Protein Dossier — PCSK9 (Proprotein convertase subtilisin/kexin type 9)
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: high cholesterol |
0.277 |
0.0294 |
3.74e-21 |
Wald ratio |
1 |
cis |
NA |
| Diagnoses - main ICD10: C50 Malignant neoplasm of breast |
0.274 |
0.0859 |
0.00143 |
Wald ratio |
1 |
cis |
NA |
| Vascular or heart problems diagnosed by doctor: Angina |
0.162 |
0.0687 |
0.0186 |
Wald ratio |
1 |
cis |
NA |
| Low grade serous ovarian cancer |
-0.592 |
0.258 |
0.0218 |
Wald ratio |
1 |
cis |
NA |
| Diagnoses - main ICD10: I83 Varicose veins of lower extremities |
0.173 |
0.0848 |
0.0407 |
Wald ratio |
1 |
cis |
NA |
| Fractured bone site(s): Other bones |
0.103 |
0.0564 |
0.0678 |
Wald ratio |
1 |
cis |
NA |
| Non-cancer illness code self-reported: depression |
-0.12 |
0.0669 |
0.0727 |
Wald ratio |
1 |
cis |
NA |
| Non-cancer illness code self-reported: anxiety or panic attacks |
0.184 |
0.104 |
0.0763 |
Wald ratio |
1 |
cis |
NA |
| Non-cancer illness code self-reported: hyperthyroidism or thyrotoxicosis |
0.237 |
0.134 |
0.0765 |
Wald ratio |
1 |
cis |
NA |
| Eye problems or disorders: Glaucoma |
-0.293 |
0.167 |
0.0793 |
Wald ratio |
1 |
cis |
NA |
| Non-cancer illness code self-reported: osteoporosis |
0.169 |
0.0981 |
0.0844 |
Wald ratio |
1 |
cis |
NA |
| Fractured or broken bones in last 5 years |
0.0707 |
0.0417 |
0.09 |
Wald ratio |
1 |
cis |
NA |
| …and 52 more outcomes (see JSON) |
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2. pQTL instrument availability (Tier-B probe)
| Dataset |
Trait |
Author |
Year |
prot-c-5231_79_3 |
PCSK9 |
Suhre K |
2019 |
3. GWAS Catalog results — traits with signal at this locus
1545 association rows across 589 traits (1493 genome-wide significant rows). Associations are loci, not causal claims; the mapped gene at a locus is not necessarily the effector gene.
| Trait |
best p |
lead SNP |
n assoc |
study |
MR status |
| Low density lipoprotein cholesterol levels |
3e-1364 |
rs11591147 |
62 |
GCST90239655 |
no MR -> candidate analysis |
| Total cholesterol levels |
1e-1070 |
rs11591147 |
78 |
GCST90239673 |
no MR -> candidate analysis |
| Non-HDL cholesterol levels |
8e-875 |
rs11591147 |
5 |
GCST90239667 |
no MR -> candidate analysis |
| Apolipoprotein B levels |
8e-521 |
rs11591147 |
24 |
GCST90019496 |
no MR -> candidate analysis |
| Low-density lipoprotein levels |
2e-449 |
rs11591147 |
2 |
GCST90662892 |
no MR -> candidate analysis |
| LDL cholesterol levels |
2e-421 |
rs11591147 |
22 |
GCST010245 |
no MR -> candidate analysis |
| LDL cholesterol |
2e-335 |
rs11591147 |
14 |
GCST90018961 |
no MR -> candidate analysis |
| low density lipoprotein cholesterol (LDLC, maximum, inv-norm |
1e-323 |
rs28362286 |
3 |
GCST90475411 |
no MR -> candidate analysis |
| low density lipoprotein cholesterol (LDLC, mean, inv-norm tr |
1e-323 |
rs28362286 |
3 |
GCST90479661 |
no MR -> candidate analysis |
| total cholesterol (mean, inv-norm transformed) |
1e-287 |
rs28362286 |
3 |
GCST90476423 |
no MR -> candidate analysis |
| low density lipoprotein cholesterol (LDLC, minimum, inv-norm |
4e-283 |
rs28362286 |
3 |
GCST90475419 |
no MR -> candidate analysis |
| total cholesterol (maximum, inv-norm transformed) |
5e-279 |
rs28362286 |
3 |
GCST90476419 |
no MR -> candidate analysis |
| …and 577 more traits (see JSON) |
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4. Phenome map — where this gene is a genetic locus, vs. where MR exists
Top diseases by Open Targets association (of 959 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 |
