Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Abstract

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

Keywords: DPP6; HLA; Immunity; TBK1; UNC13A; Whole-genome sequencing FTLD-TDP.

Figures

Figure 1.. Age distributions in each FTLD-TDP pathological subtype

Age at onset, age at death and survival after onset are represented as histogram per FTLD-TDP pathological subtype. A density curve is superimposed to the histograms.

Figure 2.. Common variant whole genome sequencing association study and DPP6 locus

(a) Manhattan plot of the FTLD-TDP patients versus control association study. The red dotted line represents the genome-wide significance level (p=5e-08). (b)Regional association (locus zoom) plot of the DPP6 locus. Each dot represents a genotyped variant. The purple dot is the most significant variant (rs4726389) among variants in the region. Dots are colored from red to blue according to their r2 value, showing their degree of linkage disequilibrium with rs4726389 (grey indicates an r2 of zero). The light blue line shows the estimated recombination rate. (c)DPP6 mRNA expression levels in function of the rs4726389 genotypes without correction for cellular composition in custom RNAseq frontal cortex dataset. (d) DPP6 mRNA expression levels in function of the rs4726389 genotypes with correction for cellular composition in custom RNAseq frontal cortex dataset. (e) DifferentialDPP6 mRNA expression levels in FTLD-TDP patients and controls without correction for cellular composition. (f) Differential DPP6 mRNA expression levels in FTLD-TDP patients and controls with correction for cellular composition.