INTRODUCTION: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as SNCA, COQ2 and LRRK2 have demonstrated that there is a genetic contribution to the disease. MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the MAPT H2 haplotype with MSA in 61 pathologically confirmed cases. METHODS: In the present study, we assessed the full MAPT haplotype diversity in MSA patients using six MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls. RESULTS: We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%, CONTROLS: 22.7%, p = 0.024) and H1E (MSA:3.0%, CONTROLS: 9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%, CONTROLS: 1.3%, p = 0.030) and H1J (MSA:3.0%, CONTROLS: 0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P < 0.0001). CONCLUSIONS: Our findings provide further evidence that MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of MAPT and other genes in MSA.
INTRODUCTION:Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder. MSA was originally considered exclusively sporadic but reports of association with genes such as SNCA, COQ2 and LRRK2 have demonstrated that there is a genetic contribution to the disease. MAPT has been associated with several neurodegenerative diseases and we previously reported a protective association of the MAPTH2 haplotype with MSA in 61 pathologically confirmed cases. METHODS: In the present study, we assessed the full MAPT haplotype diversity in MSA patients using six MAPT tagging SNPs. We genotyped a total of 127 pathologically confirmed MSA cases, 86 patients with clinically diagnosed MSA and 1312 controls. RESULTS: We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%, CONTROLS: 22.7%, p = 0.024) and H1E (MSA:3.0%, CONTROLS: 9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%, CONTROLS: 1.3%, p = 0.030) and H1J (MSA:3.0%, CONTROLS: 0.9%, p = 0.021). We evaluated the association of MSA subtypes with the common protective H2 haplotype and found a significant difference with controls for MSA patients with some degree of MSA-C (MSA-C or MSA-mixed), for whom H2 occurred in only 8.6% of patients in our pathologically confirmed series (P < 0.0001). CONCLUSIONS: Our findings provide further evidence that MAPT variation is associated with risk of MSA. Interestingly, our results suggest a greater effect size in the MSA-C compared to MSA-P for H2. Additional genetic studies in larger pathologically confirmed MSA series and meta-analytic studies will be needed to fully assess the role of MAPT and other genes in MSA.
Authors: C Vilariño-Güell; A I Soto-Ortolaza; A Rajput; D C Mash; S Papapetropoulos; R Pahwa; K E Lyons; R J Uitti; Z K Wszolek; D W Dickson; M J Farrer; O A Ross Journal: Neurology Date: 2011-02-15 Impact factor: 9.910
Authors: Megan K Herbert; Jorine M Eeftens; Marjolein B Aerts; Rianne A J Esselink; Bastiaan R Bloem; H Bea Kuiperij; Marcel M Verbeek Journal: Parkinsonism Relat Disord Date: 2013-09-12 Impact factor: 4.891
Authors: Rosa Rademakers; Stacey Melquist; Marc Cruts; Jessie Theuns; Jurgen Del-Favero; Parvoneh Poorkaj; Matt Baker; Kristel Sleegers; Richard Crook; Tim De Pooter; Samira Bel Kacem; Jennifer Adamson; Dirk Van den Bossche; Marleen Van den Broeck; Jennifer Gass; Ellen Corsmit; Peter De Rijk; Natalie Thomas; Sebastiaan Engelborghs; Michael Heckman; Irene Litvan; Julia Crook; Peter P De Deyn; Dennis Dickson; Gerard D Schellenberg; Christine Van Broeckhoven; Michael L Hutton Journal: Hum Mol Genet Date: 2005-09-29 Impact factor: 6.150
