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, 2 (3), e41

Assumption-free Estimation of Heritability From Genome-Wide Identity-By-Descent Sharing Between Full Siblings

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Assumption-free Estimation of Heritability From Genome-Wide Identity-By-Descent Sharing Between Full Siblings

Peter M Visscher et al. PLoS Genet.

Abstract

The study of continuously varying, quantitative traits is important in evolutionary biology, agriculture, and medicine. Variation in such traits is attributable to many, possibly interacting, genes whose expression may be sensitive to the environment, which makes their dissection into underlying causative factors difficult. An important population parameter for quantitative traits is heritability, the proportion of total variance that is due to genetic factors. Response to artificial and natural selection and the degree of resemblance between relatives are all a function of this parameter. Following the classic paper by R. A. Fisher in 1918, the estimation of additive and dominance genetic variance and heritability in populations is based upon the expected proportion of genes shared between different types of relatives, and explicit, often controversial and untestable models of genetic and non-genetic causes of family resemblance. With genome-wide coverage of genetic markers it is now possible to estimate such parameters solely within families using the actual degree of identity-by-descent sharing between relatives. Using genome scans on 4,401 quasi-independent sib pairs of which 3,375 pairs had phenotypes, we estimated the heritability of height from empirical genome-wide identity-by-descent sharing, which varied from 0.374 to 0.617 (mean 0.498, standard deviation 0.036). The variance in identity-by-descent sharing per chromosome and per genome was consistent with theory. The maximum likelihood estimate of the heritability for height was 0.80 with no evidence for non-genetic causes of sib resemblance, consistent with results from independent twin and family studies but using an entirely separate source of information. Our application shows that it is feasible to estimate genetic variance solely from within-family segregation and provides an independent validation of previously untestable assumptions. Given sufficient data, our new paradigm will allow the estimation of genetic variation for disease susceptibility and quantitative traits that is free from confounding with non-genetic factors and will allow partitioning of genetic variation into additive and non-additive components.

Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Empirical Distribution of Actual Additive Genetic Relationships of 4,401 Quasi-Independent Pairs of Full Sibs
Histogram of the genome-wide additive genetic relationships of full-sib pairs estimated from genetic markers.
Figure 2
Figure 2. Comparison of the Empirical and Theoretical Standard Deviations in Genome-Wide Sharing in 4,401 Quasi-Independent Pairs of Full Sibs
IBD sharing (A) and genome-wide IBD2 sharing (B) from marker data on 22 autosomes. The x- and y- axes are the theoretical and empirical SD, respectively. Numbers around the regression line indicate chromosomes.
Figure 3
Figure 3. Correlation between Genome-Wide Mean IBD and Mean IBD2 Sharing
The x- and y- axes are the genome-wide additive and dominance relationships, respectively. Each point represents the genome-wide additive and dominance relationship for a sibling pair, estimated from genetic markers (n = 4,401 pairs).

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