bio-causal-genomics-proteome-mr-drug-target

What this skill does

## Version Compatibility

Reference examples tested with: TwoSampleMR 0.5.11+, MendelianRandomization 0.10+, MR-PRESSO 1.0+, coloc 5.2.3+, susieR 0.12.35+, ieugwasr 1.0+, plink2 2.00a5+, R 4.4+.

Before using code patterns, verify installed versions match. If versions differ:
- R: `packageVersion('<pkg>')` then `?function_name` to verify parameters
- CLI: `plink2 --version`; VEP `vep --help`

If code throws OAuth or rate-limit errors from OpenGWAS, or a missing `dataset$N` from coloc, introspect the installed API and adapt the example rather than retrying. UKB-PPP, deCODE, and Fenland summary statistics changed file layouts between 2023 and 2025; verify column headers before passing into `format_data()`.

# Proteome-Wide Drug-Target Mendelian Randomization

**"Does genetically lowering plasma protein X cause a change in disease Y, mimicking a drug?"** -> Use cis-pQTLs in the gene window for protein X as instruments under the Schmidt 2020 framework (Nat Commun 11:3255), restrict the exclusion-restriction violation to the geometric neighbourhood of the encoding gene, triangulate with colocalization (3-tier PP.H4 ladder below) and cross-platform replication (Olink vs SomaScan), and flag protein-altering-variant (PAV) confounding. A single significant cis-MR estimate is necessary but not sufficient for a drug-target claim; the operational bar is MR + coloc + cross-platform agreement + PAV-excluded sensitivity.

### PP.H4 Three-Tier Threshold Ladder

| Tier | PP.H4 | Use case |
|------|-------|----------|
| Suggestive | >= 0.7 | Open Targets / exploratory; consistent with shared-causal |
| Standard publication | >= 0.8 | Wallace 2020 PLoS Genet 16:e1008720; most peer-reviewed pubs |
| Industry / clinical | >= 0.95 | Drug-claim grade; pharma internal target-validation standard |

Operational rule: drug-target nomination requires PP.H4 >= 0.8 minimum; industry-grade clinical claim requires PP.H4 >= 0.95 plus the full triangulation panel.

- R (canonical): `TwoSampleMR::mr()` orchestrates the cis-IVW + Egger + median + Wald-ratio panel
- R (correlated cis-pQTLs in a window): `MendelianRandomization::mr_ivw(model='default', correl=TRUE, correl.x=ld_matrix)`
- R (triangulation): `coloc::coloc.abf()` or `coloc::coloc.susie()` on the same cis-window
- pheWAS: `ieugwasr::associations()` against the OpenGWAS catalogue, looped over outcomes
- VEP CLI: annotate every cis-pQTL with `vep --species homo_sapiens --canonical --check_existing` for PAV flagging

## Data Source Taxonomy

| pQTL dataset | Platform | N | Proteins | Reference | Fails when |
|--------------|----------|---|----------|-----------|------------|
| UKB-PPP | Olink Explore 3072 (antibody PEA) | 54,219 | 2923 (54k primary cis-pQTLs across studies; 14,287 primary pQTLs across cis+trans) | Sun 2023 Nature 622:329 | Target not on Olink panel; ancestry mostly EUR; antibody epitope may miss isoforms |
| deCODE | SomaScan v4 (aptamer SOMAmer) | 35,559 | 4907 | Ferkingstad 2021 Nat Genet 53:1712 | Population isolate; LD differs from outbred EUR; aptamers can be PAV-confounded |
| Fenland | SomaScan v4 | 10,708 | 4775 | Pietzner 2021 Science 374:eabj1541 | UK Fenland-specific ascertainment; SomaScan caveats |
| INTERVAL | SomaScan v3 (older) | 3301 | 3622 | Sun 2018 Nature 558:73 | Smaller N; older SomaScan version; useful only as replication |
| ARIC | SomaScan v4 | ~7000 (multi-ancestry sub-cohorts) | 4877 | Zhang 2022 Nat Genet 54:593 | Stratify by ancestry; do not pool |
| FinnGen-PPP | Olink Explore | ~12,000 | ~3000 | FinnGen DF12 (2024 release) | Finnish-specific allele frequencies; not always meta-analyse with UKB |
| AGES-Reykjavik | SomaScan v4 | ~5400 | 4782 | Emilsson 2018 Science 361:769 | Elderly Icelandic cohort; ascertainment bias |
| Olink Explore 1536 disease-specific cohorts (CARDIoGRAMplusC4D, etc) | Olink Explore subset | varies | varies | per-study | Lower N per cohort; use as replication |

Methodology evolves; check the UKB-PPP portal (ukb-ppp.gwas.eu), deCODE Genetics summary-stat releases, and the eQTL Catalogue / GTEx Portal for the current data version. UKB-PPP was substantially re-released in 2024 (extended ancestry meta-analyses); pin a download date in the methods.

