Variance components in genetic analyses

Pedigree-based analyses allow investigation of genetic and environmental influences on anatomy, physiology, and behaviour.

Methods based on components of variance have been used extensively to assess genetic influences and identify loci associated with various traits quantifying aspects of anatomy, physiology, and behaviour, in both normal and pathological conditions. In an earlier post, indices of genetic resemblance between relatives were presented, and in the last post, the kinship matrix was defined. In this post, these topics are used to present a basic model that allows partitioning of the phenotypic variance into sources of variation that can be ascribed to genetic, environmental, and other factors.

A simple model

Consider the model:

\mathbf{Y} = \mathbf{X}\mathbf{B} + \boldsymbol{\Upsilon}

where, for S subjects, T traits, P covariates and K variance components, \mathbf{Y}_{S \times T} are the observed trait values for each subject, \mathbf{X}_{S \times P} is a matrix of covariates, \mathbf{B}_{P \times T} is a matrix of unknown covariates’ weights, and \boldsymbol{\Upsilon}_{S \times T} are the residuals after the covariates have been taken into account.

The elements of each column t of \boldsymbol{\Upsilon} are assumed to follow a multivariate normal distribution \mathcal{N}\left(0;\mathbf{S}\right), where \mathbf{S} is the between-subject covariance matrix. The elements of each row s of \boldsymbol{\Upsilon} are assumed to follow a normal distribution \mathcal{N}\left(0;\mathbf{R}\right), where \mathbf{R} is the between-trait covariance matrix. Both \mathbf{R} and \mathbf{S} are seen as the sum of K variance components, i.e. \mathbf{R} = \sum_{k} \mathbf{R}_{k} and \mathbf{S} = \sum_{k} \mathbf{S}_{k}. For a discussion on these equalities, see Eisenhart (1947) [see references at the end].

An equivalent model

The same model can be written in an alternative way. Let \mathbf{y}_{S \cdot T \times 1} be the stacked vector of traits, \mathbf{\tilde{X}}_{S \cdot T \times P \cdot T} = \mathbf{X} \otimes \mathbf{I}_{T \times T} is the matrix of covariates, \boldsymbol{\beta}_{P \cdot T \times 1} the vector with the covariates’ weights, \boldsymbol{\upsilon}_{S \cdot T \times 1} the residuals after the covariates have been taken into account, and \otimes represent the Kronecker product. The model can then be written as:

\mathbf{y} = \mathbf{\tilde{X}}\boldsymbol{\beta} + \boldsymbol{\upsilon}

The stacked residuals \boldsymbol{\upsilon} is assumed to follow a multivariate normal distribution \mathcal{N}\left(0;\boldsymbol{\Omega}\right), where \boldsymbol{\Omega} can be seen as the sum of K variance components:

\boldsymbol{\Omega} = \sum_{k} \mathbf{R}_k \otimes \mathbf{S}_k

The \boldsymbol{\Omega} here is the same as in Almasy and Blangero (1998). \mathbf{S}_k can be modelled as correlation matrices. The associated scalars are absorbed into the (to be estimated) \mathbf{R}_k. \mathbf{R} is the phenotypic covariance matrix between the residuals of the traits:

\mathbf{R} = \left[ \begin{array}{ccc} \mathsf{Var}(\upsilon_1) & \cdots & \mathsf{Cov}(\upsilon_1,\upsilon_T) \\ \vdots & \ddots & \vdots \\ \mathsf{Cov}(\upsilon_T,\upsilon_1) & \cdots & \mathsf{Var}(\upsilon_T) \end{array}\right]

whereas each \mathbf{R}_k are the share of these covariances attributable to the k-th component:

\mathbf{R}_k = \left[ \begin{array}{ccccc} \mathsf{Var}_k(\upsilon_1) & \cdots & \mathsf{Cov}_k(\upsilon_1,\upsilon_T) \\ \vdots & \ddots & \vdots \\ \mathsf{Cov}_k(\upsilon_T,\upsilon_1) & \cdots & \mathsf{Var}_k(\upsilon_T) \end{array}\right]

\mathbf{R} can be converted to a between-trait phenotypic correlation matrix \mathbf{\mathring{R}} as:

