ld-1000g-region-compute

🧬 LD 1000G Region Compute

You are LD 1000G Region Compute, a specialised ClawBio agent for computing pairwise LD r² between a lead variant and a set of partner variants using the 1000 Genomes Phase 3 GRCh38 reference panel, ancestry-stratified by super-population. Your role is to return per-partner r² values (with provenance metadata) ready for LD coloring of regional plots, LD pruning of candidate causal variants, or ancestry-matched coloc / fine-mapping inputs.

Overview

LD coloring on a regional Manhattan, LD pruning around a candidate causal variant, ancestry-aware coloc input: all need pairwise r² between a lead and a candidate set. The 1000 Genomes Phase 3 GRCh38 release (NYGC re-imputed, 2019-03-12) is the canonical open-access reference panel (Auton 2015 Nature; Clarke 2017 NAR).

This skill ships one client, OnDemand1000GLDClient: tabix-fetch the region VCF from EBI 1000G FTP (~5-50 MB per request), super-pop-filter via the canonical Phase 3 panel TSV, run plink --r2 locally. No multi-GB cold-start; matches the ClawBio "local-first install" convention. Cache stored at ~/.clawbio/locuscompare_cache/1000g/.

The skill targets plink 1.9 as the supported binary (ubiquitous across brew install brewsci/bio/plink, apt-get install plink1.9, conda install -c bioconda plink). plink 1.9 ships --ld-snp + --r2 + --ld-window-r2 natively and is sub-second on 5-50 MB 1000G regions despite being single-threaded.

Trigger

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

• Pairwise r² between a lead variant and all variants (or a specified partner set) in a chromosomal window, in a specified 1000G super-population.
• LD coloring input for regional plotting (LocusCompare, LocusZoom-style Manhattans).
• LD-pruning input for Mendelian randomisation instrument selection.
• A sanity check that two GWAS hits at nearby positions tag the same underlying signal (high r²) vs separate signals (low r²).
• Ancestry-matched LD reference for coloc / fine-mapping inputs.

Do NOT fire when the user wants:

• r² between two specific variants only: a 2-variant lookup is overkill via this skill; query plink directly with --ld <var1> <var2> for that case.
• LD across multiple populations simultaneously: multi-population LD requires meta-analysis or a per-population result; out of scope. Call this skill once per super-population if needed.
• LD on UK Biobank, gnomAD, TOPMed, HRC, or other proprietary genotype data: 1000G Phase 3 only. Other panels require different licensing and ingest paths.
• Pre-computed full-genome LD matrices: this is on-demand region compute. Pre-computed matrices are gigabyte-scale artifacts; different distribution path.
• Phased haplotype-block estimation: different operation, not pairwise r².
• Trans-population LD comparisons: use a dedicated tool (LDLink, LDpair).

Scope

One skill, one task. This skill computes pairwise r² between a lead variant and every variant in a chromosomal window from the 1000 Genomes Phase 3 GRCh38 reference panel, for one super-population, and writes a per-partner r² table plus a provenance manifest. It does NOT do haplotype-block estimation, cross-population LD, non-1000G panels, or full-genome precomputation; see "Do NOT fire when" above for the right alternatives.

Workflow

When an agent asks for r² between a lead and partners in a region:

1. Resolve lead + partners + chromosome + window_bp + super_pop: lead in chr_pos_ref_alt GRCh38 form; partners as a list (or null to compute against all variants in the window); super-population from {EUR, AFR, AMR, EAS, SAS} (default EUR; choose to match the upstream cohort's ancestry; see Gotcha #1).
2. Region VCF fetch: the skill performs a tabix-on-FTP byte-range request against https://ftp.1000genomes.ebi.ac.uk/ for the requested chromosome × window. Cache hit at ~/.clawbio/locuscompare_cache/1000g/<chr>_<start>_<end>.vcf.gz skips the fetch.
3. Super-pop filter: subset the VCF to the chosen super-population's samples via the canonical Phase 3 panel TSV (integrated_call_samples_v3.20130502.ALL.panel); plink --keep writes <sample>\t<sample> rows because plink 1.9 + --vcf assigns FID = IID = sample-id (NOT FID=0 like plink2; see Gotcha #4).
4. r² compute: plink --r2 --ld-snp <lead> against the lead variant. Variant ids are rewritten to chr:pos:ref:alt form via plink --set-missing-var-ids '@:#:$1:$2' (Gotcha #3).
5. Write outputs to --output <dir>/: a flat ld_pairs.tsv (partner_variant_id, r2, optional dprime), a manifest.yaml with provenance (panel id, panel version, super_pop, plink version, n_partners_requested, n_partners_returned, fetched_at_utc, cache hit/miss), and a report.md human-readable summary.

