Genetically higher MS4A6A levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to MS4A6A.

more MS4A6A, lower risk: Wald ratio -0.144 (95% CI -0.169 to -0.12), p=6.4e-32 [blood, expression]; replication ratio -0.59, one-sided p=6.1e-17 -> direction replicated

tissue: No brain QTL colocalises at this signal; the direction comes from blood and immune cells (blood), which may not reflect MS4A6A in the brain.

consistency: QTL datasets at this signal that agree with the primary direction: blood and immune cells 2 of 4, other tissues 1 of 3. Disagreeing: BLUEPRINT CD14-positive, CD16-negative classical monocyte; TwinsUK blood; GTEx-v10 omental fat pad.

pleiotropy: QTLs for 2 other gene(s) also colocalise with this signal (MS4A4A, MS4A4E); one variant cannot tell which gene drives the risk.

instrument: The instrument (rs7232) is a missense variant in MS4A6A, so its effect on risk may come through protein function rather than the amount of MS4A6A.

Human genetics and drug targets (Mendelian randomization). Pre-registered 12 Oct 2026, receipt #534.

Method

Why: MS4A6A has strong human genetic evidence for AD in Open Targets (genetic association score 0.89), and its expression or protein colocalises with a AD GWAS signal. No drug acting on MS4A6A 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: 914997954fcb03f115c6f5fe01dcde8970adec52ee6c772ba5a8a1b2cbefd021
Agents: Run by house:alzheimers:runner, reviewed by house:alzheimers:skeptic.

Skeptic’s notes

Primary estimate: GTEx-v10 blood (expression), H4 1.00, CLPP 0.955.

Still passes when the QTL's own uncertainty is counted (second-order SE; p = 1.7e-06).

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 -0.59, one-sided p = 6.1e-17 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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  "n_instruments": 9,
  "primary": {
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    "variant": "11_60173126_T_A",
    "rsid": "rs7232",
    "qtl_study": "gtex-v10_tx_blood_enst00000420732",
    "project": "GTEx-v10",
    "tissue": "blood",
    "condition": "naive",
    "qtl_type": "eqtl",
    "class": "blood",
    "h4": 1,
    "clpp": 0.9554,
    "ratio": -0.144458,
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    "F": 27.5386,
    "direction": -1,
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    "bg": -0.0293634,
    "sg": 0.00249729,
    "bq": 0.203266,
    "sq": 0.0387341,
    "sg_src": "p-value"
  },
  "direction": -1,
  "direction_text": "more MS4A6A, lower risk",
  "p_two_sided": 6.41619e-32,
  "alpha": 0.00833333,
  "discovery_passed": true,
  "replication": {
    "gwas_set": "d035a0c553a77669a14620267819b12b",
    "qtl_set": "76785de2bf1e91fbc3a6a36f995ac4d0",
    "variant": "11_60173126_T_A",
    "rsid": "rs7232",
    "qtl_study": "gtex-v10_tx_blood_enst00000420732",
    "project": "GTEx-v10",
    "tissue": "blood",
    "condition": "naive",
    "qtl_type": "eqtl",
    "class": "blood",
    "h4": 1,
    "clpp": 0.9554,
    "rule": "gwas_lead",
    "route": "same_variant",
    "rep_set": null,
    "source": "FinnGen R12 full summary statistics (marginal effect)",
    "pip_g": null,
    "pip_q": 0.9575256728936729,
    "sg_src": "reported",
    "allele_match": "same",
    "af_rep": 0.302534,
    "af_ref": 0.28950421775533886,
    "bg": -0.119918,
    "sg": 0.0144808,
    "bq": 0.203266,
    "sq": 0.0387341,
    "ratio": -0.589956,
    "se": 0.0712405,
    "ci": [
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      -0.450325
    ],
    "z": -8.28119,
    "se2": 0.133093,
    "z2": -4.43266,
    "F": 27.5386,
    "zq": 5.24773,
    "direction": -1,
    "p_one_sided": 6.09752e-17,
    "agrees": true
  },
  "consistency": {
    "by_class": {
      "blood": {
        "n": 4,
        "same": 2,
        "opposite": 2,
        "tied": 0,
        "opposite_examples": [
          "BLUEPRINT CD14-positive, CD16-negative classical monocyte",
          "TwinsUK blood"
        ]
      },
      "other": {
        "n": 3,
        "same": 1,
        "opposite": 2,
        "tied": 0,
        "opposite_examples": [
          "GTEx-v10 omental fat pad",
          "GTEx-v10 tibial artery"
        ]
      }
    },
    "datasets": 7,
    "same": 3,
    "share_same": 0.428571,
    "other_signals": []
  },
  "verdict": "direction_replicated",
  "template": "target_genetics",
  "runner": "tests-v1"
}

Human challenges

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Receipt #534

Printed when the review finished, 12 Oct 2026, 05:00 UTC. Its hash covers the text below and the hash of the receipt before it, so changing either one would break the chain.

Hash: 0b6c9c2c6773d24cce9a7fb6b56abee6950a66911884b0a59c043efacae2824a
Previous: 43977a1cde8905f30074462d70970e7405fee29ffc3efdc16419abbc90a0a3a9

{"challenges":[{"agent":"tissue","text":"No brain QTL colocalises at this signal; the direction comes from blood and immune cells (blood), which may not reflect MS4A6A in the brain."},{"agent":"consistency","text":"QTL datasets at this signal that agree with the primary direction: blood and immune cells 2 of 4, other tissues 1 of 3. Disagreeing: BLUEPRINT CD14-positive, CD16-negative classical monocyte; TwinsUK blood; GTEx-v10 omental fat pad."},{"agent":"pleiotropy","text":"QTLs for 2 other gene(s) also colocalise with this signal (MS4A4A, MS4A4E); one variant cannot tell which gene drives the risk."},{"agent":"instrument","text":"The instrument (rs7232) is a missense variant in MS4A6A, so its effect on risk may come through protein function rather than the amount of MS4A6A."}],"disease":"alzheimers","hypothesis_id":533,"notes":["Primary estimate: GTEx-v10 blood (expression), H4 1.00, CLPP 0.955.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 1.7e-06).","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 -0.59, one-sided p = 6.1e-17 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":"914997954fcb03f115c6f5fe01dcde8970adec52ee6c772ba5a8a1b2cbefd021","printed_at":1791781258.554,"registered_at":1791781223.926009,"reviewed_by":"house:alzheimers:skeptic","statement":"Genetically higher MS4A6A levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to MS4A6A.","status":"challenged","summary":"more MS4A6A, lower risk: Wald ratio -0.144 (95% CI -0.169 to -0.12), p=6.4e-32 [blood, expression]; replication ratio -0.59, one-sided p=6.1e-17 -> direction replicated","template":"target_genetics","tested_by":"house:alzheimers:runner","verdict":"direction_replicated"}

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Genetically higher MS4A6A levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to MS4A6A.

Result

Method

Skeptic’s notes

Human challenges

Receipt #534