Fig. 3: Association between CHIP and heteroplasmy.

The percentage of individuals presenting with both CHIP and heteroplasmy, only with CHIP, or only with heteroplasmy in (A) UKB and (B) ARIC. The prevalence of heteroplasmy in different CHIP gene subsets was evaluated using multivariable logistic regression without multiple testing correction in (C) UKB (CHIP vs. no CHIP, P < 2e-16; VAF ≥ 20% vs. 2% ≤ VAF < 20%, P < 2e-16; multiple mutations vs. single mutation, P = 1.05e-7; and spliceosome mutated CHIP vs. other CHIP, P < 2e-16) and in (D) ARIC (CHIP vs. no CHIP, P = 5.5e-3; VAF ≥ 20% vs. 2% ≤ VAF < 20%, P = 0.0887; multiple mutations vs. single mutation, P = 0.0376; and spliceosome mutated CHIP vs. other CHIP, P = 0.0528). The absolute number of individuals with heteroplasmy is indicated by the numbers on the left side of the bars. The prevalence of multiple heteroplasmies within individuals with heteroplasmy across different CHIP gene subsets was evaluated using multivariable logistic regression without multiple testing correction in (E) UKB (CHIP vs. no CHIP, P < 2e-16; VAF ≥ 20% vs. 2% ≤ VAF < 20%, P = 3.11e-13; multiple mutations vs. single mutation, P = 3.22e-5; and spliceosome mutated CHIP vs. other CHIP, P = 1.86e-8) and in (F) ARIC (CHIP vs. no CHIP, P = 0.621; VAF ≥ 20% vs. 2% ≤ VAF < 20%, P = 0.116; multiple mutations vs. single mutation, P = 0.407; and spliceosome mutated CHIP vs. other CHIP, P = 0.125). The absolute number of individuals with multiple heteroplasmies is indicated by the numbers on the left side of the bars. mMSS of different CHIP subsets in individuals with heteroplasmy was compared using multivariable linear regression without multiple testing correction in (G) UKB (number of individuals used to derive statistics; median mMSS [Q1, Q3] no CHIP: n = 111,524; 0.020 [0.000, 0.157]; CHIP: n = 11,445; 0.052 [0.006, 0.293]; 2%; ≤VAF < 20% : n = 9131; 0.040 [0.005, 0.248]; VAF ≥ 20%: n = 2314; 0.128 [0.014, 0.545]; single mutation: n = 10,311; 0.046 [0.005, 0.275]; multiple mutations: n = 1134; 0.123 [0.013, 0.541]; DNMT3A: n = 3963; 0.061 [0.007, 0.306]; TET2: n = 2434; 0.068 [0.007, 0.376]; ASXL1: n = 761; 0.111 [0.013, 0.529]; PPM1D: n = 255; 0.071 [0.008, 0.328]; TP53: n = 232; 0.071 [0.007, 0.360]; SRSF2: n = 183; 0.334 [0.016, 0.763]; SF3B1: n = 130; 0.183 [0.016, 0.522]; U2AF1: n = 62; 0.309 [0.036, 0.717]. CHIP vs. no CHIP, P < 2e-16; VAF ≥ 20% vs. 2% ≤ VAF < 20%, P < 2e-16; multiple mutations vs. single mutation, P = 9.36e-16; and spliceosome mutated CHIP vs. other CHIP, P = 9.28e-16) and in (H) ARIC (number of individuals used to derive statistics; median mMSS [Q1, Q3] no CHIP: n = 2027; 0.033 [0.000, 0.191]; CHIP: n = 132; 0.074 [0.009, 0.502]; 2% ≤ VAF < 20%: n = 96; 0.056 [0.008, 0.436]; VAF ≥ 20%: n = 36; 0.103 [0.010, 0.587]; single mutation: n = 110; 0.067 [0.007, 0.506]; multiple mutations: n = 22; 0.162 [0.013, 0.444]; DNMT3A: n = 43; 0.154 [0.009, 0.405]; TET2: n = 38; 0.065 [0.012, 0.687]; ASXL1: n = 8; 0.461 [0.068, 0.773]; PPM1D: n = 0; NA [NA, NA]; TP53: n = 2; 0.127 [0.065, 0.188]; SRSF2: n = 0; NA [NA, NA]; SF3B1: n = 5; 0.066 [0.000, 1.040]; U2AF1: n = 3; 0.013 [0.010, 0.440]. CHIP vs. no CHIP, P = 2.3e-7; VAF ≥ 20% vs. 2% ≤ VAF < 20%, P = 0.368; multiple mutations vs. single mutation, P = 0.603; and spliceosome mutated CHIP vs. other CHIP, P = 0.976). Graphical representation of mMSS was truncated at mMSS = 2. All values of mMSS were included for the analyses. For all analysis, two-sided tests were used. Abbreviations: CHIP, clonal hematopoiesis of indeterminate potential; DDR, DNA damage response; mMSS, modified mitochondrial local constraint (MLC) score sum; and VAF, variant allele fraction. DTA includes DNMT3A, TET2, ASXL1. * Indicates the comparison between spliceosome mutations and other CHIP genes. In the UKB, these analyses were adjusted for age modeled as a restricted cubic spline, sex, smoking status, and a history of cancer. In ARIC, these analyses were adjusted for age modeled as a restricted cubic spline, sex, and smoking status. For the analyses including mMSS, the models were also adjusted for heteroplasmy count. Source data are provided as a Source Data file.