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Gene discovery, estimation of heritability captured by SNP arrays, inference on genetic architecture and prediction analyses of complex traits are usually performed using different statistical models and methods, leading to inefficiency and loss of power. Here we use a Bayesian mixture model that simultaneously allows variant discovery, estimation of genetic variance explained by all variants and prediction of unobserved phenotypes in new samples. We apply the method to simulated data of quantitative traits and Welcome Trust Case Control Consortium (WTCCC) data on disease and show that it provides accurate estimates of SNP-based heritability, produces unbiased estimators of risk in new samples, and that it can estimate genetic architecture by partitioning variation across hundreds to thousands of SNPs. We estimated that, depending on the trait, 2,633 to 9,411 SNPs explain all of the SNP-based heritability in the WTCCC diseases. The majority of those SNPs (>96%) had small effects, confirming a substantial polygenic component to common diseases. The proportion of the SNP-based variance explained by large effects (each SNP explaining 1% of the variance) varied markedly between diseases, ranging from almost zero for bipolar disorder to 72% for type 1 diabetes. Prediction analyses demonstrate that for diseases with major loci, such as type 1 diabetes and rheumatoid arthritis, Bayesian methods outperform profile scoring or mixed model approaches.

Polymorphisms that affect complex traits or quantitative trait loci (QTL) often affect multiple traits. We describe two novel methods (1) for finding single nucleotide polymorphisms (SNPs) significantly associated with one or more traits using a multi-trait, meta-analysis, and (2) for distinguishing between a single pleiotropic QTL and multiple linked QTL. The meta-analysis uses the effect of each SNP on each of n traits, estimated in single trait genome wide association studies (GWAS). These effects are expressed as a vector of signed t-values (t) and the error covariance matrix of these t values is approximated by the correlation matrix of t-values among the traits calculated across the SNP (V). Consequently, t'V-1t is approximately distributed as a chi-squared with n degrees of freedom. An attractive feature of the meta-analysis is that it uses estimated effects of SNPs from single trait GWAS, so it can be applied to published data where individual records are not available. We demonstrate that the multi-trait method can be used to increase the power (numbers of SNPs validated in an independent population) of GWAS in a beef cattle data set including 10,191 animals genotyped for 729,068 SNPs with 32 traits recorded, including growth and reproduction traits. We can distinguish between a single pleiotropic QTL and multiple linked QTL because multiple SNPs tagging the same QTL show the same pattern of effects across traits. We confirm this finding by demonstrating that when one SNP is included in the statistical model the other SNPs have a non-significant effect. In the beef cattle data set, cluster analysis yielded four groups of QTL with similar patterns of effects across traits within a group. A linear index was used to validate SNPs having effects on multiple traits and to identify additional SNPs belonging to these four groups.

The data from genome-wide association studies can be applied to genotype data to predict the phenotype of a complex trait. Here the authors discuss the potential pitfalls of such analyses and the inherent limitations of the method. The success of genome-wide association studies (GWASs) has led to increasing interest in making predictions of complex trait phenotypes, including disease, from genotype data. Rigorous assessment of the value of predictors is crucial before implementation. Here we discuss some of the limitations and pitfalls of prediction analysis and show how naive implementations can lead to severe bias and misinterpretation of results.

Mammals have a large cohort of endo- and ecto- symbiotic microorganisms (the microbiome) that potentially influence host phenotypes. There have been numerous exploratory studies of these symbiotic organisms in humans and other animals, often with the aim of relating the microbiome to a complex phenotype such as body mass index (BMI) or disease state. Here, we describe an efficient methodology for predicting complex traits from quantitative microbiome profiles. The method was demonstrated by predicting inflammatory bowel disease (IBD) status and BMI from human microbiome data, and enteric greenhouse gas production from dairy cattle rumen microbiome profiles. The method uses unassembled massively parallel sequencing (MPS) data to form metagenomic relationship matrices (analogous to genomic relationship matrices used in genomic predictions) to predict IBD, BMI and methane production phenotypes with useful accuracies (r = 0.423, 0.422 and 0.466 respectively). Our results show that microbiome profiles derived from MPS can be used to predict complex phenotypes of the host. Although the number of biological replicates used here limits the accuracy that can be achieved, preliminary results suggest this approach may surpass current prediction accuracies that are based on the host genome. This is especially likely for traits that are largely influenced by the gut microbiota, for example digestive tract disorders or metabolic functions such as enteric methane production in cattle.

