BACH2_hbf

Scripts and supplementary files for the manuscript:

"Human genetics implicates a BACH2-NRF2 axis in fetal hemoglobin activation"
Preprint: https://www.medrxiv.org/content/10.1101/2023.03.24.23287659v3

Table of contents

• Overview
• Repository structure
• StatGen_analysis/ — Statistical genetics (meta-GWAS, fine-mapping, heritability, genetic correlation)
• SCAVENGE_analysis/ — Trait-relevant cell-type enrichment from scATAC-seq
• BulkRNAseq_analysis/ — Bulk RNA-seq processing and differential expression
• CUTRUN_analysis/ — CUT&RUN chromatin profiling (BACH2 and NRF2 binding)

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Overview

The analyses in this repository support the identification of a BACH2–NRF2 regulatory axis controlling fetal hemoglobin (HbF) expression. The workflow broadly proceeds as follows:

1. Statistical genetics — Meta-GWAS, fine-mapping, and heritability/genetic-correlation analyses identify and characterize HbF-associated loci, implicating BACH2.
2. SCAVENGE — Propagates fine-mapped GWAS variant scores across a bone marrow scATAC-seq cell graph to identify the hematopoietic cell types most relevant to HbF regulation.
3. Bulk RNA-seq — Characterizes transcriptional changes upon BACH2 knockdown, highlighting upregulation of fetal globin genes (HBG1/HBG2).
4. CUT&RUN — Maps BACH2 and NRF2 occupancy genome-wide in erythroid cells, linking GWAS variants to regulatory elements.

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Repository structure

Directory	Description
StatGen_analysis/	Meta-GWAS, COJO fine-mapping, SNP heritability estimation, and genetic correlation analyses
SCAVENGE_analysis/	Per-cell trait relevance scoring using SCAVENGE on Granja 2019 bone marrow scATAC-seq data
BulkRNAseq_analysis/	STAR alignment, featureCounts quantification, and DESeq2 differential expression for BACH2-sh2 vs. scramble control
CUTRUN_analysis/	End-to-end CUT&RUN pipeline: trimming, spike-in normalization, hg38 alignment, peak calling, bigWig tracks, and FIMO motif scanning