Fig. 5: Variants affecting SVEP1 levels are associated with CHD, blood pressure, and T2D.
From: Coding and regulatory variants are associated with serum protein levels and disease
a The Manhattan plot reveals variants at chromosomes 1 and 9 associated with serum SVEP1 levels. Study-wide significant associations (linear regression, P < 1.92 × 10−10, two-sided) are indicated by the horizontal line. The y-axis shows the −(log10) of the P-values for the association of each genetic variant on the exome array present along the x-axis. b One of the variants associated with SVEP1 levels and underlying the peak at chromosome 9 is the low-frequency CHD risk variant rs111245230 (NP_699197.3: pD2702G). The CHD risk allele C (highlighted in bold) is associated with increased serum SVEP1 levels. The x-axis of the box plot shows the genotypes for the protein-associated SNP, while the y-axis denotes the Box–Cox transformed, age, and sex-adjusted serum protein levels. The P-value (two-sided) shown at the top of the plot is derived from linear regression analysis. Box plots indicate median (middle line), 25th, 75th percentile (box), and 5th and 95th percentile (whiskers). c Serum levels of SVEP1 were associated with incident CHD (P = 8 × 10−9) and T2D (P = 8 × 10−5). The P-values (two-sided) at the top of each boxplot for CHD and T2D come from logistic regression. The comparison of protein quintiles of the SVEP1 levels in serum with systolic (SBP) or diastolic (DBP) show a significant positive correlation with SBP (β = 0.210, P = 4 × 10−12, two-sided) but not with DBP (P > 0.05, two-sided). The relationship between the top and bottom quintiles of serum SVEP1 levels and blood pressure is depicted in the right-most panel. The x-axis of the box plots shows the health status of individuals, while the y-axis denotes the Box–Cox transformed, age, and sex-adjusted serum protein levels. Box plots indicate median (middle line), 25th, 75th percentile (box), and 5th and 95th percentile (whiskers). d Consistent with the directionality of the effects described above, we find that elevated levels of SVEP1 were associated with higher rates of mortality post-incident CHD. The Kaplan–Meier plot calculates the hazard ratio (HR) by comparing the 75th and 25th percentiles of SVEP1 serum levels. The vertical ticks correspond to individuals lost to follow-up while the shaded areas indicated the 95% confidence intervals. The P-value (two-sided) and HR are shown at the top of the plot. e Scatterplot for the SVEP1 protein supported as having a causal effect on T2D in a two-sample MR analysis. The figure demonstrates the SNP effect on serum SVEP1 levels (x-axis) and T2D from a GWAS in Europeans35 (y-axis), with 74,124 T2D patients and 824,006 controls. Each center data point displays the estimated effect as beta coefficient = log(odds ratio), along with 95% confidence intervals for the SNP effect on disease (vertical lines) or SNP effect on the protein (horizontal lines). The broken line indicates the inverse variance weighted causal estimate (β = 0.104, SE = 0.023, P = 5.7 × 10−6, two-sided), while the dotted line demonstrates the MR–Egger regression (see Supplementary Data 5).
