{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T18:36:22Z","timestamp":1767119782567,"version":"3.48.0"},"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["F32AG079618"],"award-info":[{"award-number":["F32AG079618"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P01AG066597"],"award-info":[{"award-number":["P01AG066597"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS109260"],"award-info":[{"award-number":["NS109260"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["RF1NS145263"],"award-info":[{"award-number":["RF1NS145263"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P30AG072979"],"award-info":[{"award-number":["P30AG072979"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>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\u2009=\u2009260). 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0338398","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T18:32:09Z","timestamp":1767119529000},"page":"e0338398","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1685-2967","authenticated-orcid":true,"given":"Barbara E.","family":"Spencer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Irwin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivianna M.","family":"Van Deerlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"EunRan","family":"Suh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward B.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Elman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin C.","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6202-3900","authenticated-orcid":true,"given":"Defne","family":"Amado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Baer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murray","family":"Grossman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Wolk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7581-6405","authenticated-orcid":true,"given":"Corey T.","family":"McMillan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"issue":"5796","key":"pone.0338398.ref001","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1126\/science.1134108","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume":"314","author":"M Neumann","year":"2006","journal-title":"Science"},{"issue":"3","key":"pone.0338398.ref002","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00401-006-0183-4","article-title":"Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration","volume":"113","author":"C Amador-Ortiz","year":"2007","journal-title":"Acta Neuropathol"},{"issue":"6","key":"pone.0338398.ref003","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00401-014-1282-2","article-title":"ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology","volume":"127","author":"PT Nelson","year":"2014","journal-title":"Acta Neuropathol"},{"issue":"6","key":"pone.0338398.ref004","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1002\/ana.24388","article-title":"Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease","volume":"77","author":"S Nag","year":"2015","journal-title":"Ann Neurol"},{"key":"pone.0338398.ref005","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/21678421.2016.1267768","article-title":"Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria","volume":"18","author":"MJ Strong","year":"2017","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"issue":"3","key":"pone.0338398.ref006","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1007\/BF00293396","article-title":"Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans","volume":"88","author":"DW Dickson","year":"1994","journal-title":"Acta Neuropathol"},{"issue":"1","key":"pone.0338398.ref007","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1212\/WNL.48.1.154","article-title":"Hippocampal sclerosis contributes to dementia in the elderly","volume":"48","author":"J Corey-Bloom","year":"1997","journal-title":"Neurology"},{"issue":"7","key":"pone.0338398.ref008","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1001\/archneur.59.7.1099","article-title":"Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study","volume":"59","author":"JB Leverenz","year":"2002","journal-title":"Arch Neurol"},{"issue":"6","key":"pone.0338398.ref009","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1016\/j.neuron.2018.02.027","article-title":"Genome-wide Analyses Identify KIF5A as a Novel ALS Gene","volume":"97","author":"A Nicolas","year":"2018","journal-title":"Neuron"},{"issue":"10","key":"pone.0338398.ref010","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/ng.442","article-title":"Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis","volume":"41","author":"MA van Es","year":"2009","journal-title":"Nat Genet"},{"issue":"3","key":"pone.0338398.ref011","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/ng.536","article-title":"Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions","volume":"42","author":"VM Van Deerlin","year":"2010","journal-title":"Nat Genet"},{"issue":"9","key":"pone.0338398.ref012","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004606","article-title":"Genome-wide association meta-analysis of neuropathologic features of Alzheimer\u2019s disease and related dementias","volume":"10","author":"GW Beecham","year":"2014","journal-title":"PLoS Genet"},{"issue":"9","key":"pone.0338398.ref013","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/ng.3622","article-title":"Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis","volume":"48","author":"W