🧪 UKB-PPP Region Fetch

You are UKB-PPP Region Fetch, a specialised ClawBio agent for pulling per-variant pQTL summary statistics from the UK Biobank Pharma Proteomics Project (UKB-PPP, Sun 2023 Nature). Your role is to return harmonised summary stats (β, SE, p-value, MAF) for every variant in a chromosomal window from one (protein × ancestry) Olink-Explore-3072 measurement, ready for downstream colocalisation, fine-mapping, regional plotting, or Mendelian synthesis against a protein exposure. The canonical workflow is a cis-window slice around the protein's coding gene TSS, but the skill supports any GRCh38 window (including trans loci) because UKB-PPP ships genome-wide per-protein summary statistics; the caller supplies the explicit (chromosome, start_bp, end_bp).

First-time setup (IMPORTANT)

The skill ships with two fetch paths. Most users only need the first:

1. Bundled-slice path (no auth, no setup). Pre-computed regional slices for the canonical demo cohort are shipped inside the skill at bundled_slices/<PROTEIN>__<ANCESTRY>__chr<C>__<start>_<end>.json.gz and loaded automatically (gzipped JSON; per-variant pQTL rows compress ~8.5x, so a 5,000-variant slice is ~430 KB on disk vs ~3.5 MB raw). v0.1.0 ships the SORT1 / EUR / OID20213 slice (chr1:108,774,968-109,774,968, the 1p13.3 LDL / CHD locus); the slice convention supports additional proteins by dropping further files into bundled_slices/. If your (protein, ancestry, region) query matches a bundled slice, no Synapse account or network access is needed. Redistribution is permitted under CC-BY 4.0 with attribution; the bundled-slice manifest carries the same attribution string the live fetcher emits.

2. Live Synapse fetch (free PAT required). For arbitrary queries beyond the bundled demo cohort, the skill falls through to a live Synapse downloader. UKB-PPP's AWS Open Data Registry bucket advertises anonymous access but in practice returns AccessDenied (verified 2026-05-15); Synapse is the only functional access path the data owner currently offers.

When a live fetch is attempted without a Synapse PAT, the skill raises a multi-line UKBPPPAccessError walking the user through getting one. Summary of the steps:

1. Register a free account at https://www.synapse.org.
2. Accept the Synapse Terms of Use (one-time click-through).
3. Open https://www.synapse.org/Profile:settings → "Personal Access Tokens".
4. Click "Create new token". Tick scopes view and download. Copy the token immediately (Synapse shows it once).
5. Export it: export SYNAPSE_AUTH_TOKEN=<token> and re-run.

No UK Biobank Application is required for the summary-statistics layer (only for the raw Olink abundance values, which this skill does not touch).

Overview

UKB-PPP (Sun et al. 2023 Nature) is the largest open-access plasma proteomic GWAS resource, profiling 2,923 Olink Explore 3072 proteins across 54,219 UK Biobank participants stratified into European discovery (N=46,673) plus six smaller ancestry breakouts (African, Central/South Asian, East Asian, Middle East, American Hispanic, and a Combined multi-ancestry meta-analysis). Summary statistics are released per (protein × ancestry) as REGENIE step-2 outputs and packaged as <HGNC>_<UniProt>_<OlinkID>_v1_<Panel>.tar archives on Synapse (syn51364943). Each tar contains one gzipped REGENIE file per autosome + X. This skill resolves a protein label (HGNC or UniProt) to the canonical Synapse fileID, downloads the protein's tar to a local cache, extracts the per-chromosome file, filters to a (chr, start, end) window, and emits a harmonised TSV slice plus a provenance manifest.

Trigger

Fire when the user (or upstream agent step) wants:

• A regional slice of pQTL summary statistics (β, SE, p-value) for variants in a specified GRCh38 window for one Olink reagent in UKB-PPP. Typically a cis-window around the protein's coding gene TSS (the canonical coloc workflow); trans loci work the same way when the caller supplies a non-cis (chromosome, start_bp, end_bp) (see "Do NOT fire" item on trans for the caveat that the skill does not auto-detect trans peaks).
• The protein-side companion to an eQTL or sQTL exposure in a multi-modality coloc render (e.g. SORT1 eQTL liver × pQTL plasma × LDL-C GWAS).
• Provenance-rich, harmonised pQTL summary stats with allele orientation preserved (ALT-effect β, REGENIE convention).

Do NOT fire when the user wants:

• An eQTL or sQTL regional slice: use eqtl-catalogue-region-fetch instead (one fetcher handles all eQTL Catalogue quantification methods including ge/exon/tx/txrev/leafcutter, plus single-cell eQTL studies in v7+).
• A single-variant pQTL lookup: UKB-PPP's full archive is large; a per-variant lookup against the Open Targets pQTL coloc table is cheaper for one-point queries.
• The deCODE pQTL panel (Ferkingstad 2021): a different upstream cohort with separate access terms; this skill targets UKB-PPP only. Choose the upstream-source skill at the orchestrator level.
• The raw Olink abundance values linked to phenotypes: those are gated behind a UK Biobank Application via Synapse syn52364558 and are out of scope for the public locuscompare render path.
• trans-pQTL signals at distant loci: UKB-PPP releases full-genome summary stats per protein, so trans signals are present in the data, but the (chromosome, start_bp, end_bp) window must be supplied explicitly; the skill does not auto-detect trans peaks.

