Genomic partitioning of inbreeding depression in humans

Across species, offspring of related individuals often exhibit significant reduction in fitness-related traits, known as inbreeding depression (ID), yet the genetic and molecular basis for ID remains elusive. Here, we develop a method to quantify enrichment of ID within specific genomic annotations and apply it to human data. We analyzed the phenomes and genomes of similar to 350,000 unrelated participants of the UK Biobank and found, on average of over 11 traits, significant enrichment of ID within genomic regions with high recombination rates (>21-fold; p < 10(-5)), with conserved function across species (>19-fold; p < 10(-4)), and within regulatory elements such as DNase I hypersensitive sites (similar to 5-fold; p = 8.9 x 10(-7)). We also quantified enrichment of ID within trait-associated regions and found suggestive evidence that genomic regions contributing to additive genetic variance in the population are enriched for ID signal. We find strong correlations between functional enrichment of SNP-based heritability and that of ID (r = 0.8, standard error: 0.1). These findings provide empirical evidence that ID is most likely due to many partially recessive deleterious alleles in low linkage disequilibrium regions of the genome. Our study suggests that functional characterization of ID may further elucidate the genetic architectures and biological mechanisms underlying complex traits and diseases.

Automated summary

The study found significant enrichment of inbreeding depression (ID) in genomic regions with high recombination rates, conserved function across species, and regulatory elements. Additionally, regions associated with traits showed enrichment of ID signal. The functional enrichment of SNP-based heritability was strongly correlated with that of ID, indicating that ID is likely due to partially recessive deleterious alleles in low linkage disequilibrium regions of the genome.