van Rheenen","year":"2016","journal-title":"Nat Genet"},{"issue":"5","key":"pone.0338398.ref014","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1212\/WNL.0b013e31820a0e3b","article-title":"TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers","volume":"76","author":"N Finch","year":"2011","journal-title":"Neurology"},{"issue":"3","key":"pone.0338398.ref015","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s00401-013-1239-x","article-title":"TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions","volume":"127","author":"MD Gallagher","year":"2014","journal-title":"Acta Neuropathol"},{"issue":"6","key":"pone.0338398.ref016","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1111\/jnc.12329","article-title":"TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia","volume":"126","author":"AM Nicholson","year":"2013","journal-title":"J Neurochem"},{"issue":"6","key":"pone.0338398.ref017","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1093\/brain\/awaa141","article-title":"Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies","volume":"143","author":"X Zhou","year":"2020","journal-title":"Brain"},{"issue":"3","key":"pone.0338398.ref018","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s00401-013-1240-4","article-title":"TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia","volume":"127","author":"M van Blitterswijk","year":"2014","journal-title":"Acta Neuropathol"},{"key":"pone.0338398.ref019","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1093\/brain\/awr007","article-title":"TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort","volume":"134","author":"J van der Zee","year":"2011","journal-title":"Brain"},{"issue":"1","key":"pone.0338398.ref020","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1002\/ana.24198","article-title":"C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis","volume":"76","author":"FP Diekstra","year":"2014","journal-title":"Ann Neurol"},{"issue":"6","key":"pone.0338398.ref021","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1007\/s00401-019-01962-9","article-title":"Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD","volume":"137","author":"C Pottier","year":"2019","journal-title":"Acta Neuropathol"},{"issue":"7","key":"pone.0338398.ref022","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1001\/jamaneurol.2018.0372","article-title":"Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum","volume":"75","author":"CM Karch","year":"2018","journal-title":"JAMA Neurol"},{"issue":"2","key":"pone.0338398.ref023","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD","volume":"72","author":"AE Renton","year":"2011","journal-title":"Neuron"},{"issue":"2","key":"pone.0338398.ref024","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS","volume":"72","author":"M DeJesus-Hernandez","year":"2011","journal-title":"Neuron"},{"key":"pone.0338398.ref025","first-page":"96","article-title":"El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases\/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial \u201cClinical limits of amyotrophic lateral sclerosis\u201d workshop contributors","author":"BR Brooks","year":"1994","journal-title":"J Neurol Sci"},{"key":"pone.0338398.ref026","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkj144","article-title":"The UCSC Genome Browser Database: update 2006","volume":"34","author":"AS Hinrichs","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"pone.0338398.ref027","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"P Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"pone.0338398.ref028","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3389\/fgene.2020.00157","article-title":"LDlinkR: An R Package for Rapidly Calculating Linkage Disequilibrium Statistics in Diverse Populations","volume":"11","author":"TA Myers","year":"2020","journal-title":"Front Genet"},{"issue":"16","key":"pone.0338398.ref029","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1093\/bioinformatics\/bti525","article-title":"BioMart and Bioconductor: a powerful link between biological databases and microarray data analysis","volume":"21","author":"S Durinck","year":"2005","journal-title":"Bioinformatics"},{"key":"pone.0338398.ref030","doi-asserted-by":"crossref","DOI":"10.12688\/f1000research.24956.2","article-title":"gprofiler2 -- an R package for gene list functional enrichment analysis and namespace conversion toolset g:Profiler","volume":"9","author":"L Kolberg","year":"2020","journal-title":"F1000Res"},{"issue":"4","key":"pone.0338398.ref031","article-title":"Building an integrated neurodegenerative disease database at an academic health center","volume":"7","author":"SX Xie","year":"2011","journal-title":"Alzheimers Dement"},{"issue":"10","key":"pone.0338398.ref032","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/ng.3656","article-title":"Next-generation genotype imputation service and methods","volume":"48","author":"S Das","year":"2016","journal-title":"Nat Genet"},{"issue":"7845","key":"pone.0338398.ref033","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/s41586-021-03205-y","article-title":"Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program","volume":"590","author":"D Taliun","year":"2021","journal-title":"Nature"},{"issue":"5","key":"pone.0338398.ref034","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/bib\/bbx012","article-title":"Strategies for processing and quality