Authors: Catherine Labbé; Alexandra I Soto-Ortolaza; Sruti Rayaprolu; Andrea M Harriott; Audrey J Strongosky; Ryan J Uitti; Jay A Van Gerpen; Zbigniew K Wszolek; Owen A Ross Journal: Parkinsonism Relat Disord Date: 2013-04-16 Impact factor: 4.891
Authors: S Gilman; G K Wenning; P A Low; D J Brooks; C J Mathias; J Q Trojanowski; N W Wood; C Colosimo; A Dürr; C J Fowler; H Kaufmann; T Klockgether; A Lees; W Poewe; N Quinn; T Revesz; D Robertson; P Sandroni; K Seppi; M Vidailhet Journal: Neurology Date: 2008-08-26 Impact factor: 9.910
Authors: A M Pittman; A J Myers; P Abou-Sleiman; H C Fung; M Kaleem; L Marlowe; J Duckworth; D Leung; D Williams; L Kilford; N Thomas; C M Morris; D Dickson; N W Wood; J Hardy; A J Lees; R de Silva Journal: J Med Genet Date: 2005-03-25 Impact factor: 6.318
Authors: Amanda J Myers; Alan M Pittman; Alice S Zhao; Kristen Rohrer; Mona Kaleem; Lauren Marlowe; Andrew Lees; Doris Leung; Ian G McKeith; Robert H Perry; Chris M Morris; John Q Trojanowski; Christopher Clark; Jason Karlawish; Steve Arnold; Mark S Forman; Vivianna Van Deerlin; Rohan de Silva; John Hardy Journal: Neurobiol Dis Date: 2006-12-15 Impact factor: 5.996
Authors: Phillip A Low; Stephen G Reich; Joseph Jankovic; Clifford W Shults; Matthew B Stern; Peter Novak; Caroline M Tanner; Sid Gilman; Frederick J Marshall; Frederick Wooten; Brad Racette; Thomas Chelimsky; Wolfgang Singer; David M Sletten; Paola Sandroni; Jay Mandrekar Journal: Lancet Neurol Date: 2015-05-27 Impact factor: 44.182
Authors: Javier Simón-Sánchez; Claudia Schulte; Jose M Bras; Manu Sharma; J Raphael Gibbs; Daniela Berg; Coro Paisan-Ruiz; Peter Lichtner; Sonja W Scholz; Dena G Hernandez; Rejko Krüger; Monica Federoff; Christine Klein; Alison Goate; Joel Perlmutter; Michael Bonin; Michael A Nalls; Thomas Illig; Christian Gieger; Henry Houlden; Michael Steffens; Michael S Okun; Brad A Racette; Mark R Cookson; Kelly D Foote; Hubert H Fernandez; Bryan J Traynor; Stefan Schreiber; Sampath Arepalli; Ryan Zonozi; Katrina Gwinn; Marcel van der Brug; Grisel Lopez; Stephen J Chanock; Arthur Schatzkin; Yikyung Park; Albert Hollenbeck; Jianjun Gao; Xuemei Huang; Nick W Wood; Delia Lorenz; Günther Deuschl; Honglei Chen; Olaf Riess; John A Hardy; Andrew B Singleton; Thomas Gasser Journal: Nat Genet Date: 2009-11-15 Impact factor: 38.330
Authors: Michael G Heckman; Koji Kasanuki; Rebecca R Brennan; Catherine Labbé; Emily R Vargas; Alexandra I Soto; Melissa E Murray; Shunsuke Koga; Dennis W Dickson; Owen A Ross Journal: Mov Disord Date: 2019-06-24 Impact factor: 10.338
Authors: Michael G Heckman; Rebecca R Brennan; Catherine Labbé; Alexandra I Soto; Shunsuke Koga; Michael A DeTure; Melissa E Murray; Ronald C Petersen; Bradley F Boeve; Jay A van Gerpen; Ryan J Uitti; Zbigniew K Wszolek; Rosa Rademakers; Dennis W Dickson; Owen A Ross Journal: JAMA Neurol Date: 2019-06-01 Impact factor: 18.302
Authors: Jared S Katzeff; Katherine Phan; Sivaraman Purushothuman; Glenda M Halliday; Woojin Scott Kim Journal: Acta Neuropathol Commun Date: 2019-07-24 Impact factor: 7.801
Authors: Rebecca R Valentino; Shunsuke Koga; Ronald L Walton; Alexandra I Soto-Beasley; Naomi Kouri; Michael A DeTure; Melissa E Murray; Patrick W Johnson; Ronald C Petersen; Bradley F Boeve; Ryan J Uitti; Zbigniew K Wszolek; Dennis W Dickson; Owen A Ross; Michael G Heckman Journal: Acta Neuropathol Commun Date: 2020-12-07 Impact factor: 7.801
Authors: Angela B Deutschlander; Takuya Konno; Alexandra I Soto-Beasley; Ronald L Walton; Jay A van Gerpen; Ryan J Uitti; Michael G Heckman; Zbigniew K Wszolek; Owen A Ross Journal: Ann Clin Transl Neurol Date: 2020-08-07 Impact factor: 4.511