Fig. 2: Results of variant-level association tests.
From: Mapping rare protein-coding variants on multi-organ imaging traits
A Manhattan plot for variant-level association tests across all 596 imaging phenotypes. Only coding variants of interest were included in the variant-level association tests and associations with P < 1 × 10−3 were plotted. P-values are derived from two-sided tests based on z-scores (or equivalently a χ2 test with one degree of freedom. The dashed lines indicate the variant-level significant P-value threshold at 2.8 × 10−10 from Bonferroni correction and the suggestive P-value threshold at 1 × 10−8 as rare variant genome-wide significance threshold (details are provided in Method). The x-axis shows all the categories of our imaging phenotypes, while we further separated the abdominal MRI traits into abdominal organs and body/fat composition, and separated CMR traits into heart chambers and aorta areas based on the specific traits. Significant coding-variant-level associations (P < 2.8 × 10−10) were labeled to the corresponding genes. For DTI parameters, the unlabeled signals all belong to VCAN gene. B Summary count for the number of signals, unique variants (unique genes in the parentheses), and unique traits within each imaging category that has significant variant-level associations. C The scatter plot for all the variant-level significant results (colored by imaging categories) and suggestive results (in grey color). The x-axis shows the minor allele frequency of each association, and the y-axis is the absolute value of the corresponding genetic effect size in s.d. units. D Graphical illustration of associations between two missense variants (rs72553883 and rs34557412) in TNFRSF13B and spleen volume. The rug plot at the first row demonstrates the locations of these two missense variants. The rug plot at the second row indicates the locations of rare variants in the ‘plof_alpha’ gene burden model, since gene-based burden test also revealed the association between TNFRSF13B and spleen volume. The summary statistics (P-values) of exome-wide associations between TNFRSF13B and blood traits based on burden tests were downloaded from Genebass17. Some elements in this figure were created in BioRender: Fan, Y. (2025) https://BioRender.com/f2ok1xo, Fan, Y. (2025) https://BioRender.com/rdhm596, and Fan, Y. (2025) https://BioRender.com/e81d7o9. E Visualization of the associations between two missense variants (rs2652098 and rs143368552) in VCAN and 12 mean diffusivity traits (β1 is the effect size in s.d. of rs2652098 and β2 is the effect size in s.d. of rs143368552).
