GWAS SNP Interpretation Skill

GWAS SNP Interpretation Skill

SNP interpretation: a GWAS hit is a REGION, not a single causal variant. The lead SNP may not be causal — it may be in LD with the causal variant. Always check LD structure and functional annotation before concluding a specific SNP is mechanistically responsible. Use LDlink_get_proxies(variant="rs...", population="EUR") to retrieve the high-R² LD proxies (needs a free LDLINK_TOKEN) — a proxy in a coding/regulatory region is a better mechanistic candidate than the lead SNP itself. Fine-mapping (SuSiE, FINEMAP credible sets) narrows the causal set but rarely identifies a single variant with certainty. L2G scores integrate eQTL, chromatin interaction, and distance data to predict the causal gene — a lead SNP mapping to gene A may actually regulate gene B 500 kb away via a distal enhancer.

LOOK UP DON'T GUESS: never assume a SNP's functional consequence, mapped gene, or population frequency — always call gwas_get_snp_by_id and OpenTargets_get_variant_info to retrieve current annotations.

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)