Background: Genome‑wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single‑nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three‑ dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome‑wide distribution of disease‑associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders. Results: For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of point‑ wise loci drawn at random either in the entire genome, or in the entire set of disease‑associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP‑based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non‑cancer diseases. Furthermore, different TAD border enrich‑ ments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. Conclusions: Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome‑wide association studies, by distinguishing two types of disease‑associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.