Pottier, C;
Ren, Y;
Perkerson, RB;
Baker, M;
Jenkins, GD;
Van Blitterswijk, M;
DeJesus-Hernandez, M;
... Rademakers, R; + view all
(2019)
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.
Acta Neuropathologica
, 137
(6)
pp. 879-899.
10.1007/s00401-019-01962-9.
Preview |
Text (Article)
Rohrer_Main text Pottier et al_revised_cleanversion.pdf - Accepted Version Download (620kB) | Preview |
![[thumbnail of Figure 1]](https://discovery-pp.ucl.ac.uk/style/images/fileicons/other.png) |
Other (Figure 1)
Rohrer_Figure1.eps Download (2MB) |
|
Other (Figure 2)
Rohrer_Figure2.eps Download (21MB) |
Preview |
Text (Supplementary material 1)
Rohrer_Online Resource 1 Pottier et al_revised_cleanversion.pdf Download (571kB) | Preview |
|
Spreadsheet (Supplementary material 2)
Rohrer_Online Resource 2.xlsx Download (28kB) |
|
Spreadsheet (Supplementary material 3)
Rohrer_Online Resource 3.xlsx Download (120kB) |
|
Spreadsheet (Supplementary material 4)
Rohrer_Online Resource 4.xlsx Download (48kB) |
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.
Archive Staff Only
 |
View Item |
