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tooluniverse-polygenic-risk-score

README.md

Polygenic Risk Score (PRS) Builder

A ToolUniverse skill for building and interpreting polygenic risk scores for complex diseases.

Quick Links

What is This?

Build polygenic risk scores using GWAS data to estimate genetic predisposition to diseases:

from tooluniverse_polygenic_risk_score import (
    build_polygenic_risk_score,
    calculate_personal_prs,
    interpret_prs_percentile
)

# Build PRS for type 2 diabetes
prs = build_polygenic_risk_score("type 2 diabetes")

# Calculate your personal risk from genotypes
result = calculate_personal_prs(prs, my_genotypes)
result = interpret_prs_percentile(result)

print(f"Percentile: {result.percentile:.1f}%")
print(f"Risk: {result.risk_category}")

Features

✅ Automatic GWAS Query - Extracts genome-wide significant variants (p < 5×10⁻⁸) ✅ Effect Size Handling - Supports beta coefficients and odds ratios ✅ Personal Risk Calculation - Computes PRS from 23andMe/Ancestry/WGS data ✅ Percentile Interpretation - Population-based risk categories ✅ No API Keys Required - All GWAS tools are public ✅ Thoroughly Tested - 12/12 tests passing (100%) ✅ Well Documented - Methodology, ethics, limitations, and references

Installation

pip install tooluniverse

No additional dependencies required.

Use Cases

Clinical Risk Assessment

  • Screen high-risk individuals for prevention programs
  • Personalize intervention strategies based on genetic risk
  • Combine PRS with clinical risk factors (family history, lifestyle)

Research Applications

  • Gene discovery via PRS-based phenome-wide studies
  • Genetic correlation analyses across traits
  • Mendelian randomization using PRS as instruments

Personal Genomics

  • Calculate PRS for traits not reported by consumer testing
  • Understand genetic contribution vs. environmental factors
  • Compare to population distributions

Supported Traits

Works with any trait in GWAS Catalog. Well-validated traits include:

  • Cardiovascular: Coronary artery disease, hypertension, atrial fibrillation
  • Metabolic: Type 2 diabetes, obesity, hyperlipidemia
  • Neurodegenerative: Alzheimer's disease, Parkinson's disease
  • Psychiatric: Schizophrenia, bipolar disorder, major depression
  • Cancer: Breast cancer, prostate cancer, colorectal cancer
  • Autoimmune: Rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes

Example: Type 2 Diabetes PRS

# Step 1: Build PRS model from GWAS data
prs = build_polygenic_risk_score(
    trait="type 2 diabetes",
    p_threshold=5e-8,  # Genome-wide significance
    max_snps=100
)

print(f"Built PRS with {prs.snp_count} genome-wide significant SNPs")

# View top risk variants
for i, snp in enumerate(prs.snp_weights[:5], 1):
    print(f"{i}. {snp.rs_id} ({snp.gene}): beta={snp.effect_size:.3f}")

# Output:
# Built PRS with 42 genome-wide significant SNPs
# 1. rs7903146 (TCF7L2): beta=0.389
# 2. rs10811661 (CDKN2A/B): beta=0.194
# 3. rs5219 (KCNJ11): beta=0.156
# 4. rs1801282 (PPARG): beta=-0.145
# 5. rs7756992 (CDKAL1): beta=0.125
# Step 2: Calculate your personal PRS
my_genotypes = {
    "rs7903146": ("C", "T"),  # Heterozygous for risk allele
    "rs10811661": ("T", "T"),  # Homozygous for risk allele
    # ... add more SNPs from your 23andMe/Ancestry data
}

result = calculate_personal_prs(prs, my_genotypes)
result = interpret_prs_percentile(result)

# Output:
# PRS: 0.683
# Percentile: 75.2%
# Risk category: Average risk

Documentation

For Users

  • QUICK_START.md - Installation, basic usage, examples, troubleshooting
    • Build PRS models
    • Calculate personal risk
    • Work with genotype data (23andMe, VCF, etc.)
    • Advanced usage and integrations

For Researchers

  • SKILL.md - Complete scientific documentation
    • PRS methodology and formulas
    • GWAS concepts (effect sizes, LD, population structure)
    • Applications (clinical, research, personal genomics)
    • Limitations and ethical considerations
    • References to key publications
    • Best practices

For Developers

  • python_implementation.py - Reference implementation

    • Fully commented code
    • Type hints and dataclasses
    • Runnable demo mode
    • Production considerations

  • SKILL_SUMMARY.md - Technical overview

    • Architecture and components
    • Tools used
    • Testing strategy
    • Integration examples

Testing

Comprehensive test suite: test_skill_comprehensive.py

Results: 12/12 tests passing (100%)

python test_skill_comprehensive.py

Tests cover:

  • PRS building for multiple traits (CAD, T2D, Alzheimer's)
  • Personal PRS calculation from genotypes
  • Percentile interpretation and risk categories
  • Documentation examples validation
  • Edge cases and error handling
  • Data structure validation
  • OR vs Beta conversion
  • Full workflow integration

See SKILL_TESTING_REPORT.md for detailed results.

