Immune-related genetic enrichment in frontotemporal dementia
Authors: Broce Iris , Karch Celeste M. , Wen Natalie , Fan Chun C. , Wang Yunpeng , Hong Tan Chin , Kouri Naomi , Ross Owen A. , Höglinger Günter U. , Muller Ulrich , Hardy John ,   International FTD-Genomics Consortium (IFGC), Momeni Parastoo , Hess Christopher P. , Dillon William P. , Miller Zachary A. , Bonham Luke W. , Rabinovici Gil D. , Rosen Howard J. , Schellenberg Gerard D. , Franke Andre , Karlsen Tom H. , Veldink Jan H. , Ferrari Raffaele , Yokoyama Jennifer S. , Miller Bruce L. , Andreassen Ole A. , Dale Anders M. , Desikan Rahul S. , Sugrue Leo P. , Ferrari R , 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 , George-Hyslop P St , 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 , der Zee J van , Cruts M , Broeckhoven C Van , 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 , Seeley W W , Miller B L , 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 , Hardy J , Momeni P 
Published: July 2017

Background

Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.

Methods and findings

Using large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs)jointlyassociated with ‘FTD-related disorders’ namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) – and one or more immune-mediated diseases including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) < 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen (HLA)region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci withinLRRK2(Leucine Rich Repeat Kinase 2), TBKBP1(TANK-binding kinase 1 Binding Protein 1), andPGBD5(PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within theHLAregion) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types.

Conclusions

We show considerable immune-mediated genetic enrichment specifically in FTD, particularly within theHLAregion. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.