FORGE2

FORGE2 maps GWAS single nucleotide polymorphisms (SNPs) to cell type- and tissue-specific regulatory elements using an expanded atlas of DNase I hotspots, five histone mark categories, and 15 hidden Markov model (HMM) chromatin states to elucidate mechanisms of disease-associated variants.

Key Features:

• Expanded annotation atlas: Includes DNase I hotspots, five histone mark categories, and 15 hidden Markov model (HMM) chromatin states.
• Cell type- and tissue-specific enrichment detection: Identifies tissue- and cell type-specific signals and significant disease/trait-tissue associations from GWAS SNPs.
• GWAS catalogue analysis: Analyzed 3,604 GWAS from the NHGRI-EBI GWAS catalogue and reported significant associations for over half of the studies.
• Chromatin state dissection: Decomposes accessible chromatin enrichments into distinct chromatin states such as enhancers and active transcription start sites.
• Repressive-state enrichment detection: Detects tissue-specific enrichments for repressive chromatin states and histone marks linked to GWAS signals.
• Trait-specific findings: Reported more than 400 immune-related associations, over 30 heart-specific associations, and more than 60 brain-related associations.

Scientific Applications:

• Functional interpretation of GWAS signals: Maps SNPs to active regulatory elements to elucidate mechanisms underlying disease-associated variants.
• Tissue and cell type prioritization: Identifies tissues and cell types implicated in disease etiology by detecting enrichment patterns across chromatin annotations.
• Discovery of candidate regulatory mechanisms: Distinguishes enhancer, active transcription start site, and repressive element contributions to trait associations for hypothesis generation.

Methodology:

Uses an expanded annotation atlas (DNase I hotspots, five histone mark categories, 15 HMM chromatin states), maps SNPs from 3,604 NHGRI-EBI GWAS catalogue studies to these annotations, performs enrichment detection for tissue- and cell type-specific signals, decomposes accessible chromatin enrichments into chromatin states including enhancers and active transcription start sites, and detects tissue-specific enrichments for repressive chromatin states and histone marks.