Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD.
Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci.
Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10–12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10−7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes.
Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.
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The IFGC and IPDGC members are listed in the supplementary acknowledgments.
Contributors R Ferrari; D G Hernandez; M A Nalls; J D Rohrer; A Ramasamy; J B J Kwok; C Dobson-Stone; P R Schofield; G M Halliday; J R Hodges; O Piguet; L Bartley; E Thompson; E Haan; I Hernández; A Ruiz; M Boada; B Borroni; A Padovani; C Cruchaga; N J Cairns; L Benussi; G Binetti; R Ghidoni; G Forloni; D Albani; D Galimberti; C Fenoglio; M Serpente; E Scarpini; J Clarimón; A Lleó; R Blesa; M Landqvist Waldö; K Nilsson; C Nilsson; I R A Mackenzie; G-Y R Hsiung; D M A Mann; J Grafman; C M Morris; J Attems; T D Griffiths; I G McKeith; A J Thomas; P Pietrini; E D Huey; E M Wassermann; A Baborie; E Jaros; M C Tierney; P Pastor; C Razquin; S Ortega-Cubero; E Alonso; R Perneczky; J Diehl-Schmid; P Alexopoulos; A Kurz; I Rainero; E Rubino; L Pinessi; E Rogaeva; P St George-Hyslop; G Rossi; F Tagliavini; G Giaccone; J B Rowe; J C M Schlachetzki; J Uphill; J Collinge; S Mead; A Danek; V M Van Deerlin; M Grossman; J Q Trojanowski; J van der Zee; M Cruts; C Van Broeckhoven; S F Cappa; I Leber; D Hannequin; V Golfier; M Vercelletto; A Brice; B Nacmias; S Sorbi; S Bagnoli; I Piaceri; J E Nielsen; L E Hjermind; M Riemenschneider; M Mayhaus; B Ibach; G Gasparoni; S Pichler; W Gu; M N Rossor; N C Fox; J D Warren; M G Spillantini; H R Morris; P Rizzu; P Heutink; J S Snowden; S Rollinson; A Richardson; A Gerhard; A C Bruni; R Maletta; F Frangipane; C Cupidi; L Bernardi; M Anfossi; M Gallo; M E Conidi; N Smirne; R Rademakers; M Baker; D W Dickson; N R Graff-Radford; R C Petersen; D Knopman; K A Josephs; B F Boeve; J E Parisi; W W Seeley; B L Miller; A M Karydas; H Rosen; J C van Swieten; E G P Dopper; H Seelaar; Y A L Pijnenburg; P Scheltens; G Logroscino; R Capozzo; V Novelli; A A Puca; M Franceschi; A Postiglione; G Milan; P Sorrentino; M Kristiansen; H-H Chiang; C Graff; F Pasquier; A Rollin; V Deramecourt; T Lebouvier; D Kapogiannis; L Ferrucci; S Pickering-Brown; A B Singleton; J Hardy; P Momeni
Contributors RF and RSD analysed and interpreted data and wrote the manuscript. YW, JV, SG, AW, CMK, AJS, CCF, JBB, PM, GSS, WPD, LPS, CPH, JSY, LWB, GDR, BLM, OAA, AMD and JH contributed to the conception or design of the work or the acquisition or analysis of data and critically reviewed the drafted manuscript at multiple stages.
Funding This research was supported by grants from the National Institutes of Health (NIH-AG046374, K01 AG049152), Larry J Hilbom Foundation, the Research Council of Norway (#213837, #225989, #223273, #237250/EU JPND), the South East Norway Health Authority (2013–123), Norwegian Health Association and the KG Jebsen Foundation. RSD was supported by the National Alzheimer's Coordinating Center Junior Investigator Award, ASNR Foundation Alzheimer's Imaging Research Grant Program and NIH/NIDA grant U24DA041123. RF is supported by Alzheimer's Society (grant number 284). For IFGC, IPDGC and IGAP funding sources, see online supplemental acknowledgements.
Disclaimer The funding organisations had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests None declared.
Ethics approval The relevant institutional review boards or ethics committees approved the research protocol of the individual GWAS used in the current analysis, and all human participants gave written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.