Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

Abstract

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.

Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum

“…9 The MAPT H1 haplotype is associated with increased risk for FTD, PSP, CBD, AD, and PD. 10,11,13,16–18 However, the most significant cis -eQTL with 24296 occurred with KIAA1267 (GenBank 284058) (also known as KANSL1 ) (Table 2). rs7224296 is in high LD with rs199533 ( D ′ = −0.97), which was previously reported to be associated with shared risk for PSP, CBD, and FTD.…”

“…37 Among FTD, PSP, and CBD, common variants in MAPT that tag the H1 haplotype represent the strongest genetic predictor of disease. 10,11,13,16–18 In addition, the MAPT H1 haplotype has been associated with PD and AD. 10,11,13,16–18 The MAPT H1 haplotype has recently been implicated in ALS risk in a meta-analysis of publications on neurodegenerative disease.…”

“…10,11,13,16–18 In addition, the MAPT H1 haplotype has been associated with PD and AD. 10,11,13,16–18 The MAPT H1 haplotype has recently been implicated in ALS risk in a meta-analysis of publications on neurodegenerative disease. 38 The risk SNP tagging the MAPT H1 haplotype, rs7224296, is associated with altered splicing of MAPT of exon 3, which, together with exon 2, encodes 2N-containing transcripts.…”

“…8–11 Using previously validated methods, we investigated the genetic overlap between ALS, FTD, PSP, CBD, AD, and PD. We then used molecular and bioinformatics approaches to begin to define the role that these shared risk genes play in neurodegeneration.…”

Therapeutic trial design for frontotemporal dementia and related disorders

“…Although more rare, other disease-causing genetic mutations have also been identified in heritable FTD, such as in VCP , TARDBP , TIA1 , TBK1 and CCNF genes for cases of FTD due to TDP proteinopathy, and in CHMP2B and FUS for cases of FTD due to tau-negative, TDP-negative, ubiquitin-positive pathology 17–19. For PSP and CBD not due to MAPT mutations (ie, sporadic disease), common variation in MAPT , specifically the MAPT H1 haplotype, is an important genetic risk factor for these disorders 20. Variants tagging the MAPT H1 haplotype were not surprisingly confirmed in a genome-wide association study (GWAS) of PSP, but several novel common variants in the STX6 , EIF2AK3 and SLC25A38/Appoptosin genes were found to increase the risk for this disease 21 22.…”