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GWAS SNP Interpretation Skill

Overview

Interpret genetic variants (SNPs) from GWAS studies by aggregating evidence from multiple sources to provide comprehensive clinical and biological context.

Use Cases:

• "Interpret rs7903146" (TCF7L2 diabetes variant)
• "What diseases is rs429358 associated with?" (APOE Alzheimer's variant)
• "Clinical significance of rs1801133" (MTHFR variant)
• "Is rs12913832 in any fine-mapped loci?" (Eye color variant)

What It Does

The skill provides a comprehensive interpretation of SNPs by:

1. SNP Annotation : Retrieves basic variant information including genomic coordinates, alleles, functional consequence, and mapped genes
2. Association Discovery : Finds all GWAS trait/disease associations with statistical significance
3. Fine-Mapping Evidence : Identifies credible sets the variant belongs to (fine-mapped causal loci)
4. Gene Mapping : Uses Locus-to-Gene (L2G) predictions to identify likely causal genes
5. Clinical Summary : Aggregates evidence into actionable clinical significance

Workflow

User Input: rs7903146
    ↓
[1] SNP Lookup
    → Get location, consequence, MAF
    → gwas_get_snp_by_id
    ↓
[2] Association Search
    → Find all trait/disease associations
    → gwas_get_associations_for_snp
    ↓
[3] Fine-Mapping (Optional)
    → Get credible set membership
    → OpenTargets_get_variant_credible_sets
    ↓
[4] Gene Predictions
    → Extract L2G scores for causal genes
    → (embedded in credible sets)
    ↓
[5] Clinical Summary
    → Aggregate evidence
    → Identify key traits and genes
    ↓
Output: Comprehensive Interpretation Report

Data Sources

GWAS Catalog (EMBL-EBI)

• SNP annotations : Functional consequences, mapped genes, population frequencies
• Associations : P-values, effect sizes, study metadata
• Coverage : 350,000+ publications, 670,000+ associations

Open Targets Genetics

• Fine-mapping : Statistical credible sets from SuSiE, FINEMAP methods
• L2G predictions : Machine learning-based gene prioritization
• Colocalization : QTL evidence for causal genes
• Coverage : UK Biobank, FinnGen, and other large cohorts

Input Parameters

Required

• rs_id (str): dbSNP rs identifier
  • Format: "rs" + number (e.g., "rs7903146")
  • Must be valid rsID in GWAS Catalog

Optional

• include_credible_sets (bool, default=True): Query fine-mapping data
  • True: Complete interpretation (slower, ~10-30s)
  • False: Fast associations only (~2-5s)
• p_threshold (float, default=5e-8): Genome-wide significance threshold
• max_associations (int, default=100): Maximum associations to retrieve

Output Format

Returns SNPInterpretationReport containing:

1. SNP Basic Info

{
    'rs_id': 'rs7903146',
    'chromosome': '10',
    'position': 112998590,
    'ref_allele': 'C',
    'alt_allele': 'T',
    'consequence': 'intron_variant',
    'mapped_genes': ['TCF7L2'],
    'maf': 0.293
}

2. Trait Associations

[
    {
        'trait': 'Type 2 diabetes',
        'p_value': 1.2e-128,
        'beta': '0.28 unit increase',
        'study_id': 'GCST010555',
        'pubmed_id': '33536258',
        'effect_allele': 'T'
    },
    ...
]

3. Credible Sets (Fine-Mapping)

[
    {
        'study_id': 'GCST90476118',
        'trait': 'Renal failure',
        'finemapping_method': 'SuSiE-inf',
        'p_value': 3.5e-42,
        'predicted_genes': [
            {'gene': 'TCF7L2', 'score': 0.863}
        ],
        'region': '10:112950000-113050000'
    },
    ...
]

4. Clinical Significance

Genome-wide significant associations with 100 traits/diseases:
  - Type 2 diabetes
  - Diabetic retinopathy
  - HbA1c levels
  ...

Identified in 20 fine-mapped loci.
Predicted causal genes: TCF7L2

Example Usage

See QUICK_START.md for platform-specific examples.

Tools Used

GWAS Catalog Tools

1. gwas_get_snp_by_id: Get SNP annotation
2. gwas_get_associations_for_snp: Get all trait associations

Open Targets Tools

1. OpenTargets_get_variant_info: Get variant details with population frequencies
2. OpenTargets_get_variant_credible_sets: Get fine-mapping credible sets with L2G

Interpretation Guide

P-value Significance Levels

• p < 5e-8: Genome-wide significant (strong evidence)
• p < 5e-6: Suggestive (moderate evidence)
• p < 0.05: Nominal (weak evidence)

L2G Score Interpretation

• > 0.5: High confidence causal gene
• 0.1-0.5 : Moderate confidence
• < 0.1: Low confidence

Clinical Actionability

1. High : Multiple genome-wide significant associations + in credible sets + high L2G scores
2. Moderate : Genome-wide significant associations but limited fine-mapping
3. Low : Suggestive associations or limited replication

Limitations

1. Variant ID Conversion : OpenTargets requires chr_pos_ref_alt format, which may need allele lookup
2. Population Specificity : Associations may vary by ancestry
3. Effect Sizes : Beta values are study-dependent (different phenotype scales)
4. Causality : Associations don't prove causation; fine-mapping improves confidence
5. Currency : Data reflects published GWAS; latest studies may not be included

Best Practices

1. Use Full Interpretation : Enable include_credible_sets=True for clinical decisions
2. Check Multiple Variants : Look at other variants in the same locus
3. Validate Populations : Consider ancestry-specific effect sizes
4. Review Publications : Check original studies for context
5. Integrate Evidence : Combine with functional data, eQTLs, pQTLs

Technical Notes

Performance

• Fast mode (no credible sets): 2-5 seconds
• Full mode (with credible sets): 10-30 seconds
• Bottleneck : OpenTargets GraphQL API rate limits

Error Handling

• Invalid rs_id: Returns error message
• No associations: Returns empty list with note
• API failures: Graceful degradation (returns partial results)

Related Skills

• Gene Function Analysis : Interpret predicted causal genes
• Disease Ontology Lookup : Understand trait classifications
• PubMed Literature Search : Find original GWAS publications
• Variant Effect Prediction : Functional consequence analysis

References

1. GWAS Catalog: https://www.ebi.ac.uk/gwas/
2. Open Targets Genetics: https://genetics.opentargets.org/
3. GWAS Significance Thresholds: Fadista et al. 2016
4. L2G Method: Mountjoy et al. 2021 (Nature Genetics)

Version

• Version : 1.0.0
• Last Updated : 2026-02-13
• ToolUniverse Version : >= 1.0.0
• Tools Required : gwas_get_snp_by_id, gwas_get_associations_for_snp, OpenTargets_get_variant_credible_sets

Weekly Installs

121

Repository

mims-harvard/to…universe

GitHub Stars

1.2K

First Seen

Feb 20, 2026

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