{"doi":"10.1186/s40478-021-01250-2","title":"Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study","abstract":"Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer's Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer's pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer's-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.","journal":"Acta Neuropathologica Communications","year":2021,"id":155606,"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":58,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":245009,"name":"Peter T. Nelson","orcid":"0000-0002-6161-1265","position":1,"is_corresponding":false},{"id":244994,"name":"Yuriko Katsumata","orcid":"0000-0002-0188-8094","position":2,"is_corresponding":false},{"id":244998,"name":"Lincoln M. P. Shade","orcid":"0000-0001-6093-4823","position":3,"is_corresponding":false},{"id":606254,"name":"Kevin L. Boehme","orcid":null,"position":4,"is_corresponding":false},{"id":248198,"name":"Merilee Teylan","orcid":null,"position":5,"is_corresponding":false},{"id":245007,"name":"Matthew D. Cykowski","orcid":"0000-0002-5973-803X","position":6,"is_corresponding":false},{"id":261837,"name":"Shubhabrata Mukherjee","orcid":"0000-0003-2522-2884","position":7,"is_corresponding":false},{"id":54266,"name":"John S. K. Kauwe","orcid":"0000-0001-8641-2468","position":8,"is_corresponding":false},{"id":254761,"name":"Timothy J. Hohman","orcid":"0000-0002-3377-7014","position":9,"is_corresponding":false},{"id":7426,"name":"Julie A. Schneider","orcid":"0000-0002-9482-1752","position":10,"is_corresponding":false},{"id":244999,"name":"David W. Fardo","orcid":"0000-0002-7207-4696","position":11,"is_corresponding":false},{"id":528560,"name":"Adam Dugan","orcid":"0000-0001-5783-3781","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-18T23:44:03.750995Z","pmid":"34526147","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":[]}