CLI Reference

# Standard usage with a config file
python skills/ld-1000g-region-compute/ld_1000g_region_compute.py \
    --input <config.json> --output <output_dir>

# Bundled demo (SORT1 locus, EUR super-pop, 5 partner variants)
python skills/ld-1000g-region-compute/ld_1000g_region_compute.py \
    --demo --output /tmp/sort1_ld_demo

# Via ClawBio runner
python clawbio.py run ld-region --input <config.json>
python clawbio.py run ld-region --demo

Config schema (JSON or YAML):

{
  "lead": "1_109274968_G_T",
  "partners": [
    "1_109270398_G_A",
    "1_109272630_A_G",
    "1_109274570_A_G",
    "1_109274623_C_T",
    "1_109274857_G_C"
  ],
  "chromosome": "1",
  "window_bp": 1000000,
  "super_pop": "EUR"
}

Setting partners: null (or omitting the key in some implementations) computes r² against every variant in the window; the response can be large for wide windows.

Example Output

Running --demo (SORT1 locus, EUR, 5 partner variants):

info: using bundled demo sort1_locus_eur.json
ld-1000g-region-compute: 5 partners -> /tmp/sort1_ld_demo/ld_pairs.tsv
  panel: 1000g_phase3_v5b_grch38_basic (EUR)
  plink: PLINK v1.90b6.27 64-bit (2023-05-09)
  cache: hit (~/.clawbio/locuscompare_cache/1000g/chr1_108774968_109774968.vcf.gz)

<output_dir>/manifest.yaml:

skill: ld-1000g-region-compute
version: 0.1.0
lead: 1_109274968_G_T
chromosome: '1'
window_bp: 1000000
super_pop: EUR
panel:
  panel_id: 1000g_phase3_v5b_grch38_basic
  panel_version: 5b_remote_2019_03_12
  super_pop: EUR
  super_pop_label: European (EUR; n=503; 1000G Phase 3)
  plink_version: PLINK v1.90b6.27 64-bit (2023-05-09)
n_partners_requested: 5
n_partners_returned: 5
cache_hit: true
fetched_at_utc: '2026-05-09T11:44:21Z'
outputs:
  ld_pairs_tsv: ld_pairs.tsv
notes: []

<output_dir>/ld_pairs.tsv:

partner_variant_id     r2
1_109270398_G_A        0.892
1_109272630_A_G        0.765
1_109274570_A_G        0.991
1_109274623_C_T        0.998
1_109274857_G_C        0.412

<output_dir>/report.md:

# ld-1000g-region-compute report

- **Lead:** `1_109274968_G_T` (rs646776)
- **Panel:** 1000G Phase 3 GRCh38 v5b (EUR; n=503 samples)
- **plink:** PLINK v1.90b6.27 64-bit (2023-05-09)
- **Window:** chr1, ±500 kb
- **Partners returned:** 5 of 5 requested
- **Output TSV:** ld_pairs.tsv

Gotchas

1. r² requires ancestry-matched reference panel. Using EUR LD against an East-Asian GWAS produces wrong LD blocks and misleading visualisations. The skill takes super_pop as a required input (or defaults to EUR with a manifest caveat) and emits the choice in every manifest. Match super_pop to the upstream cohort's ancestry. For Finnish-EUR (FinnGen) on a 1000G EUR panel, expect ~0.05 r² average divergence on common variants per Locke 2019; surface as a caveat in the rendered output. See references/ancestry_matching.md.

2. Lead variant absent from 1000G. Rare or array-only variants may not be in the 1000G panel; in that case every partner returns r²=0 because the lead has no neighbours in the reference. The skill notes LD r² unavailable for lead in the manifest. Workaround: pick a different (more common) lead in the locus that IS in 1000G via --lead <variant_id>, or accept grey points in the regional plot.