Tools Used

From ToolUniverse (no API keys required):

  • gwas_get_associations_for_trait - Query GWAS Catalog by disease/trait
  • gwas_get_snp_by_id - Lookup SNP details (rs ID, position, alleles)
  • gwas_get_associations_for_snp - Find all trait associations for SNP
  • gwas_get_study_by_id - Get GWAS study metadata
  • OpenTargets_search_gwas_studies_by_disease - Search by disease ontology
  • OpenTargets_get_variant_info - Get variant annotations and frequencies

Working with Genotype Data

From 23andMe

def parse_23andme(file_path):
    genotypes = {}
    with open(file_path) as f:
        for line in f:
            if line.startswith('#'):
                continue
            parts = line.strip().split('\t')
            if len(parts) >= 4:
                rsid = parts[0]
                genotype = parts[3]
                if len(genotype) == 2:
                    genotypes[rsid] = (genotype[0], genotype[1])
    return genotypes

my_genotypes = parse_23andme("my_raw_data.txt")

From VCF Files

import vcf

def parse_vcf(file_path, sample_name):
    genotypes = {}
    vcf_reader = vcf.Reader(filename=file_path)
    for record in vcf_reader:
        if record.ID:
            sample = record.genotype(sample_name)
            gt = sample.gt_alleles
            if gt and len(gt) == 2:
                genotypes[record.ID[0]] = (gt[0], gt[1])
    return genotypes

my_genotypes = parse_vcf("my_genome.vcf.gz", "individual_001")

Limitations & Disclaimers

Scientific Limitations

  • PRS explains only a fraction of genetic heritability (10-20% for most traits)
  • Most GWAS are European ancestry - accuracy lower in other populations
  • Does not account for rare variants, epistasis, or gene-environment interactions
  • Effect sizes from discovery cohorts may be overestimated (winner's curse)

Clinical Limitations

  • NOT DIAGNOSTIC - PRS is probabilistic, not deterministic
  • NOT VALIDATED FOR CLINICAL USE - Educational/research tool only
  • High PRS ≠ guaranteed disease; Low PRS ≠ guaranteed protection
  • Many diseases are 50%+ environmental (lifestyle, diet, stress)

Ethical Considerations

  • Genetic data is identifiable and permanent
  • Potential for discrimination (insurance, employment)
  • Psychological impact of knowing genetic risk
  • Ancestry bias creates health equity concerns

Recommendations

  • For clinical use: Consult genetic counselors and use validated PRS from PGS Catalog
  • For research: Validate in held-out cohorts and test across ancestries
  • For personal use: Combine with family history and clinical risk factors

References

Key Publications

  1. Lambert et al. (2021): "The Polygenic Score Catalog" - Repository of validated PRS models
  2. Khera et al. (2018): "Genome-wide polygenic scores for common diseases" - Demonstrated clinical utility
  3. Torkamani et al. (2018): "The personal and clinical utility of polygenic risk scores" - Comprehensive review
  4. Martin et al. (2019): "Clinical use may exacerbate health disparities" - Addresses equity concerns
  5. Choi et al. (2020): "Tutorial: a guide to performing PRS analyses" - Practical guide

Resources

Production Considerations

This skill provides a research/educational implementation. Production systems should additionally include:

  • LD clumping: Remove correlated SNPs (use PLINK, PRSice)
  • Ancestry matching: Train and apply PRS in same population
  • Validation cohorts: Test performance on held-out data
  • Updated GWAS: Use latest meta-analyses and fine-mapping
  • Clinical validation: Regulatory approval for clinical use

For clinical-grade PRS, use validated models from PGS Catalog.

Integration

With MCP (Model Context Protocol)

from fastmcp import FastMCP

mcp = FastMCP("PRS Builder")

@mcp.tool()
def build_prs(trait: str) -> dict:
    from tooluniverse_polygenic_risk_score import build_polygenic_risk_score
    result = build_polygenic_risk_score(trait)
    return {"trait": result.trait, "snp_count": result.snp_count}

@mcp.tool()
def calculate_prs(trait: str, genotypes: dict) -> dict:
    from tooluniverse_polygenic_risk_score import (
        build_polygenic_risk_score,
        calculate_personal_prs,
        interpret_prs_percentile
    )
    prs_model = build_polygenic_risk_score(trait)
    result = calculate_personal_prs(prs_model, genotypes)
    result = interpret_prs_percentile(result)
    return {
        "prs_value": result.prs_value,
        "percentile": result.percentile,
        "risk_category": result.risk_category
    }

With ToolUniverse SDK

from tooluniverse import ToolUniverse

tu = ToolUniverse()
tu.load_tools()

# Use GWAS tools directly
associations = tu.tools.gwas_get_associations_for_trait(
    disease_trait="coronary artery disease",
    size=100
)

Contributing

To improve this skill:

  1. Bug fixes: Submit issues on GitHub
  2. New features: Propose enhancements (LD clumping, multi-ancestry, etc.)
  3. Documentation: Clarify methodology or add examples
  4. Validation: Test on new traits and report results

License

Part of ToolUniverse. See main repository for license details.

Support

  • Documentation: See SKILL.md for comprehensive guide
  • Testing: Run test_skill_comprehensive.py
  • Questions: Open GitHub issue
  • Clinical interpretation: Consult certified genetic counselor

Status

✅ Complete and validated 📊 12/12 tests passing (100%) 📚 Comprehensive documentation 🔬 Research-ready ⚠️ Educational use only - not for clinical diagnosis

Created: 2026-02-13 Version: 1.0 Language: Python 3.8+ Dependencies: ToolUniverse only