Acta Neuropathologica

, Volume 127, Issue 3, pp 407–418 | Cite as

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

  • Michael D. Gallagher
  • Eunran Suh
  • Murray Grossman
  • Lauren Elman
  • Leo McCluskey
  • John C. Van Swieten
  • Safa Al-Sarraj
  • Manuela Neumann
  • Ellen Gelpi
  • Bernardino Ghetti
  • Jonathan D. Rohrer
  • Glenda Halliday
  • Christine Van Broeckhoven
  • Danielle Seilhean
  • Pamela J. Shaw
  • Matthew P. Frosch
  • Irina Alafuzoff
  • Anna Antonell
  • Nenad Bogdanovic
  • William Brooks
  • Nigel J. Cairns
  • Johnathan Cooper-Knock
  • Carl Cotman
  • Patrick Cras
  • Marc Cruts
  • Peter P. De Deyn
  • Charles DeCarli
  • Carol Dobson-Stone
  • Sebastiaan Engelborghs
  • Nick Fox
  • Douglas Galasko
  • Marla Gearing
  • Ilse Gijselinck
  • Jordan Grafman
  • Päivi Hartikainen
  • Kimmo J. Hatanpaa
  • J. Robin Highley
  • John Hodges
  • Christine Hulette
  • Paul G. Ince
  • Lee-Way Jin
  • Janine Kirby
  • Julia Kofler
  • Jillian Kril
  • John B. J. Kwok
  • Allan Levey
  • Andrew Lieberman
  • Albert Llado
  • Jean-Jacques Martin
  • Eliezer Masliah
  • Christopher J. McDermott
  • Ann McKee
  • Catriona McLean
  • Simon Mead
  • Carol A. Miller
  • Josh Miller
  • David G. Munoz
  • Jill Murrell
  • Henry Paulson
  • Olivier Piguet
  • Martin Rossor
  • Raquel Sanchez-Valle
  • Mary Sano
  • Julie Schneider
  • Lisa C. Silbert
  • Salvatore Spina
  • Julie van der Zee
  • Tim Van Langenhove
  • Jason Warren
  • Stephen B. Wharton
  • Charles L. White III
  • Randall L. Woltjer
  • John Q. Trojanowski
  • Virginia M. Y. Lee
  • Vivianna Van Deerlin
  • Alice S. Chen-Plotkin
Original Paper

