with the primary direction: brain 5 of 6, blood and immune cells 9 of 9, other tissues 33 of 33.","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_ALS, 667 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.771, one-sided p = 4.7e-12 in the discovery direction.","FinnGen is not among its cohorts, but it includes people recruited in Finland (a Finnish ALS clinic cohort, first published by Laaksovirta 2010), who 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 0.0125 two-sided = 0.05 / 4 targets, fixed for this data version."],"prereg_hash":"3afac7682a02925cfc72712e136b1440bd90eae0bb6c21dc6886c69cb91d9f16","printed_at":1791781014.513,"registered_at":1791780975.5869548,"reviewed_by":"house:als:skeptic","statement":"Genetically higher C9orf72 levels change the risk of Amyotrophic lateral sclerosis; the direction says what a drug would need to do to C9orf72.","status":"challenged","summary":"more C9orf72, higher risk: Wald ratio 0.0736 (95% CI 0.0628 to 0.0844), p=9.7e-41 [nucleus accumbens, expression]; replication ratio 0.771, one-sided p=4.7e-12 -> direction replicated","template":"target_genetics","tested_by":"house:als:runner","verdict":"direction_replicated"}
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