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Journal of Neurology

, Volume 261, Issue 11, pp 2170–2177 | Cite as

Heritability in frontotemporal dementia: more missing pieces?

  • Kieren Po
  • Felicity V. C. Leslie
  • Natalie Gracia
  • Lauren Bartley
  • John B. J. Kwok
  • Glenda M. Halliday
  • John R. Hodges
  • James R. BurrellEmail author
Original Communication

Abstract

Frontotemporal dementia (FTD) is reportedly highly heritable, even though a recognized genetic cause is often absent. To explain this contradiction, we explored the “strength” of family history in FTD, Alzheimer’s disease (AD), and controls. Clinical syndromes associated with heritability of FTD and AD were also examined. FTD and AD patients were recruited from an FTD-specific research clinic, and patients were further sub-classified into FTD or AD phenotypes. The strength of family history was graded using the Goldman score (GS), and GS of 1–3 was regarded as a “strong” family history. A subset of FTD patients underwent screening for the main genetic causes of FTD. In total, 307 participants were included (122 FTD, 98 AD, and 87 controls). Although reported positive family history did not differ between groups, a strong family history was more common in FTD (FTD 17.2 %, AD 5.1 %, controls 2.3 %, P < 0.001). The bvFTD and FTD-ALS groups drove heritability, but 12.2 % of atypical AD patients also had a strong family history. A pathogenic mutation was identified in 16 FTD patients (10 C9ORF72 repeat expansion, 5 GRN, 1 MAPT), but more than half of FTD patients with a strong family history had no mutation detected. FTD is a highly heritable disease, even more than AD, and patients with bvFTD and FTD-ALS drive this heritability. Atypical AD also appears to be more heritable than typical AD. These results suggest that further genetic influences await discovery in FTD.

Keywords

Frontotemporal dementia Alzheimer's disease Genetics Progranulin Tau C9ORF72 repeat expansion Modified Goldman score 

Notes

Acknowledgments

This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia (NHMRC) program Grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021). We are grateful to the research participants involved with the ForeFront research studies. In addition, JRB is supported by a NHMRC Early Career Fellowship (#1072451) and GMH by a NHMRC Senior Principal Research Fellow (#630434). Genomic DNA was extracted from blood samples by Genetic Repositories Australia, an Enabling Facility supported by NHMRC project Grant #401184, and by Mia McMillan in Professor Halliday’s laboratory. Genetic testing was funded by NHMRC project Grant #510218. We are grateful to Carol Dobson-Stone, Yue Huang and Mia McMillan for assistance with screening for repeat expansions in the C9ORF72 gene.

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standard

Institutional ethics approval was obtained prior to assessment and all participants, or next of kin where necessary, provided written informed consent.

Supplementary material

415_2014_7474_MOESM1_ESM.docx (91 kb)
Supplementary material 1 (DOCX 91 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kieren Po
    • 1
    • 2
  • Felicity V. C. Leslie
    • 3
  • Natalie Gracia
    • 3
  • Lauren Bartley
    • 3
  • John B. J. Kwok
    • 1
    • 3
    • 4
  • Glenda M. Halliday
    • 1
    • 3
    • 4
  • John R. Hodges
    • 1
    • 3
    • 4
  • James R. Burrell
    • 1
    • 3
    • 4
    Email author
  1. 1.Concord Repatriation General HospitalSydneyAustralia
  2. 2.Sydney Medical SchoolUniversity of SydneySydneyAustralia
  3. 3.Neuroscience Research AustraliaSydneyAustralia
  4. 4.University of New South WalesSydneyAustralia

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