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Association analysis of mitochondrial DNA heteroplasmic variants: methods and application.
Thursday,2024-02-01 20:51 America/Los_Angeles — ecterry
| 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/Institutional Authors | TOPMed mtDNA working group |
| Journal | medRxiv |
| Date Published | 2024 Jan 13 |
| Abstract | <p>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 bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.</p> |
| DOI | 10.1101/2024.01.12.24301233 |
| Alternate Journal | medRxiv |
| PubMed ID | 38260412 |
| PubMed Central ID | PMC10802757 |
ePub date:
24/01