Prediction of genetic merit using dense SNP genotypes can be used for estimation of breeding values for selection of livestock, crops, and forage species; for prediction of disease risk; and for forensics. The accuracy of these genomic predictions depends in part on the genetic architecture of the trait, in particular number of loci affecting the trait and distribution of their effects. Here we investigate the difference among three traits in distribution of effects and the consequences for the accuracy of genomic predictions. Proportion of black coat colour in Holstein cattle was used as one model complex trait. Three loci, KIT, MITF, and a locus on chromosome 8, together explain 24% of the variation of proportion of black. However, a surprisingly large number of loci of small effect are necessary to capture the remaining variation. A second trait, fat concentration in milk, had one locus of large effect and a host of loci with very small effects. Both these distributions of effects were in contrast to that for a third trait, an index of scores for a number of aspects of cow confirmation (\"overall type\"), which had only loci of small effect. The differences in distribution of effects among the three traits were quantified by estimating the distribution of variance explained by chromosome segments containing 50 SNPs. This approach was taken to account for the imperfect linkage disequilibrium between the SNPs and the QTL affecting the traits. We also show that the accuracy of predicting genetic values is higher for traits with a proportion of large effects (proportion black and fat percentage) than for a trait with no loci of large effect (overall type), provided the method of analysis takes advantage of the distribution of loci effects.

Doubled haploids are routinely created and phenotypically selected in plant breeding programs to accelerate the breeding cycle. Genomic selection, which makes use of both phenotypes and genotypes, has been shown to further improve genetic gain through prediction of performance before or without phenotypic characterization of novel germplasm. Additional opportunities exist to combine genomic prediction methods with the creation of doubled haploids. Here we propose an extension to genomic selection, optimal haploid value (OHV) selection, which predicts the best doubled haploid that can be produced from a segregating plant. This method focuses selection on the haplotype and optimizes the breeding program toward its end goal of generating an elite fixed line. We rigorously tested OHV selection breeding programs, using computer simulation, and show that it results in up to 0.6 standard deviations more genetic gain than genomic selection. At the same time, OHV selection preserved a substantially greater amount of genetic diversity in the population than genomic selection, which is important to achieve long-term genetic gain in breeding populations.

Background It has been challenging to implement genomic selection in multi-breed tropical beef cattle populations. If commercial (often crossbred) animals could be used in the reference population for these genomic evaluations, this could allow for very large reference populations. In tropical beef systems, such animals often have no pedigree information. Here we investigate potential models for such data, using marker heterozygosity (to model heterosis) and breed composition derived from genetic markers, as covariates in the model. Models treated breed effects as either fixed or random, and included genomic best linear unbiased prediction (GBLUP) and BayesR. A tropically-adapted beef cattle dataset of 29,391 purebred, crossbred and composite commercial animals was used to evaluate the models. Results Treating breed effects as random, in an approach analogous to genetic groups allowed partitioning of the genetic variance into within-breed and across breed-components (even with a large number of breeds), and estimation of within-breed and across-breed genomic estimated breeding values (GEBV). We demonstrate that moderately-accurate (0.30–0.43) GEBV can be calculated using these models. Treating breed effects as random gave more accurate GEBV than treating breed as fixed. A simple GBLUP model where no breed effects were fitted gave the same accuracy (and correlations of GEBV very close to 1) as a model where GEBV for within-breed and the GEBV for (random) across-breed effects were included. When GEBV were predicted for herds with no data in the reference population, BayesR resulted in the highest accuracy, with 3% accuracy improvement averaged across traits, especially when the validation population was less related to the reference population. Estimates of heterosis from our models were in line with previous estimates from beef cattle. A method for estimating the number of effective breed comparisons for each breed combination accumulated across contemporary groups is presented. Conclusions When no pedigree is available, breed composition and heterosis for inclusion in multi-breed genomic evaluation can be estimated from genotypes. When GEBV were predicted for herds with no data in the reference population, BayesR resulted in the highest accuracy.

