CausalSentinel

Protein Dossier — TIMP4 (Metalloproteinase inhibitor 4)

MR feasibility tier: A — Published pQTL-MR estimates exist for this protein (retrieved below - not computed here).

1. Published MR estimates (retrieved, not computed)

Outcome	beta	se	p	method	nSNP	cis/trans	coloc
Non-cancer illness code self-reported: hypothyroidism or myxoedema	-0.144	0.0332	1.43e-05	Wald ratio	1	cis	NA
Lumbar spine bone mineral density	-0.076	0.0238	0.00143	Wald ratio	1	cis	NA
Type 2 diabetes	0.119	0.0393	0.00249	Wald ratio	1	cis	NA
Schizophrenia	-0.0885	0.0294	0.00258	Wald ratio	1	cis	NA
Hearing difficulty or problems: Yes	0.0312	0.0108	0.00392	Wald ratio	1	cis	NA
Happiness	-0.0218	0.00799	0.00646	Wald ratio	1	cis	NA
Non-cancer illness code self-reported: anxiety or panic attacks	-0.177	0.0668	0.00813	Wald ratio	1	cis	NA
Non-cancer illness code self-reported: uterine fibroids	0.122	0.0463	0.00836	Wald ratio	1	cis	NA
Diagnoses - main ICD10: G47 Sleep disorders	-0.286	0.114	0.012	Wald ratio	1	cis	NA
Non-cancer illness code self-reported: depression	-0.0682	0.0285	0.0168	Wald ratio	1	cis	NA
Fractured bone site(s): Other bones	0.0629	0.0264	0.0173	Wald ratio	1	cis	NA
Serum cystatin C (eGFRcys)	-0.012	0.0053	0.0233	Wald ratio	1	cis	NA
…and 107 more outcomes (see JSON)

2. pQTL instrument availability (Tier-B probe)

No prot-* pQTL GWAS dataset found for this protein (matched by UniProt accession and symbol).

3. GWAS Catalog results — traits with signal at this locus

No GWAS Catalog associations mapped to this gene.

4. Phenome map — where this gene is a genetic locus, vs. where MR exists

Top diseases by Open Targets association (of 634 total). Associations are loci, not causal claims. The causal-status column is a four-state triage per pair: established (curated) = a curated clinical assertion exists (ClinGen/G2P/GEL/Orphanet/ClinVar — any validity level, MR adds little); exploratory rare-variant signal = ExWAS burden evidence without curation — a candidate NEW gene-disease relationship; common-variant locus = GWAS signal, classic pQTL-MR territory; multi-layer = burden+GWAS together, an allelic-series candidate (the strongest causal setup). Burden estimand is carrier-vs-noncarrier, not per-SD MR.

Disease	genetic assoc.	burden (ExWAS)	causal status	MR status
type 2 diabetes mellitus	0.573	—	common-variant locus	no MR -> candidate analysis
acne	0.529	—	common-variant locus	no MR -> candidate analysis
myeloid leukemia	0.505	—	common-variant locus	no MR -> candidate analysis
Abnormality of skin pigmentation	0.473	—	common-variant locus	no MR -> candidate analysis
hypothyroidism	0.45	—	common-variant locus	MR: beta=-0.144, p=1.43e-05 (cis)
myxedema	0.386	—	common-variant locus	no MR -> candidate analysis
atrial fibrillation	0.356	—	common-variant locus	no MR -> candidate analysis
ACPA-positive rheumatoid arthritis	0.283	—	common-variant locus	no MR -> candidate analysis
hemorrhagic disease	0.273	—	common-variant locus	no MR -> candidate analysis
hyperlipidemia	0.254	—	common-variant locus	no MR -> candidate analysis
Hypercholesterolemia	0.252	—	common-variant locus	MR: beta=-0.0188, p=0.176 (cis)
metabolic disease	0.249	—	common-variant locus	no MR -> candidate analysis
Abnormality of the skeletal system	0.237	—	common-variant locus	no MR -> candidate analysis
diabetes mellitus	0.212	—	common-variant locus	no MR -> candidate analysis
thrombocytopenia 4	0.207	—	common-variant locus	no MR -> candidate analysis

Of the 15 rows above, 13 have no MR estimate in this resource. Across all retrieved diseases for this gene: 0 exploratory rare-variant signal(s), 0 multi-layer (allelic-series candidate) pair(s). Final triage still belongs to a statistical geneticist.

5. Downstream annotation (druggability & safety preview)

Layer	Result
ChEMBL druggability	not available — no ChEMBL target (undrugged)
gnomAD constraint	pLI=2e-10, LOEUF=1.41 — LoF-tolerant
GWAS Catalog	104 unique SNPs / 232 rows
ClinVar	88 records; 2 pathogenic in sample of 30
PharmGKB/ClinPGx	no annotations

Caveats declared by the tools

• phenome — Top 30 of 634 associated diseases by overall score. genetic_association aggregates GWAS common-variant AND rare-variant evidence. These are ASSOCIATIONS (loci), not causal claims.
• chembl — No ChEMBL target for ‘TIMP4’.
• clinvar — Pathogenic count is over the 30 record(s) retrieved, NOT over all 88 ClinVar records for this gene; it is a sample, not a rate.
• pharmgkb — No PharmGKB/ClinPGx clinical annotations (gene may not be a pharmacogene).
• gwas_traits — No GWAS Catalog associations mapped to this gene.

Sources

• uniprot: https://www.uniprot.org/uniprotkb/Q99727 — UniProt release 2026_02 (10-June-2026)
• mr_outcomes: https://epigraphdb.org/pqtl/ — EpiGraphDB pQTL MR (Zheng et al., Nat Genet 2020) — pre-computed two-sample MR; retrieved, not computed by this agent; EpiGraphDB build 1.0, pQTL dataset v3.0
• phenome: https://platform.opentargets.org/target/ENSG00000157150/associations — Open Targets data release 26.06
• gnomad: https://gnomad.broadinstitute.org/gene/TIMP4 — gnomAD constraint via GraphQL API (reference genome GRCh38)
• gwas: https://www.ebi.ac.uk/gwas/genes/TIMP4 — GWAS Catalog REST (live; release not exposed by this endpoint)
• clinvar: https://www.ncbi.nlm.nih.gov/clinvar/?term=TIMP4%5Bgene%5D — ClinVar build Build260809-1055.1

Provenance

• Generated: 2026-08-14T05:22:09 · Tier: A
• Fully mechanical: every cell above is rendered from tool return values. No language model wrote any part of this dossier.
• MR estimates, where present, are retrieved from published work (EpiGraphDB pQTL, Zheng et al. Nat Genet 2020); nothing is computed here.
• Tool errors this run: none

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