{"doi":"10.1371/journal.pone.0338398","title":"Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies","abstract":"TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and limbic-predominant age-related TDP-43 encephalopathy, encompass a spectrum of clinical and neuropathological traits. Despite mounting evidence for shared genetic risk across TDP-43 proteinopathies, the modifiers of individual-level traits are unknown. We aimed to identify polygenic contributions to trait heterogeneity across TDP-43 proteinopathies. We used weighted correlation analysis of GWAS summary statistics for ALS, FTLD-TDP, and hippocampal sclerosis of aging (HS-Aging) to identify data-driven clusters of highly correlated single nucleotide polymorphisms (SNPs). We performed gene ontology enrichment analysis for each identified cluster. We derived cluster-specific polygenic scores and evaluated their association with clinical and neuropathological traits in an independently evaluated sample of individuals who met neuropathological and/or genetic criteria for FTLD-TDP or ALS (n = 260). We identified 5 distinct data-driven clusters, including 3 GWAS phenotype-specific clusters (FTLD-TDP, ALS, HS-Aging) and 2 clusters representing the overlap between a pair of GWAS phenotypes (ALS-FTLD and FTLD-HS). Pathway analysis revealed biologically meaningful associations including distinct GWAS phenotype-specific processes within clusters. Cluster-specific ALS and FTLD-TDP polygenic risk each associated with individual-level clinical traits, even within the context of autosomal dominant mutation carriers, where higher ALS polygenic risk associated with neuromuscular impairment and higher FTLD-TDP polygenic risk associated with cognitive-behavioral impairment. Moreover, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden within characteristic FTLD-TDP brain regions. We suggest that there are polygenic modifiers of clinical and neuropathological traits across TDP-43 proteinopathies that may contribute to individual-level differences, including likelihood for developing FTLD or ALS.","journal":"PLoS ONE","year":2025,"id":587429,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227417,"name":"David J. Irwin","orcid":"0000-0002-5599-5098","position":1,"is_corresponding":false},{"id":27603,"name":"Vivianna M. Van Deerlin","orcid":"0000-0002-7400-9097","position":2,"is_corresponding":false},{"id":80303,"name":"Eunran Suh","orcid":null,"position":3,"is_corresponding":false},{"id":107087,"name":"Edward B. Lee","orcid":"0000-0002-4589-1180","position":4,"is_corresponding":false},{"id":495593,"name":"Lauren Elman","orcid":"0000-0003-4706-950X","position":5,"is_corresponding":false},{"id":1503213,"name":"Colin C. Quinn","orcid":null,"position":6,"is_corresponding":false},{"id":625500,"name":"Defne A. Amado","orcid":"0000-0001-6202-3900","position":7,"is_corresponding":false},{"id":1067629,"name":"Michael Baer","orcid":"0009-0001-3739-4344","position":8,"is_corresponding":false},{"id":58510,"name":"Murray Grossman","orcid":"0000-0002-7447-6218","position":9,"is_corresponding":false},{"id":230045,"name":"David A. Wolk","orcid":"0000-0002-3554-3481","position":10,"is_corresponding":false},{"id":227422,"name":"Corey T. McMillan","orcid":"0000-0002-7581-6405","position":11,"is_corresponding":false},{"id":434086,"name":"Barbara E. Spencer","orcid":"0000-0002-1685-2967","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:59:36.020030Z","pmid":"41468379","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":[]}