Fig. 4: Rare coding variation associated with NMR measures and convergence with common variant associations.
From: A genetic map of human metabolism across the allele frequency spectrum
a, Effect estimates against MAF of significantly associated gene burden (diamonds; two-sided P < 1.2 × 10−8 and rare exonic variants (MAF <0.05%; circles; two-sided P < 2.0 × 10−10). b, Effect estimates and two-sided raw −log10(P values) for associations of the rare intronic variant chr11:117186662:C>T within SIDT2 across all 249 NMR measures. The dotted horizontal line indicates the multiple testing threshold (P < 2.0 × 10−10). c, Genomic distance between gene burden (blue) or rare exonic variants (orange) toward the next common credible set variant. d, Evidence for allelic series based on (i) gene burden analysis (bottom), (ii) rare exonic variants (middle) and (iii) common variants with prioritized effector gene matching to the evidence from exonic analysis. For each gene, only the NMR measure most significantly associated with the strongest common variant is shown in cases where multiple NMR measures were associated. Some bars for the number of associated rare exonic variants have been capped to fit into plotting margin, but the number is given in the plot. e, Effect estimates (dots) and 95% CIs (lines) from our European-based exWAS for 7 variants mapping to APOA1 as well as a cumulative burden of high-confidence pLOF variants within APOA1 and bespoke circulating measures of ApoA1 (clinical indicates measurements by immunoturbidimetric analysis on a Beckman Coulter AU5800) and HDL particles (color gradient). f, Top: a heatmap of standardized effect estimates (per variant) across 87 NMR measures for each associated variant and a cumulative burden within APOA1. Variants mapping into the region encoding the protein are surrounded by a rectangle. Variant effects have been aligned to the minor allele. Middle: the corresponding variants mapped to their respective transcripts encoding different forms of APOA1. Bottom: missense variants mapped onto the amino acid sequence of the protein. Variant names colored similarly had highly correlated association profiles.
