Genetic links for clinical subtypes of frontotemporal dementia.

FTD is the second most common cause of dementia after Alzheimer’s disease in patients younger than 65 years of age. Genome-wide association studies (GWAS) so far showed limited success in mapping loci associated with FTD 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. We performed gene-based association analysis that overcomes these issues associated with GWAS on 3348 clinically identified frontotemporal dementia cases and 9390 controls. We identified significant associations of TOMM40 and APOE genes with behavioral FTD (bvFTD), and ARHGAP35 and SERPINA1 genes with progressive non-fluent aphasia (PNFA).
In addition, salient features of this work are:
1. Epsilon 4 and 2 alleles of the APOE gene show disease increasing and protective effects respectively on FTD subtypes verses neurologically normal controls, suggesting their potential role across neurodegenerative diseases.
2. The association of TOMM40 gene conditioned on epsilon alleles with bvFTD suggests the presence of two haplotypes at TOMM40/APOE locus conferring different risk on FTD.
3. This is the first report on genetic link for PNFA, reporting association of ARHGAP35 and SERPINA1 genes. These associations point towards the role of a stress signaling pathway in pathophysiology of PNFA.

Figure: Regional plots at (A) ARHGAP35 and (B) SERPINA1 loci in PNFA cohorts. (1) and (2) are discvery and replication cohorts, respectively.

From: Mishra A, Ferrari R, Heutink P, Hardy J, Pijnenburg Y, Posthuma D; International FTD-Genomics Consortium. Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia. Brain. 2017 Apr 5. doi: 10.1093/brain/awx066.