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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10−11; odds ratio, minor allele (C) 0.61, 95% CI 0.53–0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10−4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

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Figure 1: Region of genome-wide association at 7p21.
Figure 2: TMEM106B expression variation by genotype and disease state.
Figure 3: Manhattan plot in cases with and without GRN mutations.

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Acknowledgements

This project was enabled by the contributions and efforts of many individuals in several supportive capacities. Most importantly, we extend our appreciation to the study subjects and families who made this research possible. Extensive technical assistance was provided by R. Greene, T. Unger and C. Kim and study coordination was provided by E. McCarty Wood. The following individuals contributed through sample ascertainment, epidemiology, coordination, and/or clinical evaluation of cases: S.Weintraub, N. Johnson, C. Shaw, V. Haroutunian, R.C. Petersen, D.S. Knopman, K.A. Josephs, D. Neary, J. Snowden, J. Heidebrink, N. Barbas, R. Reñe, J.R. Burke, K. Hayden, J. Browndyke, P. Gaskell, M. Szymanski, J.D. Glass, M. Rossor, F. Moreno, B. Indakoetxea, M. Barandiaran, S. Engelborghs, P.P. De Deyn, W.S. Brooks, T. Chow, V. Meininger, L. Lacomblez and E. Gruenblatt. The following individuals contributed through pathological characterization and evaluation of cases: D. Clark, A. King, I. Bodi, D. Purohit, L. Kwong, J.E. Parisi, W. Kamphorst, I. Ruiz, T. Revesz, J.-J. Martin, R. Highley and C. Duyckaerts. The following individuals contributed through general technical assistance and/or genetic studies: J. Kirby, E. Moore, M. Baker, R. Crook, S. Rollinson, N. Halliwell, S. Usher, R.M. Richardson, M. Mishra, C. Foong, J. Ervin, K. Price Bryan, J. Ervin, C. Kubilus, A. Gorostidi, M. Cruts, I. Gijselinck, H. McCann, P.R. Schofield, G. Forster, K. Firch, J. Pomaician, I. Leber, V. Sazdovitch and I. Volkmann. We also thank the Brain Bank of University of Barcelona, Hospital Clinic, Clinic for Alzheimer's Disease and Related Disorders University of British Columbia, Australian Brain Donor Programs supported by the National Health and Medical Research Council of Australia, Biobank at the Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium and the French clinical and genetic research network on FTD/FTD-motor neuron disease (MND). Many grant funding agencies provided financial support for this study, including the US National Institutes of Health (NIH) (grant numbers AG10124, AG17586, AG16574, AG03949, AG17586, NS44266, AG15116, NS53488, AG10124, AG010133, AG08671, NS044233, NS15655, AG008017, AG13854, AG12300, AG028377, AG 019724, AG13846, AG025688, AG05133, AG08702, AG05146, AG005136, AG005681, AG03991, AG010129, AG05134, NS038372, AG02219, AG05138, AG10161, AG19610, AG19610, AG16570, AG16570, AG05142, AG005131, AG5131, AG18440, AG16582, AG16573, AG033101 and NIH Intramural Program). Additional funds were provided by Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, the Pacific Alzheimer's disease Research Foundation (PARF) grant #C06-01, the Alzheimer's Research Trust, Alzheimer's Society, Medical Research Council (Programme Grant and Returning Scientist Award), Stichting Dioraphte (07010500), Hersenstichting (15F07.2.34), Prinses Beatrix Fonds (006-0204), Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, Instituto Carlos III, Federal Ministry of Education and Research (01GI0505), SAIOTEK Program (Basque Government), Department of Innovation, Diputación Foral de Gipúzkoa (DFG 0876/08), ILUNDAIN Fundazioa, Centro de Investigaciones Biomedicas en Red en Enfermededades Neurodegenerativas (CIBERNED), Wellcome Trust, Canadian Institutes of Health Research (75480), Fund for Scientific Research Flanders (FWO-V), Alzheimer Research (SAO/FRMA), Interuniversity Attraction Poles (IAP) P6/43 network of the Belgian Science Policy Office (BELSPO), J.v.d.Z receives a postdoctoral fellowship from the FWO-V, the Joseph Iseman Fund, the Louis and Rachel Rudin Foundation, National Health and Medical Research Council of Australia, Veteran's Affairs Research Funds, Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05-901 to the Arizona Parkinson's Disease Consortium), the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson's Research, the Daljits and Elaine Sarkara Chair in Diagnostic Medicine, BrainNet Europe II, Ministerio de Ciencia y Tecnología, Ref Saud y Farmacia 2001–4888, Burroghs Wellcome Fund Career Award for Medical Scientists and Fundacion 'La Caxia'.

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Contributions

V.M.V.D., P.M.A.S., M.M.-L. and A.C.-P. contributed equally to this manuscript. The overall study was designed and implemented by V.M.-Y.L., J.Q.T., V.M.V.D., H.H. and M.M.-L. and discussed with G.D.S., L.-S.W. and A.C.-P. Coordination, sample handling, DNA extraction, genetic analysis and data management were done primarily by V.M.V.D. and M.M.-L. Genotyping and additional testing, including immunohistochemical analysis, was done by P.M.A.S., H.H., V.M.V.D. or M.M.-L. Data analysis and quality control were performed by P.M.A.S., L.-S.W. and A.C.-P. and discussed and reviewed by V.M.V.D., H.H., G.D.S., V.M.-Y.L., J.Q.T. and M.M.-L. Expression analysis was designed and implemented by A.C.-P. The manuscript was prepared by A.C.-P., V.M.V.D. and P.M.A.S. and reviewed by M.M.-L., G.D.S., H.H., J.Q.T., V.M.-Y.L. and L.-S.W. The members of the International FTLD Collaboration, which includes all other authors, contributed cases, evaluated pathology, performed genetic studies and reviewed the manuscript.

Corresponding authors

Correspondence to Vivianna M Van Deerlin or John Q Trojanowski.

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Competing interests

A patent application on TMEM106B has been submitted. J.L. is currently involved in clinical trials involving Elan, Janssen, Medivation and Ceregene. H.F. is a full-time employee in Neuroscience Global Clinical Research and Development at Bristol-Myers Squibb from January 2009.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1–10. (PDF 772 kb)

Supplementary Data 1

Raw data for the experiments shown in Figure 2a-c and Supplementary Figure 2. (XLS 15 kb)

Supplementary Data 2

Raw data for the experiment shown in Figure 2d. (XLS 13 kb)

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Van Deerlin, V., Sleiman, P., Martinez-Lage, M. et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42, 234–239 (2010). https://doi.org/10.1038/ng.536

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