control of Illumina genotyping arrays","volume":"19","author":"S Zhao","year":"2018","journal-title":"Brief Bioinform"},{"issue":"3","key":"pone.0338398.ref035","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s00401-015-1445-9","article-title":"Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration","volume":"130","author":"E Suh","year":"2015","journal-title":"Acta Neuropathol"},{"issue":"4","key":"pone.0338398.ref036","doi-asserted-by":"crossref","DOI":"10.1016\/j.jalz.2013.06.003","article-title":"A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank","volume":"10","author":"JB Toledo","year":"2014","journal-title":"Alzheimers Dement"},{"issue":"6435","key":"pone.0338398.ref037","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/364362c0","article-title":"Mutations in Cu\/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis","volume":"364","author":"DR Rosen","year":"1993","journal-title":"Nature"},{"issue":"5","key":"pone.0338398.ref038","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/nn.4000","article-title":"Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia","volume":"18","author":"A Freischmidt","year":"2015","journal-title":"Nat Neurosci"},{"issue":"5","key":"pone.0338398.ref039","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/ng.132","article-title":"TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis","volume":"40","author":"E Kabashi","year":"2008","journal-title":"Nat Genet"},{"issue":"5","key":"pone.0338398.ref040","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.neuron.2010.11.036","article-title":"Exome sequencing reveals VCP mutations as a cause of familial ALS","volume":"68","author":"JO Johnson","year":"2010","journal-title":"Neuron"},{"issue":"7105","key":"pone.0338398.ref041","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/nature05017","article-title":"Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21","volume":"442","author":"M Cruts","year":"2006","journal-title":"Nature"},{"issue":"7105","key":"pone.0338398.ref042","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/nature05016","article-title":"Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17","volume":"442","author":"M Baker","year":"2006","journal-title":"Nature"},{"issue":"1","key":"pone.0338398.ref043","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00401-011-0845-8","article-title":"A harmonized classification system for FTLD-TDP pathology","volume":"122","author":"IRA Mackenzie","year":"2011","journal-title":"Acta Neuropathol"},{"issue":"1","key":"pone.0338398.ref044","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-009-0612-2","article-title":"Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update","volume":"119","author":"IRA Mackenzie","year":"2010","journal-title":"Acta Neuropathol"},{"issue":"1","key":"pone.0338398.ref045","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00401-017-1679-9","article-title":"Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration","volume":"134","author":"EB Lee","year":"2017","journal-title":"Acta Neuropathol"},{"key":"pone.0338398.ref046","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1742-2094-2-24","article-title":"The microglial \u201cactivation\u201d continuum: from innate to adaptive responses","volume":"2","author":"T Town","year":"2005","journal-title":"J Neuroinflammation"},{"issue":"7638","key":"pone.0338398.ref047","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"SA Liddelow","year":"2017","journal-title":"Nature"},{"issue":"9","key":"pone.0338398.ref048","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1093\/jnen\/63.9.964","article-title":"Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism","volume":"63","author":"W Zhao","year":"2004","journal-title":"J Neuropathol Exp Neurol"},{"issue":"9","key":"pone.0338398.ref049","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/nbt.1957","article-title":"Astrocytes from familial and sporadic ALS patients are toxic to motor neurons","volume":"29","author":"AM Haidet-Phillips","year":"2011","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pone.0338398.ref050","doi-asserted-by":"crossref","first-page":"10046","DOI":"10.1038\/s41598-017-10488-7","article-title":"Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS","volume":"7","author":"AM D\u2019Erchia","year":"2017","journal-title":"Sci Rep"},{"issue":"8","key":"pone.0338398.ref051","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0160520","article-title":"RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord","volume":"11","author":"DG Brohawn","year":"2016","journal-title":"PLoS One"},{"issue":"5","key":"pone.0338398.ref052","doi-asserted-by":"crossref","DOI":"10.1212\/NXI.0000000000000829","article-title":"Motor cortex transcriptome reveals microglial key events in amyotrophic lateral sclerosis","volume":"7","author":"O Dols-Icardo","year":"2020","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"issue":"3","key":"pone.0338398.ref053","doi-asserted-by":"crossref","first-page":"823","DOI":"10.18632\/aging.101195","article-title":"Amyotrophic lateral sclerosis, gene deregulation in the anterior horn of the spinal cord and frontal cortex area 8: implications in frontotemporal lobar degeneration","volume":"9","author":"P Andr\u00e9s-Benito","year":"2017","journal-title":"Aging (Albany NY)"},{"issue":"5","key":"pone.0338398.ref054","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1007\/s00401-015-1468-2","article-title":"Rab1-dependent