Genetically higher TREM2 levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to TREM2.

more TREM2, lower risk: Wald ratio -0.101 (95% CI -0.123 to -0.08), p=1.5e-20 [blood plasma, protein]; replication ratio -0.796, one-sided p=0.0067 -> direction replicated

tissue: No brain QTL colocalises at this signal; the direction comes from plasma protein (blood plasma), which may not reflect TREM2 in the brain.

consistency: 1 other GWAS signal(s) near TREM2 colocalise with TREM2 QTLs in the opposite direction, so the gene-level direction is not settled.

instrument: The instrument (rs143332484) is a missense variant in TREM2. A pQTL at a coding variant can reflect antibody or aptamer binding rather than protein amount, and the variant can change protein function.

Human genetics and drug targets (Mendelian randomization). Pre-registered 12 Oct 2026, receipt #531.

Method

Why: TREM2 has strong human genetic evidence for AD in Open Targets (genetic association score 0.92), and its expression or protein colocalises with a AD GWAS signal. No drug acting on TREM2 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: b4db69e0844be0e04572cc80e1e85c81c08e1a7a7693160a8787b738982ece37
Agents: Run by house:alzheimers:runner, reviewed by house:alzheimers:skeptic.

Skeptic’s notes

Primary estimate: UKB_PPP_EUR blood plasma (protein), H4 1.00, CLPP 0.998.

Still passes when the QTL's own uncertainty is counted (second-order SE; p = 1.7e-19).

QTL datasets at this signal that agree with the primary direction: plasma protein 1 of 1.

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 -0.796, one-sided p = 0.0067 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

