TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions.
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.
Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Michael D
MD
Gallagher
Eunran
E
Suh
Murray
M
Grossman
Lauren
L
Elman
Leo
L
McCluskey
John C
JC
Van Swieten
Safa
S
Al-Sarraj
Manuela
M
Neumann
Ellen
E
Gelpi
Bernardino
B
Ghetti
Jonathan D
JD
Rohrer
Glenda
G
Halliday
Christine
C
Van Broeckhoven
Danielle
D
Seilhean
Pamela J
PJ
Shaw
Matthew P
MP
Frosch
Irina
I
Alafuzoff
Anna
A
Antonell
Nenad
N
Bogdanovic
William
W
Brooks
Nigel J
NJ
Cairns
Johnathan
J
Cooper-Knock
Carl
C
Cotman
Patrick
P
Cras
Marc
M
Cruts
Peter P
PP
De Deyn
Charles
C
DeCarli
Carol
C
Dobson-Stone
Sebastiaan
S
Engelborghs
Nick
N
Fox
Douglas
D
Galasko
Marla
M
Gearing
Ilse
I
Gijselinck
Jordan
J
Grafman
Päivi
P
Hartikainen
Kimmo J
KJ
Hatanpaa
J Robin
JR
Highley
John
J
Hodges
Christine
C
Hulette
Paul G
PG
Ince
Lee-Way
LW
Jin
Janine
J
Kirby
Julia
J
Kofler
Jillian
J
Kril
John B J
JB
Kwok
Allan
A
Levey
Andrew
A
Lieberman
Albert
A
Llado
Jean-Jacques
JJ
Martin
Eliezer
E
Masliah
Christopher J
CJ
McDermott
Ann
A
McKee
Catriona
C
McLean
Simon
S
Mead
Carol A
CA
Miller
Josh
J
Miller
David G
DG
Munoz
Jill
J
Murrell
Henry
H
Paulson
Olivier
O
Piguet
Martin
M
Rossor
Raquel
R
Sanchez-Valle
Mary
M
Sano
Julie
J
Schneider
Lisa C
LC
Silbert
Salvatore
S
Spina
Julie
J
van der Zee
Tim
T
Van Langenhove
Jason
J
Warren
Stephen B
SB
Wharton
Charles L
CL
White
Randall L
RL
Woltjer
John Q
JQ
Trojanowski
Virginia M Y
VM
Lee
Vivianna
V
Van Deerlin
Alice S
AS
Chen-Plotkin
D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000401:mortality; D000073885:C9orf72 Protein; D015331:Cohort Studies; D042622:DNA Repeat Expansion; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000097:blood / Q000235:genetics* / Q000401:mortality; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D011506:Proteins / Q000235:genetics*
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D011506:Proteins; C556915:TMEM106B protein, human