Evidence of Inbreeding Depression on Human Height

Abstract

Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

Excess of runs of homozygosity is associated with severe cognitive impairment in intellectual disability

“…9 The rate of long ROHs in the two groups was calculated regardless of the array type because all the arrays used are able to detect them. The level of significance for the different proportions of long ROHs in the two groups was obtained with the χ 2 test.…”

“…[6][7][8] The widespread availability of high-density singlenucleotide polymorphism (SNP) array data in the past few years has made possible the study runs of homozygosity (ROHs), long genomic stretches of DNA inherited identical-by-descent from the same ancestor that are directly correlated to the inbreeding level. 9 In this scenario, ROHs have become a powerful tool for investigating the role of distant inbreeding in any population on a large scale. The cumulative effect of multiple recessive variants, as tested in ROH studies, plays an important role in the etiology of complex diseases.…”

Measuring individual inbreeding in the age of genomics: marker-based measures are better than pedigrees

“…We conducted 'LD pruning' because F E assumes all markers are in linkage equilibrium (Polašek et al, 2010). Additionally, F ROH is typically estimated after LD pruning to avoid detecting fixed or nearly fixed ROH arising due to ancient population processes (for example, selective sweeps) (for example, McQuillan et al, 2012). For LD pruning, we used a sliding window of 25 SNPs, a step size of 10 SNPs and we removed one SNP from each pair in a window above the LD threshold of r 2 = 0.5.…”

“…Other measures of IBD G use mapped genetic markers to identify IBD chromosome segments (referred to here as IBD tracts), which are characterized by long contiguous runs of homozygosity (ROH) at mapped genetic markers (Chapman and Thompson, 2003;McQuillan et al, 2008). The F ROH statistic estimates IBD G as the proportion of the genome within inferred ROH that satisfy user-defined criteria (for example, number of SNPs, physical length and SNP density) (Purcell et al, 2007;McQuillan et al, 2012). Leutenegger et al (2003) introduced a maximum likelihood estimator (F E ) that uses mapped genetic markers and a hidden Markov model to identify putative IBD tracts and to estimate IBD G .…”

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

“…7 Such an association with inbreeding, as measured by runs of homozygous polymorphisms (ROH), has previously been identified with several behavioural traits, such as schizophrenia, Parkinson's disease and personality measures, [8][9][10] as well as non-behavioural traits such as height. 11 The relationship between inbreeding on a population level and cognitive ability is particularly interesting due to assortative mating, non-random mating, which is greater for cognitive ability than for other behavioural traits, as well as physical traits such as height and weight. Positive assortative mating has been reported for cognitive ability, particularly for verbal traits, with spousal correlations generally around 0.5.…”