Abstract

Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.

Highlights

  • Frontotemporal dementia (FTD) is one of the leading causes of dementia in patients younger than 65 years of age (Rabinovici and Miller, 2010; Seelaar et al, 2011)

  • The summary statistics of variants used for deriving gene- based P-values for TOMM40 and APOE are given in Supplementary Tables 1A and B, respectively, and the regional plots are shown in Fig. 1A and B

  • We identified association of the TOMM40 and APOE genes with bvFTD, and the ARHGAP35 and SERPINA1 genes with progressive non-fluent aphasia (PNFA)

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Summary

Introduction

Frontotemporal dementia (FTD) is one of the leading causes of dementia in patients younger than 65 years of age (Rabinovici and Miller, 2010; Seelaar et al, 2011). It is characterized by degeneration of the frontal and anterior temporal lobes leading to a decline in behaviour and language. FTD is a heterogeneous condition clinically, pathologically and genetically (Cairns et al, 2007; Seelaar et al, 2011) It is broadly categorized into the behavioural variant (bvFTD) and the language variant or primary progressive aphasia (PPA), which is further categorized into semantic dementia and progressive non-fluent aphasia (PNFA). Few large genome wide association studies (GWAS) have been performed for FTD (Van Deerlin et al, 2010; Ferrari et al, 2014, 2015) reporting an association with TMEM106B for FTLD with TDP-43 pathology (Van Deerlin et al, 2010), and with the locus comprising RAB38 and CTSC as well as the HLA-DRA/HLA-DRB5 locus for bvFTD and FTD, respectively (Ferrari et al, 2014)

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