Runs of homozygosity: windows into population history and trait architecture

Key Points The inheritance of identical haplotypes from a common ancestor creates long tracts of homozygous genotypes known as runs of homozygosity (ROH). ROH are ubiquitous across human populations, and they correlate with pedigree inbreeding. Larger populations have fewer, shorter ROH, whereas isolated or bottlenecked populations have more, somewhat longer ROH. Admixed groups have the fewest ROH, whereas consanguineous communities carry very long ROH. Native American populations have the highest burdens of ROH in the world. ROH can be detected in microarray or whole-genome sequencing (WGS) data, using either observational approaches, for example, that implemented in PLINK, or model-based approaches. Simulations show that PLINK outperforms many other methods. ROH are non-randomly distributed across the genome, being more prevalent in areas of low recombination, but are also concentrated in small regions called ROH islands. Quantitative traits related to stature and cognition have been robustly associated with ROH burden, implying recessive variants contribute to their genetic architecture. Case–control analyses of ROH, on the other hand, appear more easily confounded by socioeconomic or cultural factors. Both megacohorts and special populations are now being used to investigate diverse aspects of the scope and mechanism of inbreeding depression in humans. Runs of homozygosity (ROH) are genomic regions of homozygosity where the identical maternal and paternal haplotypes are descended from a shared common ancestor, and they are well known to occur as a result of inbreeding. This article discusses strategies for detecting ROH, their underappreciated prevalence across diverse outbred populations and implications for complex traits and human disease. Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.