| familial hypercholesterolemia |
0.859 |
0.737 |
established (curated) |
no MR -> candidate analysis |
| Hypercholesterolemia |
0.923 |
0.925 |
established (curated) |
MR: beta=0.277, p=3.74e-21 (cis) |
| hypercholesterolemia, autosomal dominant, 3 |
0.939 |
— |
established (curated) |
no MR -> candidate analysis |
| cardiovascular disorder |
0.887 |
— |
common-variant locus |
no MR -> candidate analysis |
| coronary artery disorder |
0.907 |
— |
common-variant locus |
no MR -> candidate analysis |
| metabolic disease |
0.932 |
0.938 |
multi-layer: burden+GWAS (allelic-series candidate) |
no MR -> candidate analysis |
| hyperlipidemia |
0.904 |
— |
common-variant locus |
no MR -> candidate analysis |
| myocardial infarction |
0.875 |
— |
common-variant locus |
no MR -> candidate analysis |
| homozygous familial hypercholesterolemia |
0.72 |
— |
established (curated) |
no MR -> candidate analysis |
| Disorder of lipid metabolism |
0.849 |
0.86 |
multi-layer: burden+GWAS (allelic-series candidate) |
no MR -> candidate analysis |
| atherosclerosis |
0.554 |
— |
common-variant locus |
no MR -> candidate analysis |
| hypercholesterolemia, familial, 1 |
0.92 |
— |
established (curated) |
no MR -> candidate analysis |
| coronary atherosclerosis |
0.868 |
— |
common-variant locus |
no MR -> candidate analysis |
| myocardial ischemia |
0.867 |
— |
common-variant locus |
no MR -> candidate analysis |
| familial hyperlipidemia |
0.852 |
— |
common-variant locus |
no MR -> candidate analysis |
Of the 15 rows above, 14 have no MR estimate in this resource. Across all retrieved diseases for this gene: 0 exploratory rare-variant signal(s), 2 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 |
2 known modulators (PCSK9 mRNA) |
| gnomAD constraint |
pLI=2.8e-18, LOEUF=1.14 — LoF-tolerant |
| GWAS Catalog |
106 unique SNPs / 246 rows |
| ClinVar |
1569 records; 0 pathogenic in sample of 30 |
| PharmGKB/ClinPGx |
no annotations |
phenome — Top 30 of 959 associated diseases by overall score. genetic_association aggregates GWAS common-variant AND rare-variant evidence. These are ASSOCIATIONS (loci), not causal claims.chembl — ChEMBL target matched by text search on ‘PCSK9’ and resolved to ‘PCSK9 mRNA’ — confirm this is the intended target.clinvar — Pathogenic count is over the 30 record(s) retrieved, NOT over all 1569 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 — Top 20 of 589 traits by best p-value, aggregated from 1545 association rows. These are GWAS ASSOCIATIONS (loci), not causal claims; mapped genes at a locus are not necessarily the effector gene.
Sources
uniprot: https://www.uniprot.org/uniprotkb/Q8NBP7 — 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 v3.0phenome: https://platform.opentargets.org/target/ENSG00000169174/associations — Open Targets data release 26.06chembl: https://www.ebi.ac.uk/chembl/target_report_card/CHEMBL4630662/ — ChEMBL_37 (released 2026-05-01)gnomad: https://gnomad.broadinstitute.org/gene/PCSK9 — gnomAD constraint via GraphQL API (reference genome GRCh38)gwas: https://www.ebi.ac.uk/gwas/genes/PCSK9 — GWAS Catalog REST (live; release not exposed by this endpoint)clinvar: https://www.ncbi.nlm.nih.gov/clinvar/?term=PCSK9%5Bgene%5D — ClinVar build Build260809-1055.1gwas_traits: https://www.ebi.ac.uk/gwas/genes/PCSK9 — GWAS Catalog search API (live; release not exposed)
Provenance
- Generated: 2026-08-14T00:47:00 · 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