Genetic determinants of polygenic prediction accuracy within a population

Genomic risk prediction is on the emerging path towards personalized medicine. However, the accuracy of polygenic prediction varies strongly in different individuals. In this study, based on up to 352,277 White British participants in the UK Biobank, we constructed polygenic risk scores for 15 physiological and biochemical quantitative traits after performing genome-wide association studies (GWASs). We identified 185 polygenic prediction variability quantitative trait loci (pvQTLs) for 11 traits by Levene’s test among 254,376 unrelated individuals. We validated the effects of pvQTLs using an independent test set of 58,927 individuals. A score aggregating 51 pvQTL SNPs for triglycerides had the strongest Spearman correlation of 0.185 (p-value < 1.0x10−300) with the squared prediction errors. We found a strong enrichment of complex genetic effects conferred by pvQTLs compared to risk loci identified in GWASs, including 89 pvQTLs exhibiting dominance effects. Incorporation of dominance effects into polygenic risk scores significantly improved polygenic prediction for triglycerides, low-density lipoprotein cholesterol, vitamin D, and platelet. After including 87 dominance effects for triglycerides, the adjusted R2 for the polygenic risk score had an 8.1% increase on the test set. In addition, 108 pvQTLs had significant interaction effects with measured environmental or lifestyle exposures. In conclusion, we have discovered and validated genetic determinants of polygenic prediction variability for 11 quantitative biomarkers, and partially profiled the underlying complex genetic effects. These findings may assist interpretation of genomic risk prediction in various contexts, and encourage novel approaches for constructing polygenic risk scores with complex genetic effects.

The heritability of BMI varies across the range of BMI: a heritability curve analysis in a twin cohort

The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family, twin, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case. This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts. The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI. Thus, we demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritabilities and major differences in mean values between countries or over time.

The Addition of Epistatic Genetic Effects Increases Genomic Prediction Accuracy for Reproduction and Production Traits in Duroc Pigs Using Genomic Models

Background: Genomic selection has been implemented in livestock genetic evaluations for years. However, currently most genomic selection models only consider the additive effects associated with SNP markers and nonadditive genetic effects have been for the most part ignored. Methods: Production traits for 26,735 to 27,647 Duroc pigs and reproductive traits for 5,338 sows were used, including off-test body weight (WT), off-test back fat (BF), off-test loin muscle depth (MS), number born alive (NBA), number born dead (NBD), and number weaned (NW). All animals were genotyped with the PorcineSNP60K Bead Chip. Variance components were estimated using a linear mixed model that includes inbreeding coefficient, additive, dominance, additive-by-additive, additive-by-dominance, dominance-by-dominance effect, and common litter environmental effect. Genomic prediction performance, including all nonadditive genetic effects, was compared with a reduced model that included only additive genetic effect. Results: Significant estimates of additive-by-additive effect variance were observed for NBA, BF, and WT (31%, 9%, and 10%, respectively). Production traits showed significant large estimates of additive-by-dominance variance (9%-23%). MS also showed large estimate of dominance-by-dominance variance (10%). Dominance effect variance estimates were low for all traits (0%-2%). Compared to the reduced model, prediction accuracies using the full model, including nonadditive effects, increased significantly by 12%, 12%, and 1% for NBA, WT, and MS, respectively. A strong dominance association signal with BF was identified near AK5.Conclusions: Sizable estimates of epistatic effects were found for the reproduction and production traits, while the dominance effect was relatively small for all traits yet significant for all production traits. Including nonadditive effects, especially epistatic effects in the genomic prediction model, significantly improved prediction accuracy for NBA, WT, and MS.

scDALI: modeling allelic heterogeneity in single cells reveals context-specific genetic regulation

While it is established that the functional impact of genetic variation can vary across cell types and states, capturing this diversity remains challenging. Current studies using bulk sequencing either ignore this heterogeneity or use sorted cell populations, reducing discovery and explanatory power. Here, we develop scDALI, a versatile computational framework that integrates information on cellular states with allelic quantifications of single-cell sequencing data to characterize cell-state-specific genetic effects. We apply scDALI to scATAC-seq profiles from developing F1 Drosophila embryos and scRNA-seq from differentiating human iPSCs, uncovering heterogeneous genetic effects in specific lineages, developmental stages, or cell types.

