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The heritability of human disease: estimation, uses and abuses

Key Points

  • Most human diseases are dichotomous and are measured on a binary scale (disease absent (0) or present (1)). Some of the observed phenotypic variation of disease can be attributed to genetic variation.

  • Heritability is the ratio of the genetic variation to the phenotypic variation. Its estimates are specific to the population, disease and circumstances on which it is estimated.

  • Methods to estimate heritability for continuous traits do not directly apply to disease, and heritability is often estimated on an assumed normally distributed liability that underlies disease. This is called the heritability of liability to disease (hx2) and should be distinguished from the heritability of disease in the observed scale or disease itself (h0/12).

  • Methods of estimation based on mixed linear models have the ability to exploit data composed of various relatives and are the recommended methods of estimation in practice.

  • Difficulties of estimation, potential biases and a lack of consistent interpretation have made heritability a controversial summary statistic of familial aggregation of disease.

  • Despite its caveats, heritability is the single most useful measure of familial aggregation of disease. The heritability captures information from multiple relatives and can be interpreted in a wider context than competing measures such as the sibling relative risk, which is useful only in the context of siblings. Moreover, unlike other measures of familial aggregation, it attempts to separate environmental and genetic sources of familial correlation.

  • The main sources of bias in heritability estimates are common environmental factors, genotype-by-environment interactions, disease diagnosis and ascertainment andthe change of scale from the observed to the liability scale when h0/12 is estimated.

  • Heritability estimates are useful because they set limits to the contribution of genetic factors to variation of disease; however, identifying genetic and environmental sources of familial covariance should remain the primary aim of future research.

Abstract

Relatives provide the basic material for the study of inheritance of human disease. However, the methodologies for the estimation of heritability and the interpretation of the results have been controversial. The debate arises from the plethora of methods used, the validity of the methodological assumptions and the inconsistent and sometimes erroneous genetic interpretations made. We will discuss how to estimate disease heritability, how to interpret it, how biases in heritability estimates arise and how heritability relates to other measures of familial disease aggregation.

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Figure 1: Comparison of the genotypic values of individuals on the observed and liability scale.
Figure 2: Proportion of total genetic variance, which is additive on the underlying scale, that becomes epistatic genetic variance on the observed scale.
Figure 3: Sibling recurrence risk for different patterns of family history as a function of the population prevalence.

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Acknowledgements

This work was supported by Cancer Research UK (C12229/A13154) and the UK Biotechnology and Biological Sciences Research Council (BB/K000195/1). We acknowledge the financial support provided by the MRC–HGU Core Fund and the Roslin Institute through its Strategic Programme Grant. We thank W. G. Hill for helpful comments on an earlier version of the manuscript.

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Nature Reviews Genetics Series on Study designs

Glossary

Tetrachoric correlation

An estimate of the correlation between two bivariate normal variables obtained from the 2 × 2 contingency table containing the counts of two categorical variables (for example, disease and non-disease in two types of relative).

Mixed linear models

Statistical models used to analyse grouped data. Grouped data, such as repeated measurements, generate within-group correlations that need to be accounted for to make correct inferences. In the context of heritability estimation, they separate fixed effects (for example, gender or age) from random effects (individuals).

Bayesian methods

Bayesian methods of inference combine prior beliefs about a hypothesis with the information provided by the available data to modify those prior beliefs. The stronger the prior beliefs are, the more data will be required to modify them. Bayesian methods could help inference that is based on small sample sizes, where maximum likelihood methods may fail.

Maximum likelihood methods

Methods or techniques used for statistical inference. These methods are used for deriving functions of the sample (technically called estimators) that when applied to particular samples give estimates of the population parameters. The maximum likelihood estimates of the unknown parameters are the most likely parameters to have generated the observed data.

Bias

A population parameter (for example, a variance) is estimated from a random population sample using an estimator (for example, a formula). An estimator is unbiased if the mean of the estimates it produces over many samples, regardless of their size, is the population parameter.

Additive genetic values

Also called breeding values, these are defined as the sum of the average effects of the alleles an individual carries and, in the context of disease, as the average disease risk a person will confer to their children. Both definitions are equivalent only when there is no interaction between loci.

Genotypic values

For a given genotype, these values are the expected phenotypes that arise from the combined expression of all of the genes contributing to the trait. In the context of disease, in the observed scale is the penetrance (that is, the probability of disease given the genotype).

Ascertainment

The process of identifying cases of disease in the population. Ascertainment and sampling are often used synonymously, especially when talking of ascertainment or sampling bias.

Index case

Also called proband; Falconer used the term propositi to refer to the probands. This is the patient within a family who is first recruited to the study. Because other relatives are actively recruited as a consequence of the index case recruitment, the families are not a representative sample of the general population.

Proband concordance rate

(qc). Defined as the proportion of twins with the disease of interest among twins who are independently ascertained. That is, each twin pair is counted once for each twin independently brought to the study. It can be computed as qtwin = 2n11/(2n11 + n10).

Nested models

Two statistical models are nested if both models contain the same terms and one model has at least one additional term. The model with the larger number of terms is the full model, and the other is the reduced model. For instance, model P = A + C + E is nested within P = A + D + C + E. Models P = A + C + E and P = A + D + E are non-nested.

Likelihood ratio test

(LRT). Used to compare how well a model (full model) and a subset of that model (reduced model) fit the data. It is calculated as LRT = −2ln(LReduced/LFull) and distributed as χr2 where r is the difference of parameters fitted in the two models.

Akaike information criterion

An approach used to compare non-nested models. The Akaike information criterion penalizes complicated models by adding two times the number of fitted parameters to twice the negative value of the maximum likelihood. The model with the smallest Akaike information criterion is chosen as the most parsimonious.

Identity-by-descent

Two alleles are identical-by-descent if they are a copy of the same allele carried in an ancestral individual.

Realized identity-by-descent

Actual, as opposed to expected, identity-by-descent sharing between pairs of individuals as estimated from their genotypes. It accounts for the deviations from the expected identity-by-descent values that arise from the random segregation of alleles.

Population attributable risk

Also called the population attributable fraction. For a given disease, risk factor and population, the population attributable risk for the population incidence rate is the fraction by which the incidence rate of the disease in the population would be reduced if the risk factor was eliminated.

Sequence-wide association studies

The extension of array-based genome-wide association studies to whole-genome sequence-based association studies.

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Tenesa, A., Haley, C. The heritability of human disease: estimation, uses and abuses. Nat Rev Genet 14, 139–149 (2013). https://doi.org/10.1038/nrg3377

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