The gray lines represent the heritability pattern for each trait in the cluster the purple line is the average over all the traits. (B) Heritability enrichment landscape over TADs for traits in the boundary-enriched cluster (n = 22). Some traits are strongly enriched for complex-trait heritability at TAD boundaries (“boundary-enriched” cluster, purple), whereas others are weakly depleted at TAD boundaries and enriched centrally within the TAD (“boundary-depleted” cluster, green). The heritability landscape across the 3D genome varies across phenotypes (A) Trait heritability patterns across the 3D genome organize into two clusters. These trends hold at different boundary definitions (40 kb and 200 kb), for germ-layer informed measures of cell type stability, and for other measurements of conservation, CTCF binding, and gene overlap (Figures S9–S12). All error bars signify 95% confidence intervals. (C–F) Across TAD-boundary stability quartiles, there is a correlation between increased cell-type stability and increased (C) complex-trait heritability enrichment (p = 0.006), (D) conserved bases (overlap with PhastCons elements, p = 6 × 10 −13), (E) CTCF binding (overlap with ChIP-seq peaks, p = 1 × 10 −83), and (F) housekeeping genes (p = 8 × 10 −58). The right axis and gray distribution represent the empirical cumulative distribution function (CDF) of boundary stability shown in the histogram. (B) Histogram of TAD boundaries by the number of cell types they are observed in (this quantifies their “stability,” colored by quartiles). Example boundaries of different stability quartiles are outlined in blue (quartile 1 in the darkest blue and quartile 4 in light blue). Each black line represents the genomic extent of a TAD. Stable TAD boundaries are enriched for complex-trait heritability, evolutionary conservation, and functional elements (A) Example TAD maps from 37 cell types (rows) for a 3.5 Mb window from human chromosome 1 (hg19). Trends are similar for fixed-size 100 kb TAD boundaries bookending TADs TAD boundaries are enriched for heritability (p = 0.001, Figure S3) and conservation (p = 3 × 10 −29, Figure S4A). Error bands signify 99% confidence intervals. They have a higher proportion of conserved bases (overlap with PhastCons elements p = 5 × 10 −11) (left blue axis) and a higher average conservation score across those overlapping PhastCons elements (right gray axis p = 3 × 10 −29). (C) Regions flanking TADs have increased sequence-level constraint. (B) Heritability patterns are consistent across the 3D genome landscape for 37 cell types. Enrichment was computed within 20 equally sized bins centered on each TAD ± 50% of its length. Regions flanking TADs are enriched for heritability of diverse common complex traits and evolutionary sequence conservation (A) Contribution to trait heritability (h 2) is enriched across variation in TAD-flanking regions and in the center of TADs when averaged across 41 common complex phenotypes and TAD maps from 37 cell types (p = 1 × 10 −193). Hi-C TAD stability Topologically associating domain complex disease evolutionary conservation genome 3D structure genome topology heritability.Ĭopyright © 2021 American Society of Human Genetics. Thus, considering TAD boundary stability across cell types provides valuable context for understanding the genome's functional landscape and enabling variant interpretation that takes 3D structure into account. Compared to boundaries unique to a specific cell type, boundaries stable across cell types are further enriched for complex-trait heritability, evolutionary constraint, CTCF binding, and housekeeping genes. Next, stratifying boundaries by their stability across cell types, we find substantial variation. We also show that TAD boundaries are more evolutionarily constrained than TADs. We demonstrate that genetic variation in TAD boundaries contributes more to complex-trait heritability, especially for immunologic, hematologic, and metabolic traits. By synthesizing TAD maps across 37 diverse cell types with 41 genome-wide association studies (GWASs), we investigate the differences in disease association and evolutionary pressure on variation in TADs versus TAD boundaries. Here, we investigate an attribute of 3D genome architecture-the stability of TAD boundaries across cell types-and demonstrate its relevance to understanding how genetic variation in TADs contributes to complex disease. TAD and TAD-boundary disruption have been implicated in rare-disease pathogenesis however, we have a limited framework for integrating TADs and their variation across cell types into the interpretation of common-trait-associated variants. The regions bordering TADs-TAD boundaries-contribute to the regulation of gene expression by restricting interactions of cis-regulatory sequences to their target genes. Topologically associating domains (TADs) are fundamental units of three-dimensional (3D) nuclear organization.
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