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tooluniverse-variant-to-mechanism

Trace genetic variants through regulatory context, target genes, and pathways to disease mechanisms.

1.7k|254|Updated Mar 3, 2025
Search Tags:#genomics#variant analysis#mechanism#gwas#OpenTargets#causal chain#eQTL
One-click install
npx skills add https://github.com/mims-harvard/ToolUniverse --skill tooluniverse-variant-to-mechanism
Or copy as Structured Prompt for Agent▼
Please help me install this Agent Skill.
Skill: tooluniverse-variant-to-mechanism
Source: https://github.com/mims-harvard/ToolUniverse/tree/main/plugins/tooluniverse/skills/tooluniverse-variant-to-mechanism
Command: npx skills add https://github.com/mims-harvard/ToolUniverse --skill tooluniverse-variant-to-mechanism

SYSTEM DOCUMENTATION & REQUIREMENTS

💡 This Skill requires tooluniverse, requests, pandas.

What problem does it solve?

Connecting a GWAS hit or non-coding variant to its actual biological mechanism requires querying many scattered databases (VEP, GTEx, RegulomeDB, OpenTargets, STRING, Reactome) and reasoning across regulatory, molecular, and disease evidence layers. This Skill orchestrates that entire variant-to-mechanism workflow into a single evidence-graded causal chain.

Core Features & Use Cases

  • Six-phase causal tracing: Variant characterization (VEP, gnomAD, CADD), regulatory context (GWAS, RegulomeDB, ENCODE, cCREs), target gene identification (GTEx eQTL, OpenTargets L2G), pathway analysis (STRING, Reactome, PANTHER), disease connection (OpenTargets, GenCC, DisGeNET), and mechanistic synthesis with confidence grading.
  • Evidence grading framework: Classifies each mechanistic link from Established to Speculative using a T1-T4 evidence hierarchy, with explicit guidance for handling ambiguous target genes and missing data.
  • Use Case: Ask how rs7903146 causes type 2 diabetes, and the Skill traces the variant through TCF7L2 regulation in pancreatic tissue, Wnt signaling pathways, and curated disease evidence into a full mechanistic report.

Quick Start

Ask the AI to trace how the variant rs7903146 leads to type 2 diabetes using the variant-to-mechanism workflow.

Frequently Asked Questions about tooluniverse-variant-to-mechanism

High-intent search queries and answers about installing and using this skill.

FAQPage Schema
How do I trace a GWAS variant to its biological mechanism?▼

Start with VEP annotation and population frequencies, then assess regulatory context via GWAS associations, RegulomeDB, and ENCODE chromatin marks. Identify the target gene using GTEx eQTLs and OpenTargets L2G scores, then follow pathways through STRING and Reactome to disease evidence.

How to identify the causal gene for a non-coding variant?▼

Do not default to the nearest gene, since regulatory elements can act over hundreds of kilobases. Prioritize eQTL evidence in disease-relevant tissue, then check OpenTargets L2G scores; when both converge on the same gene, confidence is high.

What databases does variant-to-mechanism analysis use?▼

The workflow integrates Ensembl VEP, MyVariant, gnomAD, GWAS Catalog, RegulomeDB, ENCODE, UCSC cCREs, GTEx, OpenTargets, STRING, Reactome, PANTHER, UniProt, GenCC, and DisGeNET across regulatory, molecular, and disease evidence layers.

Why does OpenTargets disease search return no results?▼

OpenTargets requires MONDO identifiers rather than EFO IDs, for example MONDO_0005148 for type 2 diabetes. Also use the queryString parameter rather than query, and resolve trait names through OLS before querying.

What are the limitations of eQTL-based variant interpretation?▼

GTEx eQTLs use bulk tissue v8 data, so cell-type-specific and splicing effects may be missed. L2G and CADD are computational predictions rather than experimental proof, and long-range regulatory effects beyond 1Mb are poorly captured.

When should I use variant interpretation instead of variant-to-mechanism?▼

Use variant interpretation for coding variant pathogenicity and ACMG classification. Use variant-to-mechanism when tracing a variant through regulatory context, target genes, and pathways to a full disease mechanism, especially for non-coding GWAS hits.

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