Genome-Wide Association Between Chromatin States and Complex Trait Heritability
DOI:
https://doi.org/10.5281/zenodo.22760732Keywords:
stratified LD score regression, heritability enrichment, chromatin state, ATAC-seq, GWAS, tissue-specific regulatory elements, complex traitsAbstract
Genome-wide association studies have identified thousands of loci associated with complex human traits and
diseases, but most associated variants fall outside protein-coding sequence, and determining which
cell-type-specific chromatin states carry disproportionate heritability for a given trait remains an important step
toward mechanistic interpretation of genome-wide association study findings. Here we generated chromatin
accessibility (ATAC-seq) and histone modification (H3K27ac, H3K4me1, H3K4me3, H3K27me3) maps across 41
primary human cell types and tissues not comprehensively represented in existing public chromatin state
references, and applied stratified linkage disequilibrium score regression to partition heritability for 28 complex traits
and diseases across cell-type-specific chromatin state annotations. Heritability enrichment was highly
cell-type-specific and trait-specific, with autoimmune and inflammatory traits showing the strongest enrichment in
immune cell active chromatin states, anthropometric traits showing strongest enrichment in a combination of
adipose and neuroendocrine cell states, and psychiatric traits showing strongest enrichment in neuronal and glial
active promoter and enhancer states, recapitulating expected biology and validating the approach. Beyond these
expected patterns, we identified 14 trait-cell-type enrichment pairs not previously reported in existing chromatin
state heritability partitioning resources, including significant enrichment of inflammatory bowel disease heritability in
a previously underrepresented intestinal stromal cell population and significant enrichment of bone mineral density
heritability in a periosteal progenitor cell population. Fine-mapping of genome-wide association study loci within
these newly implicated cell-type-specific active chromatin states nominated candidate causal variants and target
genes at 23 loci where the likely causal cell type had not been previously specified. These results extend the
catalogue of cell types carrying disproportionate heritability for complex traits and demonstrate the value of
expanding chromatin state references to previously underrepresented primary cell populations for genome-wide
association study interpretation.
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