Inbreeding depression on human complex traits

In many species the offspring of related parents suffer reduced survival, vigour and reproductive success – a phenomenon known in evolutionary genetics as inbreeding depression. Historically, inbreeding depression has been experimentally studied in model organisms and wild populations, but the huge quantities of human genetic and phenotype data being currently gathered provides new opportunities. In humans, it is well known that reproduction between close relatives (consanguinity) increases the risk of recessive Mendelian disorders, but the extent of inbreeding depression on complex traits remains less well-established – partly because effects are small, and consanguinity is often confounded by social and cultural factors. This thesis explores the characteristics of human inbreeding, identified in genetic microarray data as continuous Runs of Homozygous genotypes (ROH), in a worldwide consortium (ROHgen) with 1,246,000 genotyped samples, and in the richly phenotyped UK Biobank (UKB). In ROHgen, an estimated inbreeding coefficient (FROH) is associated with significant changes in 18 out of 49 complex traits investigated, and in UKB FROH is associated with at least 155 complex traits. Effect sizes are small, but almost exclusively deleterious to health and reproductive success, and appear to be caused by the increased homozygosity of rare, recessive variants within ROH segments. Importantly, a novel, within-siblings method is introduced which, with larger sample sizes, will eliminate any biases caused by social confounding. For now, sibling sample sizes are sufficient to determine that most complex traits associated with FROH have a substantial genetic component. The distribution of inbreeding depression effects throughout the human genome was investigated and found to be remarkably even with, intriguingly, no enrichment at protein-coding genes. This is consistent with the theory of mutation-selection balance where deleterious variants in less constrained regions reach higher allele frequencies. In summary, inbreeding depression occurs in modern humans and manifests as small deleterious effects on a multitude of human complex traits. These effects appear to be caused by numerous rare, recessive genetic variants evenly distributed throughout the genome