A Genome-Wide Screening and Snps-To-Genes Approach to Identify Novel Genetic Risk Factors Associated with Frontotemporal Dementia
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Neurobiology of Aging xxx (2015) 1e14 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia Raffaele Ferrari a,b,*,1, Mario Grassi c,1, Erika Salvi d,1, Barbara Borroni e,1, Fernando Palluzzi c, Daniele Pepe c, Francesca D’Avila d, Alessandro Padovani e, Silvana Archetti e, Innocenzo Rainero f, Elisa Rubino f, Lorenzo Pinessi f, Luisa Benussi g, Giuliano Binetti g, Roberta Ghidoni g, Daniela Galimberti h, Elio Scarpini h, Maria Serpente h, Giacomina Rossi i, Giorgio Giaccone i, Fabrizio Tagliavini i, Benedetta Nacmias j, Irene Piaceri j, Silvia Bagnoli j, Amalia C. Bruni k, Raffaele G. Maletta k, Livia Bernardi k, Alfredo Postiglione l, Graziella Milan m, Massimo Franceschi n, Annibale A. Puca o,p, Valeria Novelli q, Cristina Barlassina d, Nicola Glorioso r, Paolo Manunta s, Andrew Singleton t, Daniele Cusi d,u, John Hardy a, Parastoo Momeni b a Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK b Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA c Department of Brain and Behavioural Sciences, Medical and Genomic Statistics Unit, University of Pavia, Pavia, Italy d Department of Health Sciences, University of Milan at San Paolo Hospital, Milan, Italy e Neurology Clinic, University of Brescia, Brescia, Italy f Neurology I, Department of Neuroscience, University of Torino and Città della Salute e della Scienza di Torino, Turin, Italy g Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy h Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy i Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano Italy j Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy k Neurogenetic Regional Centre ASPCZ Lamezia Terme, Lamezia TErme, Italy l Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy m Geriatric Center FrullonedASL Napoli 1 Centro, Naples, Italy n Department of Neurology, IRCCS Multimedica, Milan, Italy o Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy p Cardiovascular Research Unit, IRCCS Multimedica, Milan, Italy q Department of Molecular Cardiology, IRCCS Fondazione S. Maugeri, Pavia, Italy r Hypertension and Related Disease Centre, AOU-University of Sassari, Sassari, Italy s Chair of Nephrology, Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy t Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA u Institute of Biomedical Technologies, Italian National Research Council, Milan, Italy article info abstract Article history: Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia Received 7 March 2015 after Alzheimer’s disease (AD). We performed a case-control association study in an Italian FTD cohort Received in revised form 29 May 2015 (n ¼ 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and Accepted 5 June 2015 functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached À p-values w10 7 and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 iden- tified a disease-associated haplotype causing decreased expression of ecis genes such as RFNG and Keywords: AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We repli- Frontotemporal dementia cated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated Association study significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), * Corresponding author at: Department of Molecular Neuroscience, Institute of Neurology, UCL, Room 610, Queen Square House, Queen Square, London, WC1N 3BG, UK. Tel.: 02034484205; fax: 02034484017. E-mail address: [email protected] (R. Ferrari). 1 These authors contributed equally to this work. 0197-4580/Ó 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). http://dx.doi.org/10.1016/j.neurobiolaging.2015.06.005 2 R. Ferrari et al. / Neurobiology of Aging xxx (2015) 1e14 Case-control the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the Genetic risk factors latter supporting our recent international FTDegenome-wide association study. This is the largest Functional annotation genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for Population future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis. Ó 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction