A Bayesian spatial model for imaging genetics.

We develop a Bayesian bivariate spatial model for multivariate regression analysis applicable to studies examining the influence of genetic variation on brain structure. Our model is motivated by an imaging genetics study of the Alzheimer's Disease Neuroimaging Initiative (ADNI), where the objective is to examine the association between images of volumetric and cortical thickness values summarizing the structure of the brain as measured by magnetic resonance imaging (MRI) and a set of 486 single nucleotide polymorphism (SNPs) from 33 Alzheimer's disease (AD) candidate genes obtained from 632 subjects. A bivariate spatial process model is developed to accommodate the correlation structures typically seen in structural brain imaging data. First, we allow for spatial correlation on a graph structure in the imaging phenotypes obtained from a neighborhood matrix for measures on the same hemisphere of the brain. Second, we allow for correlation in the same measures obtained from different hemispheres (left/right) of the brain. We develop a mean-field variational Bayes algorithm and a Gibbs sampling algorithm to fit the model. We also incorporate Bayesian false discovery rate (FDR) procedures to select SNPs. We implement the methodology in a new release of the R package bgsmtr. We show that the new spatial model demonstrates superior performance over a standard model in our application. Data used in the preparation of this article were obtained from the ADNI database (https://adni.loni.usc.edu).

Efficient computation of the kinship coefficients.

MOTIVATION: For families, kinship coefficients are quantifications of the amount of genetic sharing between a pair of individuals. These coefficients are critical for understanding the breeding habits and genetic diversity of diploid populations. Historically, computations of the inbreeding coefficient were used to prohibit inbred marriages and prohibit breeding of some pairs of pedigree animals. Such prohibitions foster genetic diversity and help prevent recessive Mendelian disease at a population level. RESULTS: This paper gives the fastest known algorithms for computing the kinship coefficient of a set of individuals with a known pedigree, especially for large pedigrees. These algorithms outperform existing methods. In addition, the algorithms given here consider the possibility that the founders of the known pedigree may themselves be inbred and compute the appropriate inbreeding-adjusted kinship coefficients, which has not been addressed in literature. The exact kinship algorithm has running-time O(n2) for an n-individual pedigree. The recursive-cut exact kinship algorithm has running time O(s2m) where s is the number of individuals in the largest segment of the pedigree and m is the number of cuts. The approximate algorithm has running-time O(nd) for an n-individual pedigree on which to estimate the kinship coefficients of n individuals of interest from n founder kinship coefficients and d is the number of samples. AVAILABILITY AND IMPLEMENTATION: The above polynomial-time exact algorithm and the linear-time approximation algorithms are implemented as PedKin in C++ and are available under the GNU GPL v2.0 open source license. The PedKin source code is available at: http://www.intrepidnetcomputing.com/research/code/.

Genome-Wide Association with Uncertainty in the Genetic Similarity Matrix.

Genome-wide association studies (GWASs) are often confounded by population stratification and structure. Linear mixed models (LMMs) are a powerful class of methods for uncovering genetic effects, while controlling for such confounding. LMMs include random effects for a genetic similarity matrix, and they assume that a true genetic similarity matrix is known. However, uncertainty about the phylogenetic structure of a study population may degrade the quality of LMM results. This may happen in bacterial studies in which the number of samples or loci is small, or in studies with low-quality genotyping. In this study, we develop methods for linear mixed models in which the genetic similarity matrix is unknown and is derived from Markov chain Monte Carlo estimates of the phylogeny. We apply our model to a GWAS of multidrug resistance in tuberculosis, and illustrate our methods on simulated data.

Estimating Genetic Similarity Matrices Using Phylogenies.

Genetic similarity is a measure of the genetic relatedness among individuals. The standard method for computing these matrices involves the inner product of observed genetic variants. Such an approach is inaccurate or impossible if genotypes are not available, or not densely sampled, or of poor quality (e.g., genetic analysis of extinct species). We provide a new method for computing genetic similarities among individuals using phylogenetic trees. Our method can supplement (or stand in for) computations based on genotypes. We provide simulations suggesting that the genetic similarity matrices computed from trees are consistent with those computed from genotypes. With our methods, quantitative analysis on genetic traits and analysis of heritability and coheritability can be conducted directly using genetic similarity matrices and so in the absence of genotype data, or under uncertainty in the phylogenetic tree. We use simulation studies to demonstrate the advantages of our method, and we provide applications to data.