### Platform and Cohort Versioning (2024-2026)

- **UKB-PPP Phase 2 (2024)** -- cross-ancestry meta-analyses; ~54k EUR plus multi-ancestry expansion; file layouts differ from Phase 1 (per-protein parquet vs flat TSV); the 14,287 primary pQTL count from Phase 1 shifts in Phase 2 results. Verify the freeze used.
- **FinnGen-PPP** -- Olink Explore platform; DF12 (2024) release is current; Finnish-specific allele frequencies require ancestry-aware downstream analysis.
- **AoU pQTL (2024)** -- All-of-Us proteomics; pre-symptomatic-cohort design strength for reverse-causation control and longitudinal follow-up.
- **SomaScan v4 vs v5** -- v5 expands to ~11k SOMAmers (vs ~5k in v4); binding consistency for shared SOMAmers documented in deCODE / SomaLogic technical notes but not guaranteed; pin platform version.
- **Olink Explore HT** -- ~5,400 proteins (vs ~3,072 in Explore Expansion, ~1,536 in Explore 1536); UKB-PPP Phase 1 used Explore 3072 -- do not assume Explore HT coverage when reading Phase 1 papers.
- Pin specific platform version + release date in the methods section of every cis-MR drug-target manuscript.

## Cis-MR Methodological Taxonomy

| Method | Cis-window assumption | Min cis-pQTLs | Strength | Fails when |
|--------|------------------------|----------------|----------|------------|
| Single cis-pQTL Wald ratio | Single sentinel SNP within +/-500 kb | 1 | Simplest, transparent point estimate `beta_Y/beta_X` and ratio SE | Confounded by LD-linked eQTL/pQTL of neighbour gene; no heterogeneity test |
| Cis-IVW (clumped r2 < 0.1) | Multiple weakly-correlated cis-pQTLs | 2 | Pools information, increases precision (Schmidt 2020) | r2 between pQTLs > 0.1 inflates SE under independence assumption |
| Cis-IVW with correlation `correl=TRUE` | Cis-pQTLs in moderate LD; supply LD matrix | 2 | Correct SE under correlated instruments (Burgess, Zuber, Valdes-Marquez, Sun, Hopewell 2017 Genet Epidemiol 41:714-725) | LD matrix mismatched to summary-stat ancestry |
| Cis-MR-Egger | Directional pleiotropy across cis-pQTLs | 3+ (>=10 for power) | Sensitivity for in-window directional pleiotropy | Underpowered <10 cis-pQTLs; NOME violation `I^2_GX < 0.9` |
| Cis-weighted-median | Up to 50% invalid cis-pQTLs | 3+ | Robust to a minority of bad instruments | >50% invalid cis-pQTLs |
| MR-PRESSO in cis-window | Outlier cis-pQTLs from LD-confounded neighbours | 4+ | Removes neighbour-eQTL-tagged cis-pQTLs; distortion test (Verbanck 2018) | <4 instruments; underpowered global test |
| Robust cis-MR (Patel 2023 Biometrics 79:3458) | Accommodates LD between cis-pQTLs without full LD matrix | 2+ | Methodologically modern alternative when LD reference is uncertain | Newer; benchmarks evolving |
| Generalized cis-IVW with correlated SNPs | Joint multivariable cis-window | 2+ | Sound under any LD provided matrix supplied | Numerical instability when r2 ~ 1 (collinear) |
| coloc.susie + Wald-ratio per CS | Multiple independent cis-signals (allelic heterogeneity) | 1+ per credible set | Per-signal MR + per-signal PP.H4 | Requires ancestry-matched LD; spurious CS under mismatch |

Verify against Burgess 2023 *Wellcome Open Res* "Guidelines for performing Mendelian randomization" (v3+) and the Open Targets Genetics drug-target pipeline (Mountjoy 2021) before pinning a primary method for a publication.

## Decision Tree by Scenario

| Scenario | Primary method | Triangulation | Why |
|----------|----------------|----------------|-----|
| Single drug target, single sentinel cis-pQTL, single outcome | Wald ratio | coloc.abf PP.H4 + cross-platform replication + PAV flag | Minimum publishable cis-MR; simplest and most transparent |
| Single drug target, multiple independent cis-pQTLs, single outcome | Cis-IVW correl=TRUE with in-window LD | coloc