Elsevier

Neurobiology of Aging

Volume 30, Issue 4, April 2009, Pages 656-665
Neurobiology of Aging

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Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration

https://doi.org/10.1016/j.neurobiolaging.2009.01.009Get rights and content

Abstract

Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08–1.88, P = 0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04–1.69, P = 0.022), the USA (OR 1.4 95% CI 1.02–1.92, P = 0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97–2.17, P = 0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72–1.37, P = 0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43.

Introduction

Frontotemporal lobar degeneration (FTLD) is the term used for a group of clinical syndromes characterized by changes in behaviour, personality and language with relative preservation of memory and spatial skills (Neary et al., 1998). FTLD is a common form of dementia in individuals under the age of 65 and around half of all patients present with a family history of a similar disease (Pickering-Brown et al., 2002). The genetic aetiology of FTLD is complex with 7 loci identified to date on chromosomes 3, 9p (two loci), 9q, 17q21 (two loci) and 17q24 (Pickering-Brown, 2007). Four of the genes that account for these linkages have been identified being CHMP2B on chromosome 3, VCP on chromosome 9p and MAPT and progranulin (PGRN) on chromosome 17q21 and collectively these account for 10–20% of all FTLD (Hutton et al., 1998, Watts et al., 2004, Skibinski et al., 2005, Baker et al., 2006, Gass et al., 2006). There are two common neuropathological subtypes observed in FTLD, one being tauopathy, the accumulation of abnormally phosphorylated and insoluble aggregates of tau protein in neurons and sometimes glia, the other being referred to as FTLD-U where ubiquitinated neuronal inclusions containing TAR DNA binding protein (TDP-43) are present in varying quantities (Cairns et al., 2007). FTLD-U has been further divided into three main subgroups determined by the distribution and morphological characteristics of the TDP-43 pathology (Mackenzie et al., 2006, Cairns et al., 2007). Familial tauopathy is often associated with mutations in MAPT whereas null-mutations of PGRN lead to FTLD-U (Hutton et al., 1998, Baker et al., 2006). Cases with mutations in PGRN have been designated as type 3 FTLD-U, whereas those cases from families linked to chromosome 9p have been designated as having type 2 FTLD-U pathology (Cairns et al., 2007). One characteristic that unites the two differing histological subtypes in FTLD is that both tau and TDP-43 inclusions are ubiquitinated to varying degrees. The observation that many proteins that accumulate within neurons and/or glia in neurodegenerative diseases are ubiquitinated has lead to the suggestion that dysfunction of the ubiquitin proteasome system could be an aetiological factor in this group of conditions (Petrucelli and Dawson, 2004).

The identification of the additional causal genes and genetic risk factors will help elucidate the important aberrant biological pathways underlying FTLD. Therefore, in order to investigate whether we could identify any evidence of genetic association between genes in the chromosome 9p linkage region in our FTLD cohort from the North West of Great Britain we undertook a large scale two-stage linkage disequilibrium mapping approach of the minimal region defined from published families (Morita et al., 2006, Vance et al., 2006) and attempted to replicate our finding in an additional 4 independent cohorts from the Netherlands, USA, Spain and London, UK. This work represents the largest case controls study performed on FTLD to date.

Section snippets

Subjects

All samples fulfilled current diagnostic criteria for FTLD (Neary et al., 1998) and were recruited with Ethical Committee approval and provided informed consent. All patients known to harbour a mutation in MAPT or PGRN genes were excluded. Manchester cohort: all patients were recruited between 1987 and 2007 through longitudinal neuropsychological and clinical assessment within the Cerebral Function Unit of the University of Manchester. The final study group comprised 214 patients (mean age at

Statistical analysis

Simple χ2 and Hardy–Weinberg Equilibrium P values for each SNP variant were calculated using Haploview (Barrett et al., 2005) and Stata with Yates correction. Haplotype block structure was examined using haploview, a block defined using the confidence intervals option, where 95% confidence bounds on D’ are generated, a block defined if 95% of informative comparisons are in strong linkage disequilibrium (Gabriel et al., 2002). For comparison with the generated data, data corresponding to genomic

Stage one screen

A total of 190 SNP's were genotyped across the 10.296 Mbp region of 9p determined by linkage analysis to be associated with FTLD. After dropping those assays that did not meet the stringent quality control measures 151 SNPs were left for analysis, possessing an average genotype call of 92.4% (76.3–98.6% call). On examination of P values calculated using a case–control analysis, 10 P values were found to be significant after Yates correction (P < 0.05). None of these P values remained significant

Discussion

We have undertaken a large scale linkage disequilibrium mapping study of the published minimal linkage region for FTLD linked to chromosome 9p using our large FTLD cohort from the North West region of Great Britain. This analysis has identified haplotypes of UBAP1 as a significant risk factor for FTLD with an OR of 1.42 95% CI 1.08–1.88, P = 0.013 in the Manchester cohort. Genetic association studies of human disease are often complicated by type 1 errors, i.e. false positive association, and are

Disclosure statement

Dr. Pickering-Brown has filed a patent relating to UBAP1 in dementia but there are no other actual or potential conflicts of interest for him or any other of the authors. All patients included in this study were recruited with local Ethical Committee approval and provided informed consent.

Acknowledgments

SPB and DMAM received funding from the Medical Research Council and the Alzheimers Research Trust to support this work. This research was also supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging (Z01-AG000949-02) and National Institute of Neurological Disorders and Stroke. RG received support from rant #SFRH/BD/27442/2006 from Fundacao para a Ciencia e Tecnologia, Portugal. This work was also supported by NIH grants P50 AG16574 (NG-R and RR) and the

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