Neurobiology of Aging 32 (2011) 754–755
Negative results
No association of PGRN 3 UTR rs5848 in frontotemporal lobar degeneration Sara Rollinson a , Jonathan D. Rohrer b , Julie van der Zee c , Kristel Sleegers c , Simon Mead f , Sebastiaan Engelborghs d,e , John Collinge f , Peter P. De Deyn d,e , David M.A. Mann g , Christine Van Broeckhoven c , Stuart M. Pickering-Brown a,∗ a
Clinical Neurosciences Research Group, Faculty of Human and Medical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK b De mentia Research Centre, Institute of Neurology, Queen Square, London, WC1N 3BG, UK c Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium d Institute Born-Bunge and University of Antwerp, Antwerpen, Belgium e Memory Clinic and Department of Neurology, ZNA Middelheim, Antwerpen, Belgium f MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology; Queen Square, London, WC1N 3BG, UK g Clinical Neurosciences Research Group, Faculty of Human and Medical Sciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Salford, M6 8HD, UK Received 9 February 2009; received in revised form 6 April 2009; accepted 10 April 2009 Available online 14 May 2009
Abstract Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has been claimed that homozygosity of the SNP rs5848 located in the 3 UTR of progranulin increases risk for FTLD. We have attempted to replicate the association of rs5848 in three independent FTLD cohorts. No association of rs5848 with FTLD was observed in any individual cohort nor was any observed when the data was combined. These data argue that rs5848 is not a risk factor for FTLD. © 2009 Elsevier Inc. All rights reserved. Keywords: Progranulin; PGRN; Frontotemporal lobar degeneration; Rs5848; TDP-43
1. Introduction Frontotemporal lobar degeneration (FTLD) is the clinical syndrome that encompasses frontotemporal dementia, progressive non-fluent aphasia and semantic dementia. Recently it has been demonstrated that mutations leading to haploinsufficiency of progranulin (PGRN) on chromosome 17q21 are a common cause of FTLD (Baker et al., 2006). More recently it has been claimed that a common polymorphism, the SNP rs5848, in the 3 UTR of PGRN, is a genetic risk factor for FTLD (Rademakers et al., 2008). The authors proposed that homozygosity of the T allele of rs5848 increases
∗
Corresponding author. E-mail address:
[email protected] (S.M. Pickering-Brown).
0197-4580/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2009.04.009
binding of the microRNA miR-659 which leads to an inhibition of PGRN translation. However, the genetic association was only demonstrated in a single cohort. Given that association studies are fraught with problems of replication, we undertook the first replication of this data in three separate European FTLD cohorts representing a total of 467 patients and 1049 controls.
2. Materials and methods All patients were recruited with Ethical Committee approval and provided informed consent. All patients known to harbour a mutation in MAPT or PGRN genes were excluded. Genotyping was performed using standard methods.
S. Rollinson et al. / Neurobiology of Aging 32 (2011) 754–755
3. Results We analysed the genotype and allele frequencies of rs5848 in three independent, European clinical FTLD cohorts with matched controls. All three cohorts were in Hardy-Weinberg equilibrium for this SNP. No significant difference from controls were observed in genotype or allele frequencies in any individual cohort either when analysed by FTLD as a whole or for any of the clinical subdivisions (p = 0.799, Supplementary Table 1). Nor was any significant difference in genotype or allele frequencies observed when all cohorts were combined. In addition we analysed those cases with confirmed FTLDTDP neuropathology by themselves (n = 82), but again, no significant difference was observed in genotype or allele frequency in any separate or combined cohorts (Supplementary Table 2).
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bias of FTLD-TDP in the Mayo cohort. However, this explanation would only hold if the proposed miR-659 binding mechanism actually occurred in vivo. It could also be a due to difference in populations with people of European descent being able to compensate for the reduction of PGRN imposed by rs5848 T alleles. However, this seems unlikely given the high proportion of people of similar European descent within the US population. In conclusion, our data do not support the concept that rs5848 is a risk factor for FTLD. It will be important to identify bone fide genetic risk factors for this highly familial disease.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.neurobiolaging. 2009.04.009.
4. Discussion Our investigation failed to identify any significant difference in genotype or allele frequency of rs5848 in FTLD compared to controls and do not support the concept of rs5848 as a risk factor for FTLD. There are several possible reasons for this. First, the original finding may represent a type 1 error, which is not uncommon in studies that lack independent replication cohorts. Whilst the rs5848TT genotype is rare in European populations, it is the most common genotype in a population from Yoruba in Ibadan, Nigeria, genotyped by the International Hapmap project (www.hapmap.org). Such a major difference in genotype frequency highlights the potential risk of a false positive association signal if case and control populations are admixed and not perfectly matched. Alternatively, it may represent an ascertainment
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