Topologically associating domain boundaries that are stable across diverse cell types are evolutionarily constrained and enriched for heritability

Topologically associating domains (TADs) are fundamental units of three-dimensional (3D) nuclear organization. The regions bordering TADs-TAD boundaries-contribute to the regulation gene expression by restricting interactions cis-regulatory sequences their target genes. TAD and TAD-boundary disruption have been implicated in rare-disease pathogenesis; however, we a limited framework for integrating TADs variation across cell types into interpretation common-trait-associated variants. Here, investigate an attribute 3D genome architecture-the stability boundaries types-and demonstrate its relevance understanding how genetic contributes complex disease. By synthesizing maps 37 diverse with 41 genome-wide association studies (GWASs), differences disease evolutionary pressure on versus boundaries. We that more complex-trait heritability, especially immunologic, hematologic, metabolic traits. also show evolutionarily constrained than TADs. Next, stratifying types, find substantial variation. Compared unique specific type, stable further enriched constraint, CTCF binding, housekeeping Thus, considering boundary provides valuable context genome's functional landscape enabling variant takes structure account.