Abstract
Inbreeding 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 corroborate those of several published studies. These results may imply that these traits have been associated with Darwinian fitness over evolutionary time. However, some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that alternative explanations for these associations have not been eliminated. 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.
Highlights
Inbreeding occurs when genetic relatives have offspring, and is associated with increased risk of disorders and decreased health and viability in offspring [1,2,3]
The distribution of runs of homozygosity (ROHs) lengths, FROH, and FSNP are shown in S1 and S2 Figs, and descriptive statistics are given in S1 Table
When we tested the effects of recent vs. distant inbreeding, the results for more recent inbreeding were similar to the full FROH models: income, grip strength, height, fluid intelligence score (FI), forced expiratory volume in 1 second (FEV1), at first sexual intercourse (AFS), and religious group participation were all associated with FROH_long, with the same direction of effect as the original models
Summary
Inbreeding occurs when genetic relatives have offspring, and is associated with increased risk of disorders and decreased health and viability in offspring [1,2,3]. Previous studies of FROH in humans have found evidence consistent with inbreeding depression for several complex traits, including height, forced expiratory volume in one second (FEV1), educational attainment, and cognitive ability (g) [7,8,9,10], with less conclusive evidence for an effect of inbreeding on psychiatric disorders [11,12] or risk factors for late-onset diseases like hypertension and other cardiovascular disease [13,14] These observed associations with FROH may suggest that directional selection has acted on these traits ancestrally
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