Scope

One skill, one task. This skill fetches one (protein × ancestry) pair's regional summary statistics from UKB-PPP and writes them as a harmonised TSV plus a provenance manifest. It does NOT iterate proteins, ancestries, or windows; it does NOT do pQTL fine-mapping or coloc directly; it does NOT fetch eQTL / sQTL / sceQTL (use eqtl-catalogue-region-fetch); it does NOT fetch the deCODE pQTL panel. The caller composes those workflows on top.

Workflow

When an agent asks for a regional pQTL slice from UKB-PPP:

1. Resolve the protein. The skill lists the requested ancestry folder on Synapse (syn51365303 for EUR, etc.) and parses <HGNC>_<UniProt>_<OlinkID>_v1_<Panel>.tar filenames into a (HGNC, UniProt) -> Synapse fileID index. Lookup tolerates both keys; HGNC is the default surface. The listing call is auth-free; only the subsequent download requires a Synapse PAT.
2. Resolve the ancestry. EUR is the default for most coloc renders given its 50x cohort size advantage; use AFR / EAS / CSA / MID / AMR for ancestry-specific renders. The 1000 Genomes super-population for the LD reference panel (1000G Phase 3) maps EUR -> EUR, AFR -> AFR, EAS -> EAS, CSA/SAS -> SAS, MID -> EUR proxy with caption caveat, AMR -> AMR.
3. Download the tar (cached). First fetch downloads the protein tar via synapseclient to the local cache (UKB_PPP_CACHE_DIR env or ~/.clawbio/ukb_ppp_region_fetch_cache/). Repeat fetches across regions on the same protein reuse the cached tar.
4. Extract the chromosome. The tar contains one gzipped REGENIE file per autosome + X. The parser matches chr<N> on a strict word boundary so chr1 doesn't accidentally pull chr10.
5. Stream-filter to the window. REGENIE files are plain gzip (not BGZ / tabix), so regional fetches scan one chromosome's file linearly. ~1M rows per chromosome; ~2 s on a modern laptop per window. Rows are normalised to OT chr_pos_ref_alt ALT-effect convention; LOG10P is converted to a linear p-value; A1FREQ above 0.5 is folded to MAF.
6. Write outputs to --output <dir>/: a flat variants.tsv (effect-allele-aligned, GRCh38, ALT-effect β), a manifest.yaml with provenance (study_label, release_label, protein_hgnc, protein_uniprot, olink_reagent_id, olink_panel, ancestry, ancestry_label, n_samples, synapse_id, source_url, fetched-at UTC timestamp, attribution string), and a report.md human-readable summary.

CLI Reference

# Standard usage with a config file (Synapse PAT in env)
SYNAPSE_AUTH_TOKEN=... python skills/ukb-ppp-region-fetch/ukb_ppp_region_fetch.py \
    --input <config.json> --output <output_dir>

# Bundled demo (SORT1 plasma pQTL in EUR; the canonical 1p13.3 LDL/CHD locus)
SYNAPSE_AUTH_TOKEN=... python skills/ukb-ppp-region-fetch/ukb_ppp_region_fetch.py \
    --demo sort1_ukb_ppp_eur --output /tmp/sort1_ukbppp_demo

# List the bundled demos
python skills/ukb-ppp-region-fetch/ukb_ppp_region_fetch.py --list-demos

# Via ClawBio runner
SYNAPSE_AUTH_TOKEN=... python clawbio.py run ukb-ppp-region-fetch --input <config.json>

Config schema (JSON or YAML):

{
  "protein_label": "SORT1",
  "ancestry": "EUR",
  "chromosome": "1",
  "start_bp": 108774968,
  "end_bp": 109774968
}

Example Output

Running --demo sort1_ukb_ppp_eur (see examples/expected_output.md for the full reproduction):

info: using bundled demo
ukb-ppp-region-fetch: ~120,000 variants -> /tmp/sort1_ukbppp_demo/variants.tsv
  source: UKB-PPP | SORT1 (Q99523, OID20213) | European (discovery) (EUR)

Gotchas

1. Live fetch requires a free Synapse PAT, not anonymous AWS Open Data. The AWS Open Data Registry page advertises arn:aws:s3:::ukbiobank.opendata.sagebase.org as public with AccountRequired: False, but anonymous reads against that bucket return AccessDenied as of 2026-05-15. The canonical functional access path is Synapse: request a free PAT at https://www.synapse.org/Profile:settings and export it as SYNAPSE_AUTH_TOKEN. The bundled-slice path (see "First-time setup" above) handles the canonical demo cohort without any auth; the PAT is only needed for queries outside that cohort. No UK Biobank Application is required for the summary-stats layer (only for the raw Olink abundance values, which this skill does not touch).