ER-Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS","volume":"130","author":"KY Soo","year":"2015","journal-title":"Acta Neuropathol"},{"key":"pone.0338398.ref055","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3389\/fnins.2015.00400","article-title":"Golgi fragmentation in amyotrophic lateral sclerosis, an overview of possible triggers and consequences","volume":"9","author":"V Sundaramoorthy","year":"2015","journal-title":"Front Neurosci"},{"issue":"6","key":"pone.0338398.ref056","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s00401-019-01964-7","article-title":"Disrupted neuronal trafficking in amyotrophic lateral sclerosis","volume":"137","author":"K Burk","year":"2019","journal-title":"Acta Neuropathol"},{"issue":"6","key":"pone.0338398.ref057","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1093\/brain\/awaa022","article-title":"The multifaceted role of kinases in amyotrophic lateral sclerosis: genetic, pathological and therapeutic implications","volume":"143","author":"W Guo","year":"2020","journal-title":"Brain"},{"issue":"10","key":"pone.0338398.ref058","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1093\/hmg\/ddn023","article-title":"Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration","volume":"17","author":"AS Chen-Plotkin","year":"2008","journal-title":"Hum Mol Genet"},{"issue":"7","key":"pone.0338398.ref059","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1093\/jnen\/nly037","article-title":"Gene Expression Profile in Frontal Cortex in Sporadic Frontotemporal Lobar Degeneration-TDP","volume":"77","author":"P Andr\u00e9s-Benito","year":"2018","journal-title":"J Neuropathol Exp Neurol"},{"key":"pone.0338398.ref060","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/978-3-030-25650-0_12","article-title":"The Cytoskeleton as a Modulator of Aging and Neurodegeneration","volume":"1178","author":"K Kounakis","year":"2019","journal-title":"Adv Exp Med Biol"},{"issue":"19","key":"pone.0338398.ref061","doi-asserted-by":"crossref","first-page":"10298","DOI":"10.3390\/ijms221910298","article-title":"Molecular Pathways Involved in Frontotemporal Lobar Degeneration with TDP-43 Proteinopathy: What Can We Learn from Proteomics?","volume":"22","author":"MO Mol","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"3509","key":"pone.0338398.ref062","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1126\/science.135.3509.1127","article-title":"Are new neurons formed in the brains of adult mammals?","volume":"135","author":"J Altman","year":"1962","journal-title":"Science"},{"issue":"11","key":"pone.0338398.ref063","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1038\/3305","article-title":"Neurogenesis in the adult human hippocampus","volume":"4","author":"PS Eriksson","year":"1998","journal-title":"Nat Med"},{"issue":"3","key":"pone.0338398.ref064","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s00401-013-1238-y","article-title":"Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD)","volume":"127","author":"J Brettschneider","year":"2014","journal-title":"Acta Neuropathol"},{"issue":"1","key":"pone.0338398.ref065","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/ana.23937","article-title":"Stages of pTDP-43 pathology in amyotrophic lateral sclerosis","volume":"74","author":"J Brettschneider","year":"2013","journal-title":"Ann Neurol"},{"key":"pone.0338398.ref066","doi-asserted-by":"crossref","DOI":"10.1002\/alz.040021","article-title":"Gene\u2010 and age\u2010informed enrichment method for preclinical Alzheimer\u2019s disease trials: Approach and estimated cost savings","volume":"16","author":"BE Spencer","year":"2020","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"pone.0338398.ref067","doi-asserted-by":"crossref","first-page":"639078","DOI":"10.3389\/fnins.2021.639078","article-title":"Moving Toward Patient-Tailored Treatment in ALS and FTD: The Potential of Genomic Assessment as a Tool for Biological Discovery and Trial Recruitment","volume":"15","author":"IJ Broce","year":"2021","journal-title":"Front Neurosci"},{"issue":"18","key":"pone.0338398.ref068","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1093\/eurheartj\/ehac093","article-title":"A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study","volume":"43","author":"X Lu","year":"2022","journal-title":"Eur Heart J"},{"issue":"6","key":"pone.0338398.ref069","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/S1470-2045(23)00156-0","article-title":"Utility of polygenic risk scores in UK cancer screening: a modelling analysis","volume":"24","author":"C Huntley","year":"2023","journal-title":"Lancet Oncol"},{"issue":"6","key":"pone.0338398.ref070","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1093\/brain\/awz099","article-title":"Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report","volume":"142","author":"PT Nelson","year":"2019","journal-title":"Brain"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0338398","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T18:32:19Z","timestamp":1767119539000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0338398"}},"subtitle":[],"editor":[{"given":"Vijay","family":"Kumar","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,30]]},"references-count":70,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0338398","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2025,12,30]]}}}