Abstract

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10−7 and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of –cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD–genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis.

Highlights

  • Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer’s disease (AD), worldwide (Ratnavalli et al, 2002)

  • Our association analysis was performed on 530 FTD cases and 926 controls

  • We evaluated effects on transcription exerted by the suggestive SNPs at the 2p16.3 locus: data were only available for the risk allele of rs12619513 (LOC730100), revealing no significant in cis effects on transcription in any of the assayed brain tissues (Supplementary Table 2)

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Summary

Introduction

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer’s disease (AD), worldwide (Ratnavalli et al, 2002). The 2 main FTD syndromes affect an individual’s behavior or language resulting either in the behavioral variant FTD (bvFTD) or the language variant broadly named primary progressive aphasia (PPA) (Gorno-Tempini et al, 2011; Rascovsky et al, 2011). The latter is subdivided into semantic variant PPA and non-fluent/agrammatic variant PPA (GornoTempini et al, 2011). International genome-wide association studies (GWAS) identified novel potential risk factors for FTD with TDP-43 pathology such as the transmembrane protein 106B (TMEM106B) gene (Van Deerlin et al, 2010), and the locus containing the RAB38, member RAS oncogene family (RAB38) and catepsin C (CTSC) genes for bvFTD, and the HLA locus for the FTD spectrum (Ferrari et al, 2014)

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