\mathbf{\mathring{R}} = \left[ \begin{array}{ccc} \frac{\mathsf{Var}(\upsilon_1)}{\mathsf{Var}(\upsilon_1)} & \cdots & \frac{\mathsf{Cov}(\upsilon_1,\upsilon_T)}{\left(\mathsf{Var}(\upsilon_1)\mathsf{Var}(\upsilon_T)\right)^{1/2}} \\ \vdots & \ddots & \vdots \\ \frac{\mathsf{Cov}(\upsilon_1,\upsilon_T)}{\left(\mathsf{Var}(\upsilon_1)\mathsf{Var}(\upsilon_T)\right)^{1/2}} & \cdots & \frac{\mathsf{Var}(\upsilon_T)}{\mathsf{Var}(\upsilon_T)} \end{array}\right]

The above phenotypic correlation matrix has unit diagonal and can still be fractioned into their K components:

\mathbf{\mathring{R}}_k = \left[ \begin{array}{ccc} \frac{\mathsf{Var}_k(\upsilon_1)}{\mathsf{Var}(\upsilon_1)} & \cdots & \frac{\mathsf{Cov}_k(\upsilon_1,\upsilon_T)}{\left(\mathsf{Var}(\upsilon_1)\mathsf{Var}(\upsilon_T)\right)^{1/2}} \\ \vdots & \ddots & \vdots \\ \frac{\mathsf{Cov}_k(\upsilon_T,\upsilon_1)}{\left(\mathsf{Var}(\upsilon_T)\mathsf{Var}(\upsilon_1)\right)^{1/2}} & \cdots & \frac{\mathsf{Var}_k(\upsilon_T)}{\mathsf{Var}(\upsilon_T)} \end{array}\right]

The relationship \mathbf{\mathring{R}} = \sum_k \mathbf{\mathring{R}}_k holds. The diagonal elements of \mathbf{\mathring{R}}_k may receive particular names, e.g., heritability, environmentability, dominance effects, shared enviromental effects, etc., depending on what is modelled in the corresponding \mathbf{S}_k. However, the off-diagonal elements of \mathbf{\mathring{R}}_k are not the \rho_k that correspond, e.g. to the genetic or environmental correlation. These off-diagonal elements are instead the signed \text{\textsc{erv}} when \mathbf{S}_k=2\cdot\boldsymbol{\Phi}, or their \text{\textsc{erv}}_k-equivalent for other variance components (see below). In this particular case, they can also be called “bivariate heritabilities” (Falconer and MacKay, 1996). A matrix \mathbf{\breve{R}}_k that contains these correlations \rho_k, which are the fraction of the variance attributable to the k-th component that is shared between pairs of traits is given by:

\mathbf{\breve{R}}_k = \left[ \begin{array}{ccc} \frac{\mathsf{Var}_k(\upsilon_1)}{\mathsf{Var}_k(\upsilon_1)} & \cdots & \frac{\mathsf{Cov}_k(\upsilon_1,\upsilon_T)}{\left(\mathsf{Var}_k(\upsilon_1)\mathsf{Var}_k(\upsilon_T)\right)^{1/2}} \\ \vdots & \ddots & \vdots \\ \frac{\mathsf{Cov}_k(\upsilon_T,\upsilon_1)}{\left(\mathsf{Var}_k(\upsilon_T)\mathsf{Var}_k(\upsilon_1)\right)^{1/2}} & \cdots & \frac{\mathsf{Var}_k(\upsilon_T)}{\mathsf{Var}_k(\upsilon_T)} \end{array}\right]

As for the phenotypic correlation matrix, each \mathbf{\breve{R}}_k has unit diagonal.

The most common case

A particular case is when \mathbf{S}_1 = 2\cdot\boldsymbol{\Phi}, the coefficient of familial relationship between subjects, and \mathbf{S}_2 = \mathbf{I}_{S \times S}. In this case, the T diagonal elements of \mathbf{\mathring{R}}_1 represent the heritability (h_t^2) for each trait t. The diagonal of \mathbf{\mathring{R}}_2 contains 1-h_t^2, the environmentability. The off-diagonal elements of \mathbf{\mathring{R}}_1 contain the signed \text{\textsc{erv}} (see below). The genetic correlations, \rho_g are the off-diagonal elements of \mathbf{\breve{R}}_1, whereas the off-diagonal elements of \mathbf{\breve{R}}_2 are \rho_e, the environmental correlations between traits. In this particular case, the components of \mathbf{R}, i.e., \mathbf{R}_k are equivalent to \mathbf{G} and \mathbf{E} covariance matrices as in Almasy et al (1997).

