Abstract
The genetic landscape of mitochondrial DNA (mtDNA) has been elusive. By analyzing mtDNA using the whole genome sequence (WGS) of Japanese individuals (n = 1928), we identified 2023 mtDNA variants and high-resolution haplogroups. Frequency spectra of the haplogroups were population-specific and were heterogeneous among geographic regions within Japan. Application of machine learning methods could finely classify the subjects corresponding to the high-digit mtDNA sub-haplogroups. mtDNA had distinct genetic structures from that of nuclear DNA (nDNA), characterized by no distance-dependent linkage disequilibrium decay, sparse tagging of common variants, and the existence of common haplotypes spanning the entire mtDNA. We did not detect any evidence of mtDNA–nDNA (or mtDNA copy number–nDNA) genotype associations. Together with WGS-based mtDNA variant imputation, we conducted a phenome-wide association study of 147,437 Japanese individuals with 99 clinical phenotypes. We observed pleiotropy of mtDNA genetic risk on the five late-onset human complex traits including creatine kinase (P = 1.7 × 10−12).
Highlights
The genetic landscape of mitochondrial DNA has been elusive
We provide a comprehensive analysis that characterizes the genetic and phenotypic landscape of mitochondria in the Japanese population. (i) We constructed a high-resolution mitochondrial DNA (mtDNA) variant list and haplotype classifications in the Japanese population based on deep whole genome sequence (WGS) of ~2000 individuals. (ii) We conducted unsupervised clustering of the mtDNA variant patterns and assessed their correspondence with defined haplogroups by using a set of machine learning (ML) methods. (iii) We quantitatively assessed positional distributions and linkage disequilibrium (LD) structure of the mtDNA variants by parallelly comparing with those of nuclear DNA (nDNA). (iv) We performed genome-wide scans to investigate the mtDNA–nDNA and mtDNA copy numbers (mtCNs)–nDNA genotype associations. (v) we conducted mitochondrial genomewide genotype imputation of genome-wide association study (GWAS) data of more than 140,000 Japanese individuals, by using the population-specific WGS reference data
Our WGS study had a relatively larger sample size than the previous ones, we did not find an evidence of mtDNA- nDNA genotype association
Summary
By analyzing mtDNA using the whole genome sequence (WGS) of Japanese individuals (n = 1928), we identified 2023 mtDNA variants and high-resolution haplogroups. Together with WGS-based mtDNA variant imputation, we conducted a phenome-wide association study of 147,437 Japanese individuals with 99 clinical phenotypes. The difference of linkage disequilibrium (LD) structure between mtDNA and nDNA has been reported[16], a comprehensive evaluation of mtDNA LD using whole genome sequence (WGS) data has not been conducted, especially in nonEuropean populations. Considering population specificity of mtDNA haplotype structure, phenome-wide association study (PheWAS) utilizing a large-scale biobank cohort with the adjustment for population structure is required to robustly identify mtDNA variants associated with human complex traits. (v) we conducted mitochondrial genomewide genotype imputation of genome-wide association study (GWAS) data of more than 140,000 Japanese individuals, by using the population-specific WGS reference data. We conducted a PheWAS of 99 complex human disease and quantitative traits
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