Association analysis of mitochondrial DNA heteroplasmic variants: Methods and application.

TitleAssociation analysis of mitochondrial DNA heteroplasmic variants: Methods and application.
Publication TypeJournal Article
Year of Publication2024
AuthorsSun, 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 AuthorsTOPMed mtDNA working group
JournalMitochondrion
Volume79
Pagination101954
Date Published2024 Sep 07
ISSN1872-8278
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 

DOI10.1016/j.mito.2024.101954
Alternate JournalMitochondrion
PubMed ID39245194