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However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 single nucleotide polymorphisms (SNPs) and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended human leukocyte antigen (HLA) region and autoimmune disorders. We found an association between a diplotype covering the homeostatic iron regulator (HFE) gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (p-value = 1.82 \u00d7 10\n                    <jats:sup>\u221211<\/jats:sup>\n                    ). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.\n                  <\/jats:p>","DOI":"10.7554\/elife.81698","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T12:05:20Z","timestamp":1718971520000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81698","source":"Crossref","is-referenced-by-count":1,"title":["Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2747-2193","authenticated-orcid":true,"given":"Ardalan","family":"Naseri","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036nfer12","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Computer Science, University of Central Florida","place":["Orlando, United 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