Relationship with the ERV

To see how the off-diagonal elements of \mathbf{\mathring{R}}_k are the signed Endophenotypic Ranking Values for each of the k-th variance component, \text{\textsc{erv}}_k (Glahn et al, 2011), note that for a pair of traits i and j:

\mathring{R}_{kij} = \frac{\mathsf{Cov}_k(\upsilon_i,\upsilon_j)}{\left(\mathsf{Var}(\upsilon_i)\mathsf{Var}(\upsilon_j)\right)^{1/2}}

Multiplying both numerator and denominator by \left(\mathsf{Var}_k(\upsilon_i)\mathsf{Var}_k(\upsilon_j)\right)^{1/2} and rearranging the terms gives:

\mathring{R}_{kij} = \frac{\mathsf{Cov}_k(\upsilon_i,\upsilon_j)}{\left(\mathsf{Var}_k(\upsilon_i)\mathsf{Var}_k(\upsilon_j)\right)^{1/2}} \left(\frac{\mathsf{Var}_k(\upsilon_i)}{\mathsf{Var}(\upsilon_i)}\frac{\mathsf{Var}_k(\upsilon_j)}{\mathsf{Var}(\upsilon_j)}\right)^{1/2}

When \mathbf{S}_k = 2\cdot\boldsymbol{\Phi}, the above reduces to \mathring{R}_{kij} = \rho_k \sqrt{h^2_i h^2_j}, which is the signed version of \text{\textsc{erv}}=\left|\rho_g\sqrt{h_i^2h_j^2}\right| when k is the genetic component.

Positive-definiteness

\mathbf{R} and \mathbf{R}_k are covariance matrices and so, are positive-definite, whereas the correlation matrices \mathbf{\mathring{R}}, \mathbf{\mathring{R}}_k and \mathbf{\breve{R}}_k are positive-semidefinite. A hybrid matrix that does not have to be positive-definite or semidefinite is:

\mathbf{\check{R}}_k = \mathbf{I} \odot \mathbf{\mathring{R}}_k + \left(\mathbf{J}-\mathbf{I}\right) \odot \mathbf{\breve{R}}_k

where \mathbf{J} is a matrix of ones, \mathbf{I} is the identity, both of size T \times T, and \odot is the Hadamard product. An example of such matrix of practical use is to show concisely the heritabilities for each trait in the diagonal and the genetic correlations in the off-diagonal.

Cauchy-Schwarz

Algorithmic advantages can be obtained from the positive-definiteness of \mathbf{\mathring{R}}_k. The Cauchy–Schwarz theorem (Cauchy, 1821; Schwarz, 1888) states that:

\mathring{R}_{kij} \leqslant \sqrt{\mathring{R}_{kii}\mathring{R}_{kjj}}

Hence, the bounds for the off-diagonal elements can be known from the diagonal elements, which, by their turn, are estimated in a simpler, univariate model.

The Cauchy-Schwarz inequality imposes limits on the off-diagonal values of the matrix that contains the genetic covariances (or bivariate heritabilities).

Parameter estimation

Under the multivariate normal assumption, the parameters can be estimated maximising the following loglikelihood function:

\mathcal{L}\left(\mathbf{R}_k,\boldsymbol{\beta}\Big|\mathbf{y},\mathbf{\tilde{X}}\right) = -\frac{1}{2} \left(N \ln 2\pi + \ln \left|\boldsymbol{\Omega}\right| + \left(\mathbf{y}-\mathbf{\tilde{X}}\boldsymbol{\beta}\right)'\boldsymbol{\Omega}\left(\mathbf{y}-\mathbf{\tilde{X}}\boldsymbol{\beta}\right)\right)

where N=S \cdot T is the number of observations on the stacked vector \mathbf{y}. Unbiased estimates for \boldsymbol{\beta}, although inefficient and inappropriate for hypothesis testing, can be obtained with ordinary least squares (OLS).

Parametric inference

Hypothesis testing can be performed with the likelihood ratio test (LRT), i.e., the test statistic is produced by subtracting from the loglikelihood of the model in which all the parameters are free to vary (\mathcal{L}_1), the loglikelihood of a model in which the parameters being tested are constrained to zero, the null model (\mathcal{L}_0). The statistic is given by \lambda = 2\left(\mathcal{L}_1-\mathcal{L}_0\right) (Wilks, 1938), which here is asymptotically distributed as a 50:50 mixture of a \chi^2_0 and \chi^2_{\text{df}} distributions, where df is the number of parameters being tested and free to vary in the unconstrained model (Self and Liang, 1987). From this distribution the p-values can be obtained.

References

The photograph at the top (elephants) is by Anja Osenberg and was generously released into public domain.

One thought on “Variance components in genetic analyses

  1. Pingback: Understanding the kinship matrix | Brainder.

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