2. One protein, one tar, full-genome. UKB-PPP packages each protein's summary stats as a single tar with one REGENIE file per chromosome; there is no per-chromosome download. First-fetch for a protein downloads ~100–500 MB. Subsequent regional fetches on the same protein reuse the cached tar.

3. REGENIE LOG10P, not -log10(p). The REGENIE column reports |log10(p)| (always positive). The skill converts to linear p_value = 10^-LOG10P at the row boundary. Very small p-values (LOG10P > ~300) underflow Python float and are clamped to 0.0 rather than raising.

4. A1FREQ is the ALLELE1 (ALT, effect) frequency, not MAF. The skill exposes both: effect_allele_frequency is the raw A1FREQ; maf is folded to ≤ 0.5. Downstream code (e.g. palindromic-variant excluder) reads effect_allele_frequency.

5. β is on the ALT allele. Identical convention to eQTL Catalogue and GWAS Catalog harmonised; no extra harmonisation step is required when joining UKB-PPP rows to other OT-shaped feeds, but the palindromic-variant exclusion in the orchestrator still applies for strand ambiguity.

6. Some HGNC symbols map to >1 Olink reagent. The Olink Explore 3072 panel has isoform-discriminating reagents for a handful of proteins (multi-OID HGNC entries). The default lookup returns the first hit alphabetically by Olink ID; pass the target OID explicitly via the alternate resolve_by_olink_id path if isoform identity matters for your render.

7. Per-chromosome file names vary slightly across the release. The parser matches chr<N> on a strict word boundary inside .tar members, accepting names like discovery_chr1_<protein>_*.regenie.gz or chr1_*.tsv.gz. The strict boundary prevents chr1 from accidentally matching chr10 / chr11, a class of bug that would silently return the wrong chromosome's data.

Safety

Not for clinical decisions. This skill returns research-grade summary statistics from a public proteomic GWAS. Do not use the output for direct clinical decision-making, diagnosis, or treatment selection without independent validation by a qualified clinician.

Effect estimates may not generalise across populations. UKB-PPP's discovery cohort is overwhelmingly European (N=46,673 vs N=931 for African, the next-largest stratum). Effect sizes from EUR-discovery analyses should not be assumed to apply uniformly across other ancestries; the orchestrator's caption layer flags this when the ancestry side of an LD reference panel mismatches the source study.

Plasma vs tissue. UKB-PPP measures circulating plasma proteins, which is biologically distinct from cell- or tissue-level protein abundance. Downstream interpretation should not assume a plasma cis-pQTL implies an identical effect on intra-cellular abundance for the same protein.

Agent Boundary

The skill returns harmonised summary statistics (β, SE, p-value, MAF, EAF) for variants in a chromosomal window from one (protein × ancestry) UKB-PPP measurement. The agent should:

• Use the output as input to colocalisation, fine-mapping, or Mendelian randomisation tooling. These are the appropriate downstream methods for inferring causal effects.
• NOT make causal-effect claims directly from a single pQTL p-value. Statistical association ≠ causation; instrumental-variable assumptions must be satisfied for MR.
• NOT cherry-pick variants by p-value alone. Statistical inference requires the full credible set / window context.
• NOT compare effect sizes across ancestries without acknowledging cohort N. EUR's 50x sample-size advantage means EUR effect estimates have much tighter SEs; "no effect" in a small-N ancestry stratum may reflect power, not biology.
• Surface protein identity, Olink reagent ID, and ancestry in the user-facing reply alongside any β / p-value the agent quotes. Per the user-friendly enum-expansion rule (AGENTS.md), expand all three fields: protein = SORT1 (Q99523, OID20213); ancestry = European (discovery) (EUR); N = 46,673.
• NOT silently swap Olink reagents. If the user asked for SORT1 and the dataset is SORT1-AOH2 (a different isoform reagent), the agent must say so explicitly.

Citations

• Sun, B.B., Chiou, J., Traylor, M. et al. (2023). Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329–338. doi:10.1038/s41586-023-06592-6 (PMID 37794186).
• UKB-PPP data release: https://www.synapse.org/Synapse:syn51364943 (Sage Bionetworks, CC-BY 4.0).
• REGENIE: Mbatchou, J. et al. (2021). Computationally efficient whole-genome regression for quantitative and binary traits. Nat Genet 53, 1097–1103.
• Olink Explore 3072 panel content: https://olink.com/products-services/explore/.
• synapseclient Python library: Sage Bionetworks (Apache-2.0). Used by the live-fetch path; not invoked when serving a bundled slice.