GRN variability contributes to sporadic frontotemporal lobar degeneration.
Mutations in the progranulin gene (GRN) are responsible for familial FTLD with ubiquitin pathology (FTLD-U). However, there are controversial data regarding the contribution of GRN variability to sporadic FTLD. We carried out an association study in 265 patients, who did not carry a GRN causal mutation, and 375 age-matched controls. Four tagging Single Nucleotide Polymorphisms (SNPs) were chosen generate 80% power to detect an allelic association with P < or = 0.01. In addition, a known functional SNP (rs5848) was included. An increased frequency of the rs4792938 CC genotype in cases compared with controls was observed (17.4 versus 10.4%, P=0.01, OR: 1.81, 95%CI: 1.15-2.85). Stratifying for gender, no differences were observed for all polymorphisms. Haplotype analysis failed to detect haplotypes associated with the disease. Our findings indicate that the GRN rs4792938 CC genotype represents a susceptibility factor for the development of FTLD in individuals who do not carry GRN causal mutations. This SNP is likely located in a regulatory region, thus an effect on GRN mRNA levels may be of mechanistic importance.
Galimberti
Daniela
D
Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy. daniela.galimberti@unimi.it
Fenoglio
Chiara
C
Cortini
Francesca
F
Serpente
Maria
M
Venturelli
Eliana
E
Villa
Chiara
C
Clerici
Francesca
F
Marcone
Alessandra
A
Benussi
Luisa
L
Ghidoni
Roberta
R
Gallone
Salvatore
S
Scalabrini
Diego
D
Restelli
Ilaria
I
Martinelli Boneschi
Filippo
F
Cappa
Stefano
S
Binetti
Giuliano
G
Mariani
Claudio
C
Rainero
Innocenzo
I
Giordana
Maria Teresa
MT
Bresolin
Nereo
N
Scarpini
Elio
E
D000368:Aged; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077153:Progranulins; D011498:Protein Precursors / Q000235:genetics*; D012307:Risk Factors
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011498:Protein Precursors