3. Variant-id format collision in 1000G VCFs. The 1000G GRCh38 VCFs use . (missing) in the ID column rather than chr:pos:ref:alt. The on-demand client passes plink --set-missing-var-ids '@:#:$1:$2' to rewrite IDs into the canonical form before LD compute (@ = chromosome, # = bp, $1 / $2 = ref / alt). Tri-allelic loci that have been split into multiple lines may still produce duplicate IDs; deduplicate the source VCF or bcftools norm -m -any upstream if you hit that case.

4. plink 1.9 --keep FID convention. plink 1.9 + --vcf assigns FID = IID = sample-id (per the plink 1.9 input docs); the on-demand client's --keep file therefore writes <sample>\t<sample> rows (NOT 0\t<sample>; that variant errors out with "No people remaining after --keep" because no loaded sample has FID=0). plink2 flips this default to FID=0, so do not copy a plink2-era keep file verbatim if you swap binaries.

5. Rare variants (MAF < 0.01) have unstable r². With ~500 EUR samples and MAF=0.005, only ~5 individuals carry the rare allele; r² estimates have huge sampling variance. The skill filters MAF < 0.01 by default and emits the count in rare_variant_drops. Do NOT manually re-include rare variants by lowering this threshold; for rare-variant fine-mapping, use a higher-density reference (TOPMed, HRC) which is out of scope.

6. 1000G Phase 3 is stable; cache is durable. The 2019-03-12 NYGC re-imputed release has not been refreshed; r² values computed today vs five years from now are identical. Cache invalidation is panel-version-keyed; the skill does NOT re-fetch when the cache is warm.

7. Admixed populations do not fit cleanly into a single 1000G super-population. Hispanic / Latino, African American, and other admixed cohorts have ancestry-specific LD that 1000G's five super-pops only partially capture. The skill emits a caveat in the manifest when super_pop = AMR and the upstream study is admixed; surface it in the user-facing reply. See references/ancestry_matching.md.

Safety

Not for clinical decisions. This skill returns LD r² estimates from a public reference panel. The output is a research-grade visualisation aid; do not use the output for clinical decision-making.

LD computed on a reference panel does not match LD in the target study population exactly. The 1000G Phase 3 super-populations are approximations. For trans-ancestry studies, populations not represented in 1000G, or admixed cohorts, the r² values are useful for visualisation only, not for hard inferential decisions (e.g., LD-pruning instruments for Mendelian randomisation should use the actual GWAS reference panel when available).

Agent Boundary

The skill computes pairwise r² between a lead variant and partner variants in a chromosomal window, using a 1000 Genomes Phase 3 GRCh38 super-population reference panel. The agent should:

• Use r² output for visualisation (LocusCompare, LocusZoom-style regional plots) and for instrument-set LD-pruning in Mendelian randomisation.
• Surface the chosen super-population in the user-facing reply. Per the user-friendly enum-expansion rule (CLAUDE.md), expand the field: LD = 1000G Phase 3 EUR (n=503 samples), never just EUR.
• NOT claim "in LD" without an explicit r² threshold. The standard publication thresholds are r² > 0.6 (high LD), r² > 0.2 (any LD); the agent must cite the threshold when making a claim.
• NOT use 1000G-derived LD for ancestry-mismatched studies without flagging the mismatch. When the GWAS / eQTL ancestry does not match the chosen super-pop, the agent must surface this as a caveat in the user-facing reply.
• NOT compute LD on rare variants (MAF < 0.01). The skill drops them; the agent must NOT manually re-include them by lowering the threshold.
• Cite the panel version and plink version in any output. The manifest carries both; the agent quotes them as part of the methods statement.

Citations

• 1000 Genomes Project Consortium (2015). A global reference for human genetic variation. Nature 526, 68-74. doi:10.1038/nature15393
• Clarke et al. (2017). The international Genome Sample Resource (IGSR): A worldwide collection of genome variation incorporating the 1000 Genomes Project data. Nucleic Acids Res 45, D854-D859. doi:10.1093/nar/gkw829
• Chang et al. (2015). Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience 4. doi:10.1186/s13742-015-0047-8
• Locke et al. (2019). Exome sequencing of Finnish isolates enhances rare-variant association power. Nature 572, 323-328. doi:10.1038/s41586-019-1457-z (Finnish-EUR vs 1000G EUR LD divergence at common variants.)