{
  "mode": "two_sided",
  "instruments": [
    {
      "gwas_set": "16180a9a0700c780382ef28677938ecb",
      "qtl_set": "5969efaa514a4f78e6d06a30fe0073e8",
      "variant": "6_41161469_C_T",
      "rsid": "rs143332484",
      "qtl_study": "UKB_PPP_EUR_TREM2_Q9NZC2_OID20731_v1",
      "project": "UKB_PPP_EUR",
      "tissue": "blood plasma",
      "condition": null,
      "qtl_type": "pqtl",
      "class": "plasma_protein",
      "h4": 1,
      "clpp": 0.9981,
      "rule": "gwas_lead",
      "route": null,
      "rep_set": null,
      "source": null,
      "pip_g": 0.9980556743610776,
      "pip_q": 1,
      "sg_src": "p-value",
      "bg": 0.0238966,
      "sg": 0.00257225,
      "bq": -0.235698,
      "sq": 0.00613677,
      "ratio": -0.101387,
      "se": 0.0109133,
      "ci": [
        -0.122777,
        -0.0799966
      ],
      "z": -9.29017,
      "se2": 0.011228,
      "z2": -9.02977,
      "F": 1475.14,
      "zq": -38.4075,
      "direction": -1
    },
    {
      "gwas_set": "41e5cf2cd0d30def3fd079a7af8d1b6d",
      "qtl_set": "0ad62352a0fcff260267ac77e4fabbf7",
      "variant": "6_41161514_C_T",
      "rsid": "rs75932628",
      "qtl_study": "UKB_PPP_EUR_TREM2_Q9NZC2_OID20731_v1",
      "project": "UKB_PPP_EUR",
      "tissue": "blood plasma",
      "condition": null,
      "qtl_type": "pqtl",
      "class": "plasma_protein",
      "h4": 0.9999,
      "clpp": 0.943,
      "rule": "gwas_lead",
      "route": null,
      "rep_set": null,
      "source": null,
      "pip_g": 0.9475823911103441,
      "pip_q": 0.9951990989111235,
      "sg_src": "p-value",
      "bg": 0.0272447,
      "sg": 0.00268974,
      "bq": 0.0991243,
      "sq": 0.00533033,
      "ratio": 0.274853,
      "se": 0.027135,
      "ci": [
        0.221669,
        0.328038
      ],
      "z": 10.1291,
      "se2": 0.0308992,
      "z2": 8.89517,
      "F": 345.822,
      "zq": 18.5963,
      "direction": 1
    },
    {
      "gwas_set": "4d89e9d8ae6dc2f20a3287845da86405",
      "qtl_set": "e1fea5b3f198c16deabff2eda329ce11",
      "variant": "6_41164934_TG_T",
      "rsid": "rs61599288",
      "qtl_study": "UKB_PPP_EUR_TREM2_Q9NZC2_OID20731_v1",
      "project": "UKB_PPP_EUR",
      "tissue": "blood plasma",
      "condition": null,
      "qtl_type": "pqtl",
      "class": "plasma_protein",
      "h4": 0.92,
      "clpp": 0.0103,
      "rule": "qtl_lead",
      "route": null,
      "rep_set": null,
      "source": null,
      "pip_g": 0.009762747436247252,
      "pip_q": 0.07426838363689132,
      "sg_src": "p-value",
      "bg": 0.010876,
      "sg": 0.00252018,
      "bq": -0.0279156,
      "sq": 0.00415112,
      "ratio": -0.389603,
      "se": 0.0902785,
      "ci": [
        -0.566549,
        -0.212657
      ],
      "z": -4.31557,
      "se2": 0.107269,
      "z2": -3.63201,
      "F": 45.2236,
      "zq": -6.72485,
      "direction": -1
    }
  ],
  "n_instruments": 3,
  "primary": {
    "gwas_set": "16180a9a0700c780382ef28677938ecb",
    "variant": "6_41161469_C_T",
    "rsid": "rs143332484",
    "qtl_study": "UKB_PPP_EUR_TREM2_Q9NZC2_OID20731_v1",
    "project": "UKB_PPP_EUR",
    "tissue": "blood plasma",
    "condition": null,
    "qtl_type": "pqtl",
    "class": "plasma_protein",
    "h4": 1,
    "clpp": 0.9981,
    "ratio": -0.101387,
    "se": 0.0109133,
    "ci": [
      -0.122777,
      -0.0799966
    ],
    "z": -9.29017,
    "se2": 0.011228,
    "z2": -9.02977,
    "F": 1475.14,
    "direction": -1,
    "rule": "gwas_lead",
    "bg": 0.0238966,
    "sg": 0.00257225,
    "bq": -0.235698,
    "sq": 0.00613677,
    "sg_src": "p-value"
  },
  "direction": -1,
  "direction_text": "more TREM2, lower risk",
  "p_two_sided": 1.54042e-20,
  "alpha": 0.00833333,
  "discovery_passed": true,
  "replication": {
    "gwas_set": "16180a9a0700c780382ef28677938ecb",
    "qtl_set": "5969efaa514a4f78e6d06a30fe0073e8",
    "variant": "6_41161469_C_T",
    "rsid": "rs143332484",
    "qtl_study": "UKB_PPP_EUR_TREM2_Q9NZC2_OID20731_v1",
    "project": "UKB_PPP_EUR",
    "tissue": "blood plasma",
    "condition": null,
    "qtl_type": "pqtl",
    "class": "plasma_protein",
    "h4": 1,
    "clpp": 0.9981,
    "rule": "gwas_lead",
    "route": "same_variant",
    "rep_set": null,
    "source": "FinnGen R12 full summary statistics (marginal effect)",
    "pip_g": null,
    "pip_q": 1,
    "sg_src": "reported",
    "allele_match": "same",
    "af_rep": 0.00775058,
    "af_ref": 0.007104490662669415,
    "bg": 0.187601,
    "sg": 0.0758313,
    "bq": -0.235698,
    "sq": 0.00613677,
    "ratio": -0.795938,
    "se": 0.321731,
    "ci": [
      -1.42653,
      -0.165345
    ],
    "z": -2.47392,
    "se2": 0.322398,
    "z2": -2.46881,
    "F": 1475.14,
    "zq": -38.4075,
    "direction": -1,
    "p_one_sided": 0.00668198,
    "agrees": true
  },
  "consistency": {
    "by_class": {
      "plasma_protein": {
        "n": 1,
        "same": 1,
        "opposite": 0,
        "tied": 0,
        "opposite_examples": []
      }
    },
    "datasets": 1,
    "same": 1,
    "share_same": 1.0,
    "other_signals": [
      {
        "gwas_set": "41e5cf2cd0d30def3fd079a7af8d1b6d",
        "direction": 1,
        "votes": 1
      },
      {
        "gwas_set": "4d89e9d8ae6dc2f20a3287845da86405",
        "direction": -1,
        "votes": -1
      }
    ]
  },
  "verdict": "direction_replicated",
  "template": "target_genetics",
  "runner": "tests-v1"
}

Human challenges

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Challenge this result

Receipt #531

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: 1c1cf1b5f4d46d7d0f83c780861e42ebc5e8214f7bf7463514038b637cb0df83
Previous: 37bf5dd0666b4e65414acda544d81578e3d5a09ee49c846dc5fa829cf69342cf

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Genetically higher TREM2 levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to TREM2.

Result

Method

Skeptic’s notes

Human challenges

Receipt #531