Neurobiology of Aging 29 (2008) 1279–1282 Negative results Genetic studies of GRN and IFT74 in amyotrophic lateral sclerosis Shangxi Xiao a , Christine Sato a , Toshitaka Kawarai a , Emily F. Goodall b , Hardev S. Pall b,c , Lorne H. Zinman d , Janice Robertson a,e , Karen Morrison b,c , Ekaterina Rogaeva a,f,∗ a Centre for Research in Neurodegenerative Diseases, Tanz Neuroscience Building, University of Toronto, 6 Queen’s Park Crescent West, Toronto, Ontario, Canada M5S 3H2 b Department of Clinical Neurosciences, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK c Queen Elizabeth Hospital, University of Birmingham, NHS Foundation Trust, Birmingham, UK d Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada e Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada f Department of Medicine, Division of Neurology, University of Toronto, Toronto, Canada Received 13 December 2006; received in revised form 22 January 2007; accepted 10 February 2007 Available online 23 March 2007 Abstract There is increasing evidence of a clinical, neuropathological and genetic overlap between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We conducted a case–control study using a UK dataset to test the hypothesis that polymorphisms in two FTD-related genes (GRN and FT74) are associated with increased susceptibility to ALS. We evaluated the majority of known genetic variability in IFT74 and GRN. The results revealed that the common variations in IFT74 and GRN neither constitute strong ALS risk factors nor modify the age-at-onset. However, the possibility of a modest risk effect remains to be assessed in large datasets. © 2007 Elsevier Inc. All rights reserved. Keywords: Amyotrophic lateral sclerosis; Single nucleotide polymorphism; Progranulin; Risk factor 1. Introduction Amyotrophic lateral sclerosis (ALS, OMIM 105400) affects primarily motor neurons of the motor cortex, brain stem and spinal cord. Up to 90% of ALS cases are sporadic without known cause of the disease. The only well-confirmed causal ALS gene is superoxide dismutase- 1(Rosen et al., 1993) responsible for 1–2% of all ALS cases. Several potential susceptibility genes have been associated with ALS, however none have yet been con- firmed by multiple studies (Simpson and Al-Chalabi, 2006). There is increasing evidence of a clinical (Lomen- ∗ Corresponding author at: Centre for Neurodegenerative Diseases, Department of Medicine, University of Toronto, 6 Queen’s Park Crescent West, Toronto, Ontario, Canada M5S 3H2. Tel.: +1 416 978 1871; fax: +1 416 978 1878. E-mail address: ekaterina.rogaeva@utoronto.ca (E. Rogaeva). Hoerth et al., 2002), neuropathological (Mackenzie and Feldman, 2005) and possibly genetic overlap between fron- totemporal dementia (FTD) and ALS. FTD represents a group of primary degenerative dementias with predomi- nant frontal or temporal lobe symptoms (e.g. decline in social and personal behavior) (Kertesz, 2005). Up to 50% of ALS cases have cognitive impairment, and common brain pathology in both ALS and FTD is the presence of ubiquitin-positive inclusions, mainly consisting of a hyper- phosphorylated and cleaved TAR DNA binding protein (Neumann et al., 2006). Recently it was shown that the dis- ease in several FTD families with such inclusions is caused by mutations in the progranulin gene (GRN) encoding a secreted growth factor (Baker et al., 2006; Cruts et al., 2006). Furthermore, a new locus for ALS–FTD has been ascribed to chromosome 9p21.3–p13.3 supporting the possibility that a common genetic risk factor is involved in ALS and 0197-4580/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2007.02.022