Background Two key findings from genomic selection experiments are 1) the reference population used must be very large to subsequently predict accurate genomic estimated breeding values (GEBV), and 2) prediction equations derived in one breed do not predict accurate GEBV when applied to other breeds. Both findings are a problem for breeds where the number of individuals in the reference population is limited. A multi-breed reference population is a potential solution, and here we investigate the accuracies of GEBV in Holstein dairy cattle and Jersey dairy cattle when the reference population is single breed or multi-breed. The accuracies were obtained both as a function of elements of the inverse coefficient matrix and from the realised accuracies of GEBV. Methods Best linear unbiased prediction with a multi-breed genomic relationship matrix (GBLUP) and two Bayesian methods (BAYESA and BAYES_SSVS) which estimate individual SNP effects were used to predict GEBV for 400 and 77 young Holstein and Jersey bulls respectively, from a reference population of 781 and 287 Holstein and Jersey bulls, respectively. Genotypes of 39,048 SNP markers were used. Phenotypes in the reference population were de-regressed breeding values for production traits. For the GBLUP method, expected accuracies calculated from the diagonal of the inverse of coefficient matrix were compared to realised accuracies. Results When GBLUP was used, expected accuracies from a function of elements of the inverse coefficient matrix agreed reasonably well with realised accuracies calculated from the correlation between GEBV and EBV in single breed populations, but not in multi-breed populations. When the Bayesian methods were used, realised accuracies of GEBV were up to 13% higher when the multi-breed reference population was used than when a pure breed reference was used. However no consistent increase in accuracy across traits was obtained. Conclusion Predicting genomic breeding values using a genomic relationship matrix is an attractive approach to implement genomic selection as expected accuracies of GEBV can be readily derived. However in multi-breed populations, Bayesian approaches give higher accuracies for some traits. Finally, multi-breed reference populations will be a valuable resource to fine map QTL.

The causes of temporal fluctuations in adult traits are poorly understood. Here, we investigate the genetic determinants of within-person trait variability of 8 repeatedly measured anthropometric traits in 50,117 individuals from the UK Biobank. We found that within-person (non-directional) variability had a SNP-based heritability of 2–5% for height, sitting height, body mass index (BMI) and weight (P ≤ 2.4 × 10 − 3 ). We also analysed longitudinal trait change and show a loss of both average height and weight beyond about 70 years of age. A variant tracking the Alzheimer’s risk APOE - E 4 allele (rs429358) was significantly associated with weight loss ( β  = −0.047 kg per yr, s.e. 0.007, P  = 2.2 × 10 −11 ), and using 2-sample Mendelian Randomisation we detected a relationship consistent with causality between decreased lumbar spine bone mineral density and height loss ( b xy  = 0.011, s.e. 0.003, P = 3.5 × 10 −4 ). Finally, population-level variance quantitative trait loci (vQTL) were consistent with within-person variability for several traits, indicating an overlap between trait variability assessed at the population or individual level. Our findings help elucidate the genetic influence on trait-change within an individual and highlight disease risks associated with these changes. The availability of longitudinal data in large biobanks is increasing. Here, using data from the UK Biobank, the authors develop and apply analytical approaches to quantify genetic contributions to change over time for traits like height and weight.

Lumpy skin disease (LSD) is a disease of bovines resulting from the mechanical transmission of lumpy skin disease virus (LSDV) by arthropod vectors. While LSD has never been reported in Australia, the disease has spread through Asia and recently expanded to neighbouring countries such as Indonesia. The detection of LSD in Australian cattle would likely lead to trade restrictions, resulting in Australian cattle industries experiencing severe economic losses. There is a need for geospatial decision support tools to support border and post border surveillance efforts through the identification of areas which would be more vulnerable to a LSDV introduction. Previous risk assessments have calculated that overall risk of introduction into Australia is negligible to very low after evaluating four entry pathways, including windborne dispersal of arthropod vectors, commercial vessels carrying hitchhiker arthropod vectors (excluding live export vessels), returning live export vessels carrying hitchhiker arthropod vectors, and movements in Torres Strait Treaty area leading to the transport of hitchhiker arthropod vectors. However, the studies also reported very high uncertainty given a lack of robust empirical data for many of the model parameters and only described risk in terms of each pathway as a whole rather than describing spatial variation in risk. This study aimed to develop a novel integrated geospatial model for simulating the likelihood of LSDV-carrying vectors entering Australia via two different entry pathways: transport of vectors through shipping channels and vectors being carried long distances by strong wind currents. This model was used to explore the spatial variation in suitability for LSDV-carrying vectors entering Australia for each pathway independently and combined to identify geographical areas with the highest suitability. Furthermore, the study incorporated species distribution modelling and current bovine LSD case data in neighbouring countries to better model the current suitability of LSD in livestock, which were not included in the previous risk assessments. Pathway one showed the ports at Port Hedland and Dampier as having the highest suitability for LSDV-carrying vectors entering Australia compared to the rest of the country. Pathway two showed highest comparative suitability in Far North Queensland, with suitability extending as far as 25 degrees south. Furthermore, likelihood of vectors being carried by wind currents into Australia was highest in the summer months. A model combining both pathways highlighted areas along the northern tip of Far North Queensland and around Port Hedland in Western Australia as having the highest suitability for LSDV-carrying vectors entering Australia compared to the rest of the country. These findings may assist future modelling of exposure and spread of LSDV in the Australian bovine population following a successful incursion event, which may help guide local authorities with planning and prioritisation of integrated surveillance activities.