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.

Figure 1

Fold-enrichment plots of enrichment versus nominal −log₁₀ p values (corrected for inflation) in FTD below the standard GWAS threshold of p<5×10−⁸ as a function of significance of association with AD (A) and PD (B) and at the level of −log₁₀(p)≥0, −log₁₀(p)≥1, −log₁₀(p)≥2 corresponding to p≤1, p≤0.1 and p≤0.01, respectively. Blue line indicates all SNPs. AD, Alzheimer’s disease; FTD, frontotemporal dementia; GWAS, genome-wide association studies; PD, Parkinson’s disease.

Figure 2

‘Conjunction’ (A) and ‘conditional’ (B) Manhattan plots of conjunction and conditional −log₁₀ (FDR) values for FTD (black) and FTD given AD (FTD|AD, red) and PD (FTD|PD, green). SNPs with conditional and conjunction −log₁₀ FDR>1.3 (ie, FDR<0.05) are shown with large points. A black line around the large points indicates the most significant SNP in each LD block, and this SNP was annotated with the closest gene, which is listed above the symbols in each locus. For additional details, see online supplementary information. AD, Alzheimer’s disease; FTD, frontotemporal dementia; LD, linkage disequilibrium; PD, Parkinson’s disease.

Figure 3

Forest plots for (A) rs6857 on chromosome 19 and (B) rs1358071 on chromosome 17.

Figure 4

(A) MAPT-locus on chromosome 17. The two SNPs, rs1358071 and rs199528, are shared between FTD and PD. Either SNP is in LD with rs1052553 whose major allele (A) tags the H1 MAPT-haplotype. The major alleles of rs1358071 and rs199528 are also the effect alleles, and they are in LD with rs1052553 (r²=0.75 and 0.84, respectively). Thus, the effect at this locus is H1 driven. (B) APOE locus. The two haplotypes a and b are depicted. Haplotype a is the one driven by rs6857 with 13 SNPs in LD (r²~0.8; font color: blue). Haplotype b is the one driven by rs405509 with 10 SNPs in LD (r²~0.8; font color: black). Rs6857 and rs405509, and the respective haplotypes a and b, are in LE (r²~0.1). FTD, frontotemporal dementia; LD, linkage disequilibrium; LE, linkage equilibrium; PD, Parkinson’s disease.