Abstract

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

Keywords

TMEM106B C9orf72 Frontotemporal dementia Frontotemporal lobar degeneration Amyotrophic lateral sclerosis Genetic modifier 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Michael D. Gallagher
    • 1
    • 2
  • Eunran Suh
    • 3
  • Murray Grossman
    • 2
  • Lauren Elman
    • 2
  • Leo McCluskey
    • 2
  • John C. Van Swieten
    • 4
    • 5
  • Safa Al-Sarraj
    • 6
  • Manuela Neumann
    • 7
    • 8
  • Ellen Gelpi
    • 9
  • Bernardino Ghetti
    • 10
  • Jonathan D. Rohrer
    • 11
  • Glenda Halliday
    • 12
    • 13
  • Christine Van Broeckhoven
    • 14
  • Danielle Seilhean
    • 15
  • Pamela J. Shaw
    • 16
  • Matthew P. Frosch
    • 17
  • Irina Alafuzoff
    • 18
  • Anna Antonell
    • 19
  • Nenad Bogdanovic
    • 20
  • William Brooks
    • 12
    • 13
  • Nigel J. Cairns
    • 21
  • Johnathan Cooper-Knock
    • 16
  • Carl Cotman
    • 22
  • Patrick Cras
    • 23
    • 24
  • Marc Cruts
    • 23
    • 25
  • Peter P. De Deyn
    • 23
    • 26
  • Charles DeCarli
    • 27
  • Carol Dobson-Stone
    • 12
    • 13
  • Sebastiaan Engelborghs
    • 23
    • 26
  • Nick Fox
    • 28
  • Douglas Galasko
    • 29
  • Marla Gearing
    • 30
  • Ilse Gijselinck
    • 23
    • 25
  • Jordan Grafman
    • 31
  • Päivi Hartikainen
    • 32
  • Kimmo J. Hatanpaa
    • 33
  • J. Robin Highley
    • 16
  • John Hodges
    • 12
    • 13
  • Christine Hulette
    • 34
  • Paul G. Ince
    • 16
  • Lee-Way Jin
    • 27
  • Janine Kirby
    • 16
  • Julia Kofler
    • 35
  • Jillian Kril
    • 36
  • John B. J. Kwok
    • 12
    • 13
  • Allan Levey
    • 30
  • Andrew Lieberman
    • 37
  • Albert Llado
    • 19
  • Jean-Jacques Martin
    • 23
  • Eliezer Masliah
    • 29
  • Christopher J. McDermott
    • 16
  • Ann McKee
    • 38
  • Catriona McLean
    • 39
  • Simon Mead
    • 40
  • Carol A. Miller
    • 41
  • Josh Miller
    • 27
  • David G. Munoz
    • 42
  • Jill Murrell
    • 43
  • Henry Paulson
    • 37
  • Olivier Piguet
    • 12
    • 13
  • Martin Rossor
    • 28
  • Raquel Sanchez-Valle
    • 19
  • Mary Sano
    • 44
  • Julie Schneider
    • 45
  • Lisa C. Silbert
    • 46
  • Salvatore Spina
    • 43
  • Julie van der Zee
    • 23
    • 25
  • Tim Van Langenhove
    • 23
    • 24
    • 25
  • Jason Warren
    • 28
  • Stephen B. Wharton
    • 16
  • Charles L. White III
    • 33
  • Randall L. Woltjer
    • 46
  • John Q. Trojanowski
    • 3
  • Virginia M. Y. Lee
    • 3
  • Vivianna Van Deerlin
    • 3
  • Alice S. Chen-Plotkin
    • 2
  1. 1.Cell and Molecular Biology Graduate Group, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Neurology, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Center for Neurodegenerative Disease Research, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.Erasmus Medical CentreRotterdamThe Netherlands
  5. 5.Alzheimercenter VumcBoelelaanThe Netherlands
  6. 6.King’s College HospitalLondonUK
  7. 7.University of TübingenTübingenGermany
  8. 8.German Center for Neurodegenerative Diseases (DZNE)BonnGermany
  9. 9.Neurological Tissue Bank of the Biobank-Hospital Clinic-Insitut d’Investigacions Biomèdiques August Pi i Sunyer, Facultad de MedicinaBarcelonaSpain
  10. 10.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  11. 11.Dementia Research Centre, Department of Neurodegenerative DiseaseUCL Institute of NeurologyLondonUK
  12. 12.Neuroscience Research AustraliaRandwickAustralia
  13. 13.Faculty of MedicineUniversity of New South WalesSydneyAustralia
  14. 14.Neurodegenerative Brain Disease Group, Department of Molecular GeneticsVIBAntwerpBelgium
  15. 15.University Pierre et Marie Curie (UPMC)-Sorbonne UniversityParisFrance
  16. 16.University of SheffieldSheffieldUK
  17. 17.Massachusetts Alzheimer’s Disease Research CenterHarvard Medical SchoolBostonUSA
  18. 18.Uppsala UniversityUppsalaSweden
  19. 19.Alzheimer and Cognitive Disorders Unit, Neurology ServiceHospital Clinic de Barcelona, SpainBarcelonaSpain
  20. 20.Karolinska InstitutetSolnaSweden
  21. 21.Washington University School of MedicineSt. LouisUSA
  22. 22.University of California, IrvineIrvineUSA
  23. 23.Institute Born-Bunge University of AntwerpAntwerpBelgium
  24. 24.Department of NeurologyAntwerp University HospitalEdegemBelgium
  25. 25.Department of Molecular GeneticsVIBAntwerpBelgium
  26. 26.Department of NeurologyHospital Network Antwerp (ZNA) MiddelheimAntwerpBelgium
  27. 27.University of CaliforniaDavisUSA
  28. 28.Department of Neurodegenerative Disease, Dementia Research CentreUniversity College London Institute of NeurologyLondonUK
  29. 29.University of California San DiegoLa JollaUSA
  30. 30.Emory UniversityAtlantaUSA
  31. 31.Northwestern UniversityChicagoUSA
  32. 32.Kuopio University HospitalKuopioFinland
  33. 33.University of Texas Southwestern Medical CenterDallasUSA
  34. 34.Duke University Medical CenterDurhamUSA
  35. 35.Department of PathologyUniversity of PittsburghPittsburghUSA
  36. 36.Department of Pathology, Sydney Medical SchoolThe University of SydneySydneyAustralia
  37. 37.University of MichiganAnn ArborUSA
  38. 38.Boston UniversityBostonUSA
  39. 39.Australian Brain Bank Network, The Florey Institute of Neuroscience and Mental Health, Melbourne Brain CentreParkvilleAustralia
  40. 40.MRC Prion Unit, Department of Neurodegenerative DiseaseUniversity College London Institute of NeurologyLondonUK
  41. 41.Keck School of Medicine of University of Southern CaliforniaLos AngelesUSA
  42. 42.University of TorontoTorontoUSA
  43. 43.Indiana UniversityBloomingtonUSA
  44. 44.Mount Sinai School of MedicineNew YorkUSA
  45. 45.Rush University Medical CenterChicagoUSA
  46. 46.Oregon Health and Science UniversityPortlandUSA

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