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| Home > Publications Database > DB10: Gene-based analysis detects novel loci associated withfrontotemporal dementia and its clinical subtypes |
| Home > Publications Database > DB10: Gene-based analysis detects novel loci associated withfrontotemporal dementia and its clinical subtypes |
| Abstract/Journal Article | DZNE-2020-00845 |
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2016
Abstract: Recent single marker genome-wide association study (GWAS)on FTD showed limited success in identifying associated locipossibly due to underpowered samples and allelic heterogeneity. Inthis study, we performed an alternative joint-SNP gene-basedanalyses using the GWAS summary data on 3526 clinicallyidentified frontotemporal dementia (FTD) cases and 9402 controlsreported by Ferrari et al. (Ferrari et al. Lancet Neurol. 2014 Jul; 13(7) 686–99) to identify genes associated with FTD and its clinicalsubtypes. The MAGMA method (de Leeuw et al. PLoS ComputBiol. 2015 Apr 17; 11(4): e1004219), which is based on a multiplelinear principal components regression model, was used to performthe gene-based association analyses. We performed separate two-cohort (discovery and replication) gene-based analyses for eachFTD subtype (behavioural FTD, semantic dementia, progressivenon-fluent aphasia and FTD with motor neuron disease); we thencombined the association test statistics from discovery and replica-tion cohorts using the Stouffer’s combination approach for thesample size weighted combination of p-values to identify associatedgenes with specific FTD subtypes. We identified association of theAPOE locus (APOE and TOMM40 genes) with behavioural FTD,and ARHGAP35 and SERPINA1 genes with progressive non-fluentaphasia. The APOE gene association with behavioural FTD pointtowards its role across different clinically observed neurodegener-ative diseases. To the best of our knowledge, this is the first workreporting a significant genetic association with progressive non-fluent aphasia: SERPINA1 and ARHGAP35 point to a potential roleof a stress-pathway in the pathogenesis of progressive non-fluentaphasia.
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