Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions

Vivianna M Van Deerlin; Patrick MA Sleiman; Maria Martinez-Lage; Alice Chen-Plotkin; Li-San Wang; Neill R Graff-Radford; Dennis W Dickson; Rosa Rademakers; Bradley F Boeve; Murray Grossman; Steven E Arnold; David MA Mann; Stuart M Pickering-Brown; Harro Seelaar; Peter Heutink; John C van Swieten; Jill R Murrell; Bernardino Ghetti; Salvatore Spina; Jordan Grafman; John Hodges; Maria Grazia Spillantini; Sid Gilman; Andrew P Lieberman; Jeffrey A Kaye; Randall L Woltjer; Eileen H Bigio; Marsel Mesulam; Safa al-Sarraj; Claire Troakes; Roger N Rosenberg; Charles L White; Isidro Ferrer; Albert Llado; Manuela Neumann; Hans A Kretzschmar; Christine Marie Hulette; Kathleen A Welsh-Bohmer; Bruce L Miller; Ainhoa Alzualde; Adolfo Lopez de Munain; Ann C McKee; Marla Gearing; Allan I Levey; James J Lah; John Hardy; Jonathan D Rohrer; Tammaryn Lashley; Ian RA Mackenzie; Howard H Feldman; Ronald L Hamilton; Steven T Dekosky; Julie van der Zee; Samir Kumar-Singh; Christine Van Broeckhoven; Richard Mayeux; Jean Paul G Vonsattel; Juan C Troncoso; Jillian J Kril; John BJ Kwok; Glenda M Halliday; Thomas D Bird; Paul G Ince; Pamela J Shaw; Nigel J Cairns; John C Morris; Catriona Ann McLean; Charles DeCarli; William G Ellis; Stefanie H Freeman; Matthew P Frosch; John H Growdon; Daniel P Perl; Mary Sano; David A Bennett; Julie A Schneider; Thomas G Beach; Eric M Reiman; Bryan K Woodruff; Jeffrey Cummings; Harry V Vinters; Carol A Miller; Helena C Chui; Irina Alafuzoff; Paivi Hartikainen; Danielle Seilhean; Douglas Galasko; Eliezer Masliah; Carl W Cotman; M Teresa Tunon; M Cristina Caballero Martinez; David G Munoz; Steven L Carroll; Daniel Marson; Peter F Riederer; Nenad Bogdanovic; Gerard D Schellenberg; Hakon Hakonarson; John Q Trojanowski; Virginia M-Y Lee

Journal article

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions

Vivianna M Van Deerlin, Patrick MA Sleiman, Maria Martinez-Lage, Alice Chen-Plotkin, Li-San Wang, Neill R Graff-Radford, Dennis W Dickson, Rosa Rademakers, Bradley F Boeve, Murray Grossman, Steven E Arnold, David MA Mann, Stuart M Pickering-Brown, Harro Seelaar, Peter Heutink, John C van Swieten, Jill R Murrell, Bernardino Ghetti, Salvatore Spina, Jordan Grafman Show all

NATURE GENETICS | NATURE PUBLISHING GROUP | Published : 2010

DOI: 10.1038/ng.536

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). 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 x 10(-1..

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University of Melbourne Researchers

Catriona McLean Author Florey Department of Neuroscience and Mental Health

Grants

Awarded by Medical Research Council

Awarded by MRC

Funding 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. Re e, 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 (0060204), 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, Diputacion Foral de Gipuzkoa (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 (FWOV), Alzheimer Research (SAO/FRMA), Interuniversity Attraction Poles (IAP) P6/43 network of the Belgian Science Policy Office (BELSPO), J.v.d.", "Z receves a postdoctoral fellowship from the FWOV, 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 05901 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 Tecnologia, Ref Saud y Farmacia 2001-4888, Burroghs Wellcome Fund Career Award for Medical Scientists and Fundacion 'La Caxia'." ]