Title | Association analysis of mitochondrial DNA heteroplasmic variants: Methods and application. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Sun, X, Bulekova, K, Yang, J, Lai, M, Pitsillides, AN, Liu, X, Zhang, Y, Guo, X, Yong, Q, Raffield, LM, Rotter, JI, Rich, SS, Abecasis, G, Carson, AP, Vasan, RS, Bis, JC, Psaty, BM, Boerwinkle, E, Fitzpatrick, AL, Satizabal, CL, Arking, DE, Ding, J, Levy, D, Liu, C |
Corporate Authors | TOPMed mtDNA working group |
Journal | Mitochondrion |
Volume | 79 |
Pagination | 101954 |
Date Published | 2024 Sep 07 |
ISSN | 1872-8278 |
Abstract | We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31 % of African Ancestry, mean age of 62, with 58 % women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p |
DOI | 10.1016/j.mito.2024.101954 |
Alternate Journal | Mitochondrion |
PubMed ID | 39245194 |