{"doi":"10.3233/adr-230120","title":"MitoH3: Mitochondrial Haplogroup and Homoplasmic/Heteroplasmic Variant Calling Pipeline for Alzheimer’s Disease Sequencing Project","abstract":"Background: Mitochondrial DNA (mtDNA) is a double-stranded circular DNA and has multiple copies in each cell. Excess heteroplasmy, the coexistence of distinct variants in copies of mtDNA within a cell, may lead to mitochondrial impairments. Accurate determination of heteroplasmy in whole-genome sequencing (WGS) data has posed a significant challenge because mitochondria carrying heteroplasmic variants cannot be distinguished during library preparation. Moreover, sequencing errors, contamination, and nuclear mtDNA segments can reduce the accuracy of heteroplasmic variant calling. Objective: To efficiently and accurately call mtDNA homoplasmic and heteroplasmic variants from the large-scale WGS data generated from the Alzheimer's Disease Sequencing Project (ADSP), and test their association with Alzheimer's disease (AD). Methods: In this study, we present MitoH3-a comprehensive computational pipeline for calling mtDNA homoplasmic and heteroplasmic variants and inferring haplogroups in the ADSP WGS data. We first applied MitoH3 to 45 technical replicates from 6 subjects to define a threshold for detecting heteroplasmic variants. Then using the threshold of 5% ≤variant allele fraction≤95%, we further applied MitoH3 to call heteroplasmic variants from a total of 16,113 DNA samples with 6,742 samples from cognitively normal controls and 6,183 from AD cases. Results: This pipeline is available through the Singularity container engine. For 4,311 heteroplasmic variants identified from 16,113 samples, no significant variant count difference was observed between AD cases and controls. Conclusions: Our streamlined pipeline, MitoH3, enables computationally efficient and accurate analysis of a large number of samples.","journal":"Journal of Alzheimer s Disease Reports","year":2024,"id":465273,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.728,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":568537,"name":"Tong Tong","orcid":"0000-0002-4731-9807","position":1,"is_corresponding":false},{"id":227323,"name":"John J. Farrell","orcid":"0000-0001-6502-1572","position":2,"is_corresponding":false},{"id":40736,"name":"Eden R. Martin","orcid":"0000-0002-4035-9152","position":3,"is_corresponding":false},{"id":261839,"name":"William S. Bush","orcid":"0000-0002-9729-6519","position":4,"is_corresponding":false},{"id":6903,"name":"Margaret A. Pericak‐Vance","orcid":"0000-0001-7283-8804","position":5,"is_corresponding":false},{"id":261852,"name":"Li‐San Wang","orcid":"0000-0002-3684-0031","position":6,"is_corresponding":false},{"id":27607,"name":"Gerard D. Schellenberg","orcid":"0000-0003-1115-2475","position":7,"is_corresponding":false},{"id":6896,"name":"Jonathan L. Haines","orcid":"0000-0002-4351-4728","position":8,"is_corresponding":false},{"id":24988,"name":"Kathryn L. Lunetta","orcid":"0000-0002-9268-810X","position":9,"is_corresponding":false},{"id":27609,"name":"Lindsay A. Farrer","orcid":"0000-0001-5533-4225","position":10,"is_corresponding":false},{"id":561977,"name":"Xiaoling Zhang","orcid":"0000-0003-0868-1923","position":11,"is_corresponding":false},{"id":562001,"name":"Congcong Zhu","orcid":"0009-0008-7457-2542","position":0,"is_corresponding":true}],"reference_count":24,"raw_metadata":null,"created_at":"2026-07-19T02:04:46.201722Z","pmid":"38746629","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}