biostudies-literatureBonham LWNIA NIH HHSNIDA NIH HHSMedical Research CouncilNIDCD NIH HHSNational Institute for Health Research (NIHR)NINDS NIH HHSAlzheimer's SocietyWellcome Trust10854https://www.ebi.ac.uk/biostudies/studies/S-EPMC6659677biostudies-literatureUnknown9(1)The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify aScientific reportsGenetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia.PMC6659677G0301152K01 AG049152103838/Z/14/ZMR/L010933/1P01 AG019724U24 DA041123MC_U123160651MR/N026004/1U01 AG052943U01 DA041174P50 AG023501U01 DA041093P30 AG062422K24 DC015544NF-SI-0617-10175U01 DA041106284R01 NS100440UKDRI-1009U01 DA041022R56 NS050915R01 NS050915U01 DA041148U01 DA041025K01 AG046374U01 DA051039MC_UU_00024/1U01 DA050989Rossi GFox NCKwok JBJScheltens PBagnoli SHodges JRJaros EAlonso EKapogiannis DGhidoni RBorroni BGriffiths TDLebouvier TRubino ERogaeva EGiaccone GPuca AALogroscino GGallo MRossor MNMcKeith IGGrafman JCruchaga CAnfossi MGrossman MPadovani ADesikan RSClarimon JKnopman DLleo ARiemenschneider MMaletta RSeeley WWMorris HRNalls MARollin AScarpini EDobson-Stone CCairns NJVan Deerlin VMFranceschi MPostiglione APiguet ONacmias BBonham LWHuey EDPasquier FBenussi LRichardson AKurz ABaranzini SEMomeni PTierney MCUphill JCollinge JBoeve BFGasparoni GFrangipane Fvan der Zee JAttems JSmirne NSteele NZRRowe JBMead SGraff CBaker MSchofield PRForloni GAlexopoulos PRuiz AConidi MEDeramecourt VGalimberti DDickson DWVan Broeckhoven CHannequin DPijnenburg YALPickering-Brown SRademakers RHernandez DGTrojanowski JQGolfier VCapozzo RKristiansen MSpillantini MGGraff-Radford NRThompson EOrtega-Cubero SGeier EGHess CPHernandez IKarch CMvan Swieten JCNovelli VFerrucci LLandqvist Waldo MBartley LRazquin CMorris CMMiller ZAFenoglio CDiehl-Schmid JRollinson SJosephs KAFerrari RBroce IRohrer JDBrice ARamasamy AHeutink PWen NLLewis PNielsen JEHjermind LESeelaar HPetersen RCGorno-Tempini MLSorbi SBoada MInternational FTD-Genomics Consortium (IFGC)Leber IWassermann EMBaborie ABruni ACDopper EGPHalliday GMMiller BLSchlachetzki JCMCruts MWarren JDHardy JPiaceri INilsson KMilan GKarydas AMHaan ECupidi CNilsson CBlesa RCappa SFPerneczky RParisi JETagliavini FDanek AHsiung G-RVercelletto MPietrini PSerpente MSnowden JSSt George-Hyslop PGerhard ABernardi LManzoni CSingleton ABMann DMAGu WYokoyama JSMackenzie IRAIbach BPinessi LRosen HSorrentino PThomas AJPastor PBinetti GPichler SRainero IRizzu PMayhaus MChiang H-Albani DfalseGenetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia.The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify a2019-01-01T00:00:00Z2019 Jul2026-04-30T15:15:06.478Z2026-04-07T16:06:04.556ZS-EPMC66596773135042010.1038/s41598-019-46415-1