Extended Data Fig. 11: mtDNA heteroplasmy estimates and genetic associations are robust to potential confounders.
From: Nuclear genetic control of mtDNA copy number and heteroplasmy in humans
a. R2 and adjusted R2 for technical covariate model and R2 for blood trait model for common mtDNA heteroplasmies and log mtCNraw. Color corresponds to model F-test p-value < 0.05 (df = N-14 for blood, N-67 for technical; N in Supplementary Table 1) after Bonferroni correction. Sensitivity analyses for the GWASs of b. chrM:567:A,ACCCCCCC before and after technical covariate correction, c. chrM:16093:T,C before and after blood trait correction d. chrM:16182:A,ACC before and after blood trait correction e. chrM:16183:A,AC before and after blood trait correction. Mean case-only heteroplasmy as a function of top-level haplogroup for f. chrM:302:A,AC and g. chrM:16179:CA,C. Bar color corresponds to two-sided coefficient p-value for the regression of heteroplasmy onto top-level haplogroup, Bonferroni corrected for 39 tested heteroplasmies. h. McFadden’s pseudo-R2 for a multinomial model of top-level haplogroup versus mtDNA PCs (left) and ”level 2” haplogroup versus mtDNA PCs within each top-level haplogroup. i. GWAS lead SNP effect size estimate correlation when correcting for 30 mtDNA PCs vs correcting for only top-level haplogroup for selected variants showing high haplogroup heterogeneity (302:A,AC; 302:A,ACC; 302:A,ACCCC; 567:A,ACCCCCC; 955:A,ACC; 16179:CA,C; 16183:A,C). GWAS lead SNP effect size estimate correlation between case-only GWASs at baseline and j. GWASs after removing heteroplasmy calls supported by allele depth < median nuclear coverage, k. GWASs after correcting for variant coverage depth, l. GWASs after correcting for mtCN, m. length heteroplasmy GWASs after correcting for CSBII median coverage. For panels i-m, colors correspond to nuclear chromosome, points correspond to GWAS effect sizes for lead SNPs from baseline case-only GWASs with top-level haplogroup covariates, error bars represent effect sizes +/− 1 s.e., main GWAS sample sizes (x-axis) are found in Supplementary Table 1 (EUR), and sensitivity analysis GWAS sample sizes (y-axis) can be found in Supplementary Table 9.
