EtienneNtumba/PRSet-Tanzania

PRSet pathway-based PRS analysis and reports for the Tanzania sickle cell cohort. # PRSet Pathway Analysis: Fetal Hemoglobin in Tanzanian Sickle Cell Disease --- ## 📊 Overview This repository contains a comprehensive **pathway-based polygenic risk score (PRS) analysis** of fetal hemoglobin (HbF) levels in Tanzanian sickle cell disease (SCD) patients using **PRSet** (Polygenic Risk Score - competitive gene Set Test) implemented in PRSice-2. ### Study Highlights - 🧬 **1,944 biological pathways** tested across 4 complementary databases - 👥 **1,527 individuals** from Tanzania (held-out validation cohort) - 📈 **8.4 million SNPs** from GWAS summary statistics - 🔬 **Competitive permutation testing** (1,000-5,000 permutations) - 🌍 **African population** - addressing underrepresentation in genetic research - 📝 **Transparent reporting** - including negative results ### Key Finding **No statistically significant pathway enrichment detected** after rigorous competitive permutation testing. This important **negative result** suggests that HbF genetic architecture in this cohort is **oligogenic** (dominated by few major loci like BCL11A) rather than **polygenic** (distributed across many pathways). --- ## 📑 Table of Contents - Background - Study Design - Pathway Databases - Methods - Results Summary - Repository Structure - Requirements - Installation - Usage - Interpretation - Citation - Team - License --- ## Background ### Why Pathway Analysis? Genome-wide association studies (GWAS) identify individual genetic variants, but **pathway-based analyses** offer complementary insights by: 1. **Aggregating weak signals** across functionally related genes 2. **Improving statistical power** for distributed polygenic effects 3. **Providing biological interpretation** through pathway enrichment 4. **Revealing mechanisms** not apparent from single-variant analysis ### Fetal Hemoglobin in Sickle Cell Disease **Fetal hemoglobin (HbF)** is the most important genetic modifier of SCD severity: - **Higher HbF** → Reduced sickling, fewer complications, be …