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 Neuropathol. 2019 Jun;137(6):879-899. doi: 10.1007/s00401-019-01962-9. Epub 2019 Feb 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • DNA Repeat Expansion
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Frontal Lobe / metabolism
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / immunology
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HLA-DQ Antigens / genetics
  • Humans
  • Loss of Function Mutation
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / physiology
  • Potassium Channels / genetics
  • Progranulins / genetics
  • Progranulins / physiology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Proteins / genetics
  • Proteins / physiology
  • RNA, Messenger / biosynthesis
  • Risk Factors
  • Sequence Analysis, RNA
  • Societies, Scientific
  • TDP-43 Proteinopathies / genetics*
  • TDP-43 Proteinopathies / immunology

Substances

  • C9orf92 protein, human
  • GRN protein, human
  • HLA-DQ Antigens
  • HLA-DQA2 antigen
  • Nerve Tissue Proteins
  • Potassium Channels
  • Progranulins
  • Proteins
  • RNA, Messenger
  • UNC13B protein, human
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • DPP6 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases

Grant support