Relationships between estimated autozygosity and complex traits in the UK Biobank

Abstract

AbstractInbreeding increases the risk of certain Mendelian disorders in humans but may also reduce fitness through its effects on complex traits and diseases. Such inbreeding depression is thought to occur due to increased homozygosity at causal variants that are recessive with respect to fitness. Until recently it has been difficult to amass large enough sample sizes to investigate the effects of inbreeding depression on complex traits using genome-wide single nucleotide polymorphism (SNP) data in population-based samples. Further, it is difficult to infer causation in analyses that relate degree of inbreeding to complex traits because confounding variables (e.g., education) may influence both the likelihood for parents to outbreed and offspring trait values. The present study used runs of homozygosity in genome-wide SNP data in up to 400,000 individuals in the UK Biobank to estimate the proportion of the autosome that exists in autozygous tracts—stretches of the genome which are identical due to a shared common ancestor. After multiple testing corrections and controlling for possible sociodemographic confounders, we found significant relationships in the predicted direction between estimated autozygosity and three of the 26 traits we investigated: age at first sexual intercourse, fluid intelligence, and forced expiratory volume in 1 second. Our findings for fluid intelligence and forced expiratory volume corroborate those of several published studies while the finding for age at first sexual intercourse was novel. These results may suggest that these traits have been associated with Darwinian fitness over evolutionary time, although there are other possible explanations for these associations that cannot be eliminated. Some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that care needs to be taken in the design and interpretation of ROH studies in order to glean reliable information about the genetic architecture and evolutionary history of complex traits.Author SummaryInbreeding is well known to increase the risk of rare, monogenic diseases, and there has been some evidence that it also affects complex traits, such as cognition and educational attainment. However, difficulties can arise when inferring causation in these types of analyses because of the potential for confounding variables (e.g., socioeconomic status) to bias the observed relationships between distant inbreeding and complex traits. In this investigation, we used single-nucleotide polymorphism data in a very large (N > 400,000) sample of seemingly outbred individuals to quantify the degree to which distant inbreeding is associated with 26 complex traits. We found robust evidence that distant inbreeding is inversely associated with fluid intelligence and a measure of lung function, and is positively associated with age at first sex, while other trait associations with inbreeding were attenuated after controlling for background sociodemographic characteristics. Our findings are consistent with evolutionary predictions that fluid intelligence, lung function, and age at first sex have been under selection pressures over time; however, they also suggest that confounding variables must be accounted for in order to reliably interpret results from these types of analyses.