GRN Variability Contributes to Sporadic Frontotemporal Lobar Degeneration

Issue title: Similarities and Differences Between Mild Cognitive Impairment and Alzheimer's Disease

Guest editors: Mark A. Lovell

Article type: Research Article

Authors: Galimberti, Daniela^{a; *} | Fenoglio, Chiara^a | Cortini, Francesca^a | Serpente, Maria^a | Venturelli, Eliana^a | Villa, Chiara^a | Clerici, Francesca^b | Marcone, Alessandra^c | Benussi, Luisa^d | Ghidoni, Roberta^{d; e} | Gallone, Salvatore^f | Scalabrini, Diego^a | Restelli, Ilaria^a | Boneschi, Filippo Martinelli^g | Cappa, Stefano^{c; h} | Binetti, Giuliano^d | Mariani, Claudio^b | Rainero, Innocenzo^f | Giordana, Maria Teresa^f | Bresolin, Nereo^a | Scarpini, Elio^a

Affiliations: [a] Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy | [b] Center for Research and Treatment on Cognitive Dysfunctions, Chair of Neurology, University of Milan, “Luigi Sacco” Hospital, Milan, Italy | [c] Division of Neurology, San Raffaele Turro Hospital, San Raffaele Scientific Institute, Milan, Italy | [d] NeuroBioGen-Lab-Memory Clinic, IRCCS “Centro S. Giovanni di Dio-FBF”, Brescia, Italy | [e] Proteomics Unit, IRCCS “Centro S. Giovanni di Dio-FBF”, Brescia, Italy | [f] Department of Neuroscience, University of Turin, Turin, Italy | [g] Department of Neurology and INSPE, Scientific Institute San Raffaele, Milan, Italy | [h] Vita-Salute San Raffaele University, Milan, Italy | Sanders-Brown Center on Aging and Alzheimer's Disease Center, Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA

Correspondence: [*] Corresponding author: Daniela Galimberti, Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy. Tel.: +39 2 55033858; Fax: +39 2 50320430; E-mail: [email protected].

Abstract: 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 ⩽ 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.

Keywords: Frontotemporal Lobar Degeneration (FTLD), polymorphism, progranulin (GRN), risk factor, variability

DOI: 10.3233/JAD-2010-1225

Journal: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 171-177, 2010