specifically, we had access to raw data of 634 samples, which were obtained from 8 Italian research centers (Supplementary Table 9). Frontotemporal dementia (FTD) is the second most prevalent After quality check (QC) steps 530 patients diagnosed with bvFTD form of early onset dementia after Alzheimer’s disease (AD), (n ¼ 418), semantic variant PPA (n ¼ 27), agrammatic variant PPA worldwide (Ratnavalli et al., 2002). The 2 main FTD syndromes (n ¼ 61), and FTD-MND (n ¼ 23) were included in the study. Mean affect an individual’s behavior or language resulting either in the (Æ standard deviation [SD]) age of onset was 64.1 Æ 20.7 years behavioral variant FTD (bvFTD) or the language variant broadly (range, 29.0e87.0) with male-to-female ratio 243/287. Four hun- named primary progressive aphasia (PPA) (Gorno-Tempini et al., dred eighty-two of 530 cases had been characterized for candidate 2011; Rascovsky et al., 2011). The latter is subdivided into seman- genes: a minority of cases carried variants in MAPT (n ¼ 2; 0.4%), tic variant PPA and non-fluent/agrammatic variant PPA (Gorno- GRN (n ¼ 37; 7.7%), and C9orf72 (n ¼ 27; 5.6%). Three cases (2 bvFTD Tempini et al., 2011). Each of these syndromes is distinct and is and 1 FTD-MND) had double variants (C9orf72 and GRN). The cases characterized by specific signatures (Ferrari et al., 2013). FTD can with variants in MAPT and GRN were kept in the study because also overlap with motor neuron disease (MND) resulting in the these were nonpathogenic polymorphisms. Conversely, all cases broad subgroup called FTD-MND (Strong et al., 2009). with known pathogenic mutations in MAPT and GRN were excluded The genetics of FTD have become clearer over the past 15 years from the study a priori, whereas those carrying C9orf72 expansions when mutationsin the microtubule associated protein tau (MAPT)and were kept because we adopted here the same strategy as in the progranulin (GRN) genes were identified (Baker et al., 2006; Cruts international FTD-GWAS (Ferrari et al., 2014). All cases were diag- et al., 2006; Hutton et al., 1998); more recently, a repeat expansion nosed according to the Neary criteria (Neary et al., 1998) and/or the in the C9orf72 gene has been reported in the FTDeamyotrophic lateral more recent Rascovsky and Gorno-Tempini criteria (Gorno-Tempini sclerosis spectrum (DeJesus-Hernandez et al., 2011; Renton et al., et al., 2011; Rascovsky et al., 2011). The cases were collected and 2001) and a small number of FTD cases (<5% all together) has been genotyped at the University College London by means of Illumina associated with variability in a handful of genes including the human 660K-Quad Beadchips assayed on the Illumina Infinium transactive response DNA binding protein 43 (TDP-43) and valosin platform (Illumina, San Diego, CA, USA). containing protein (Ferrari et al., 2013; Rohrer and Warren, 2011). Recently, international genome-wide association studies (GWAS) 2.1.2. Controls identified novel potential risk factors for FTD with TDP-43 pathology The control sample used in the present study has been collected such as the transmembrane protein 106B (TMEM106B)gene(Van during the HYPERGENES project (European Network for Genetic- Deerlin et al., 2010), and the locus containing the RAB38, member Epidemiological Studies; www.hypergenes.eu)(Salvi et al., 2012). RAS oncogene family (RAB38) and catepsin C (CTSC)genesforbvFTD, The sample set (n ¼ 1327; 926 after QC) included 349 (37.7%) and the HLA locus for the FTD spectrum (Ferrari et al., 2014). women and the mean (ÆSD) age was 58.2 Æ 6.1 years (range, Currently, there are no comprehensive epidemiological data on 50.0e97.0). All participants were unrelated, collected in Italy, and of monogenic FTD in the Italian population. However, the majority of Caucasian ancestry. All subjects had no abnormal findings on FTD cases has been associated with GRN mutations (Benussi et al., physical and neurological examination. The control samples were 2009; Borroni et al., 2011), whilst only a few cases with MAPT genotyped at the University of Milan, using the Illumina 1M-duo (Alberici et al., 2004; Binetti et al., 2003). In addition, a few cases array. have been associated with mutations in TDP-43 (Borroni et al.,