Genetic Regulation of Transcription in the Endometrium in Health and Disease

The endometrium is a complex and dynamic tissue essential for fertility and implicated in many reproductive disorders. The tissue consists of glandular epithelium and vascularised stroma and is unique because it is constantly shed and regrown with each menstrual cycle, generating up to 10 mm of new mucosa. Consequently, there are marked changes in cell composition and gene expression across the menstrual cycle. Recent evidence shows expression of many genes is influenced by genetic variation between individuals. We and others have reported evidence for genetic effects on hundreds of genes in endometrium. The genetic factors influencing endometrial gene expression are highly correlated with the genetic effects on expression in other reproductive (e.g., in uterus and ovary) and digestive tissues (e.g., salivary gland and stomach), supporting a shared genetic regulation of gene expression in biologically similar tissues. There is also increasing evidence for cell specific genetic effects for some genes. Sample size for studies in endometrium are modest and results from the larger studies of gene expression in blood report genetic effects for a much higher proportion of genes than currently reported for endometrium. There is also emerging evidence for the importance of genetic variation on RNA splicing. Gene mapping studies for common disease, including diseases associated with endometrium, show most variation maps to intergenic regulatory regions. It is likely that genetic risk factors for disease function through modifying the program of cell specific gene expression. The emerging evidence from our gene mapping studies coupled with tissue specific studies, and the GTEx, eQTLGen and EpiMap projects, show we need to expand our understanding of the complex regulation of gene expression. These data also help to link disease genetic risk factors to specific target genes. Combining our data on genetic regulation of gene expression in endometrium, and cell types within the endometrium with gene mapping data for endometriosis and related diseases is beginning to uncover the specific genes and pathways responsible for increased risk of these diseases.

Genetic and non-genetic effects associated with ewe productivity in Harnali sheep

Summary The objective of the current study was to estimate the genetic parameters for ewe productivity traits of Harnali sheep by examining non-genetic effects. The data records of 440 animals born to 85 sires and 259 dams were collected with respect to various traits such as litter size at birth (LSB), litter weight at birth (LWB), litter size at weaning (LSW), litter weight at weaning (LWW) and age at first lambing (AFL) for the period of 2001 to 2020. Genetic parameters were estimated by fitting a series of animal models using an average information restricted maximum likelihood (REML) algorithm in WOMBAT software. Least-squares analysis revealed significant (P < 0.05) influences of period of lambing, age and weight of ewe at lambing on the studied traits. These results indicated that heavier ewes had significantly higher (P < 0.05) values of litter weight traits than their counterparts. On the basis of likelihood ratio test, the estimates of direct heritability under best model for AFL, LSB, LWB, LSW and LWW were 0.06, 0.18, 0.09, 0.07 and 0.16, respectively. Maternal permanent environment effect made a significant contribution to the LSB trait (0.20). The genetic correlation between litter size and LWW was negative, while the remaining correlations were positive. The present results suggest that selection based on ewe productivity traits will result in low genetic progress and therefore the management role is more important for better gains.

Relationship between indirect genetic effects for growth, environmental enrichment, coping style and sex with the serum metabolome profile of pigs

Including Indirect Genetic Effects (IGE) in breeding programs to reduce aggression in group housed animals has been proposed. However, the effect of selection for IGE for growth on animal metabolism and physiology is unknown. The purpose of this study was twofold: (1) To investigate the effects of this new breeding method along with two housing (barren and straw), coping style (high and low resisters) and sex (female and castrated males) options on the metabolome profile of pigs. (2) To identify and map biological processes associated with a regrouping test at 9 weeks of age. We used Nuclear Magnetic Resonance to quantify 49 serum metabolites at week 8, 9 and 22. Also, we quantified 3 catecholamines (tyramine, epinephrine, phenylethylamine) and serotonin and three water soluble vitamins (B2, B5 and B7). Overall, no significant differences were observed between negative and positive IGE animals. The magnitude of change (delta) of many metabolites as a response to the regrouping test was significantly affected by IGE, especially that of the amino acids (P < 0.05), being greater in positive IGE pigs. The regrouping test was associated with alteration in glycine, serine and threonine metabolism. In conclusion positive and negative IGE animals respond differently to the regrouping test.