Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
Authors: Bonham Luke W. , Steele Natasha Z. R. , Karch Celeste M. , Broce Iris , Geier Ethan G. , Wen Natalie L. , Momeni Parastoo , Hardy John , Miller Zachary A. , Gorno-Tempini Maria Luisa , Hess Christopher P. , Lewis Patrick , Miller Bruce L. , Seeley William W. , Manzoni Claudia , Desikan Rahul S. , Baranzini Sergio E. , Ferrari Raffaele , Yokoyama Jennifer S. ,   International FTD-Genomics Consortium (IFGC), Hernandez D. G. , Nalls M. A. , Rohrer J. D. , Ramasamy A. , Kwok J. B. J. , Dobson-Stone C. , Schofield P. R. , Halliday G. M. , Hodges J. R. , Piguet O. , Bartley L. , Thompson E. , Haan E. , Hernández I. , Ruiz A. , Boada M. , Borroni B. , Padovani A. , Cruchaga C. , Cairns N. J. , Benussi L. , Binetti G. , Ghidoni R. , Forloni G. , Albani D. , Galimberti D. , Fenoglio C. , Serpente M. , Scarpini E. , Clarimón J. , Lleó A. , Blesa R. , Landqvist Waldö M. , Nilsson K. , Nilsson C. , Mackenzie I. R. A. , Hsiung G. -Y. R. , Mann D. M. A. , Grafman J. , Morris C. M. , Attems J. , Griffiths T. D. , McKeith I. G. , Thomas A. J. , Pietrini P. , Huey E. D. , Wassermann E. M. , Baborie A. , Jaros E. , Tierney M. C. , Pastor P. , Razquin C. , Ortega-Cubero S. , Alonso E. , Perneczky R. , Diehl-Schmid J. , Alexopoulos P. , Kurz A. , Rainero I. , Rubino E. , Pinessi L. , Rogaeva E. , St George-Hyslop P. , Rossi G. , Tagliavini F. , Giaccone G. , Rowe J. B. , Schlachetzki J. C. M. , Uphill J. , Collinge J. , Mead S. , Danek A. , Van Deerlin V. M. , Grossman M. , Trojanowski J. Q. , van der Zee J. , Cruts M. , Van Broeckhoven C. , Cappa S. F. , Leber I. , Hannequin D. , Golfier V. , Vercelletto M. , Brice A. , Nacmias B. , Sorbi S. , Bagnoli S. , Piaceri I. , Nielsen J. E. , Hjermind L. E. , Riemenschneider M. , Mayhaus M. , Ibach B. , Gasparoni G. , Pichler S. , Gu W. , Rossor M. N. , Fox N. C. , Warren J. D. , Spillantini M. G. , Morris H. R. , Rizzu P. , Heutink P. , Snowden J. S. , Rollinson S. , Richardson A. , Gerhard A. , Bruni A. C. , Maletta R. , Frangipane F. , Cupidi C. , Bernardi L. , Anfossi M. , Gallo M. , Conidi M. E. , Smirne N. , Rademakers R. , Baker M. , Dickson D. W. , Graff-Radford N. R. , Petersen R. C. , Knopman D. , Josephs K. A. , Boeve B. F. , Parisi J. E. , Karydas A. M. , Rosen H. , van Swieten J. C. , Dopper E. G. P. , Seelaar H. , Pijnenburg Y. A. L. , Scheltens P. , Logroscino G. , Capozzo R. , Novelli V. , Puca A. A. , Franceschi M. , Postiglione A. , Milan G. , Sorrentino P. , Kristiansen M. , Chiang H. -H. , Graff C. , Pasquier F. , Rollin A. , Deramecourt V. , Lebouvier T. , Kapogiannis D. , Ferrucci L. , Pickering-Brown S. , Singleton A. B. 
Published: July 2019

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 and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.