Genetic correlation-guided mega-analysis of DO mice provides mechanistic insight and candidate genes for age-related pathologies

Fig 1. Performance of Haseman-Elston regression implementation and estimation of rg among traits measured across diet and time point. A, Comparison of h2 estimates for 36 DO mouse traits derived from our implementation of Haseman-Elston regression to those from an orthogonal method, Residual Maximum Likelihood (REML). The line of identity is denoted by a solid line; the best-fit line is denoted by a dashed line. The Pearson correlation coefficient and accompanying p-value are reported in the upper-left of the plot area. Traits are colored by type: ‘AS’ - Acoustic Startle. ‘DX’ - DEXA scan. ‘EC’ - Echocardiogram. ‘GS’ - Grip Strength. ‘RR’ - Rotarod. ‘WR’ - Wheel Running. B, Comparison of rg estimates among all pairs of 36 DO mouse traits derived from Haseman-Elston regression to those from REML. C, Mean intratrait rg,t across time points for individual traits measured in the DRiDO study. Black bars denote the average mean intratrait rg for traits of a particular type, and gray bars represent the mean intratrait rg + /- the standard error of the mean. ‘AS’ - acoustic startle. ‘BW’ - body weight. ‘CBC’ - complete blood count. ‘FACS’ - immune cell composition via fluorescence activated…

Fig 2. An atlas of rg and rpg estimates among complex phenotypes in DO mice. A, The distribution of h2, rg, and rpg, estimates for DO mouse phenotypes used in downstream analysis. The median, 25th percentile, and 75th percentile of the distribution are denoted via box and whisker plots. B, The relationship between the pairwise genetic correlation (rg) and Pearson correlation of genetic correlations (rpg) for each pair of traits in the dataset. Pearson and Spearman correlation coefficients are reported. C, A hierarchically clustered heatmap of rg (lower triangle) and rpg (upper triangle) estimates among 1,898 DO phenotypes. Phenotypes measured in individual dietary groups from the DRiDO study are excluded. The accompanying dendrogram shows euclidean distances among traits based on their rpg estimates. D, The distribution of rpg values among traits measured in the same study (intra-study, blue) or in different studies (inter-study, red). The median, 25th percentile, and 75th percentile of the distribution are denoted via box and whisker plots. E-F, Force-directed network diagrams of the 1,898 DO mouse phenotypes used in downstream analysis, with nodes corresponding to individual traits.…

Fig 3. Genetic correlations involving measurements of lifespan in DO mice. A, Heatmap of genetic correlations and heritability estimates among three independent measurements of lifespan in DO mice. The diagonal of the heatmap reports the h2 of each lifespan trait. The lower triangle of the heatmap shows rg among the lifespan traits and the upper triangle shows the rpg among lifespan traits. Asterisks denote statistically significant h2, rg, or rpg estimates. The dendrogram shows the results of hierarchical clustering of the lifespan traits based on euclidean distance derived from the rpg values among each pair of traits. Clusters of traits that result in a maximal mean h2 ratio when combined are represented by colors in the dendrogram as well as black boxes in the heatmap. B, Scatterplots of rpg estimates between lifespan traits and the 380 other non-lifespan meta-traits. C, The strongest positive and negative rpg estimates between meta-traits and combined lifespan data. Error bars correspond to the standard error of each rpg estimate. Meta-trait number (cluster number) is shown on the left hand side of the plot and a brief summary of the phenotypes included in each meta-trait is shown…

Fig 4. Genetic correlations among frailty and lifespan phenotypes. A, Pairwise (rg, bottom triangle) and Pearson (rpg, upper triangle), genetic correlations among Manual Frailty Index (MFI), Digital Frailty Index (DFI), and lifespan. Statistically significant genetic correlations are denoted with an asterisk. Box color represents the magnitude of the genetic correlation and box size is inversely correlated with the size of the standard error. B-C, Heritability and standard error of individual (B) and aggregate (C) frailty phenotypes. The dashed red line at h2 = 0.1 is the threshold used to determine if phenotypes were included in downstream analysis. D, Hierarchically clustered heatmap showing rg (lower triangle) and rpg (upper triangle) among frailty phenotypes. The accompanying dendrogram shows euclidean distances among traits based on their rpg estimates. Clusters of frailty traits (F1 - F10) that result in a maximal mean h2 ratio when combined are represented by colors in the dendrogram as well as black boxes in the heatmap. rg and rpg among frailty and unclustered lifespan phenotypes are shown in the adjacent panels of the heatmap. E, Heritability and standard error of the…

Fig 5. Genetic correlations among extracellular matrix traits in the aorta. A, Hierarchically clustered heatmap showing rg (lower triangle) and rpg (upper triangle) among aorta phenotypes. The accompanying dendrogram shows euclidean distances among traits based on their rpg estimates. Clusters of aorta phenotypes that result in a maximal mean h2 ratio when combined are represented by colors in the dendrogram as well as black boxes in the heatmap. B, Manhattan plot of an additive whole-genome scan on aggregated aortic elastin thickness and pct. area phenotypes. The red line indicates a genome-wide significance threshold of ⍺ = 0.05 based on 1,000 permutations of the data (see Methods). The dashed red line indicates a nominal significance threshold of LOD >= 6. C, Manhattan plot of an additive whole-genome scan on aggregated aortic elastin breakage phenotypes. D, Manhattan plot of an additive whole-genome scan on aggregated aortic elastin layers phenotypes. E–I, Correlations of haplotype effects between the peak markers at QTL influencing elastin phenotypes and cis-eQTL in an external DO cardiac tissue transcriptomic dataset. Candidate genes are highlighted with red text.

Fig 6. Genetic correlations among lung structural and functional phenotypes. A, Hierarchically clustered heatmap showing rg (lower triangle) and rpg (upper triangle) among lung phenotypes. The accompanying dendrogram shows euclidean distances among traits based on their rpg estimates. Clusters of lung phenotypes that result in a maximal mean h2 ratio when combined are represented by colors in the dendrogram as well as black boxes in the heatmap. B, Manhattan plot of an additive whole-genome scan on aggregated fibrosis volume phenotypes. The red line indicates a genome-wide significance threshold of ⍺ = 0.05 based on 1,000 permutations of the data (see Methods). The dashed red line indicates a nominal significance threshold of LOD >= 6. C–E, Allelic effects (BLUPs) and corresponding standard errors of the QTL influencing fibrosis volume in the lung (left), and variant association mapping of the 2 LOD support intervals around each QTL (right). Genes within the confidence intervals are shown in the bottom panel, and candidate genes are shown above variant association results. F, Manhattan plot of an additive whole-genome scan on aggregated fibrosis intensity phenotypes. G–I, Allelic…