Catherine Labbé1, Kotaro Ogaki1, Oswaldo Lorenzo-Betancor1, Alexandra I Soto-Ortolaza1, Ronald L Walton1, Sruti Rayaprolu1, Shinsuke Fujioka1, Melissa E Murray1, Michael G Heckman1, Andreas Puschmann1, Allan McCarthy1, Timothy Lynch1, Joanna Siuda1, Grzegorz Opala1, Monika Rudzinska1, Anna Krygowska-Wajs1, Maria Barcikowska1, Krzysztof Czyzewski1, Yanosh Sanotsky1, Irena Rektorová1, Pamela J McLean1, Rosa Rademakers1, Nilüfer Ertekin-Taner1, Anhar Hassan1, J Eric Ahlskog1, Bradley F Boeve1, Ronald C Petersen1, Demetrius M Maraganore1, Charles H Adler1, Tanis J Ferman1, Joseph E Parisi1, Neill R Graff-Radford1, Ryan J Uitti1, Zbigniew K Wszolek1, Dennis W Dickson1, Owen A Ross2. 1. From the Departments of Neuroscience (C.L., K.O., O.L.-B., A.I.S.-O., R.L.W., S.R., M.E.M., P.J.M., R.R., N.E.-T., D.W.D., O.A.R.), Neurology (S.F., N.E.-T., N.R.G.-R., R.J.U., Z.K.W.), and Psychiatry and Psychology (T.J.F.), Division of Biomedical Statistics and Informatics (M.G.H.), and Mayo Graduate School (P.J.M., O.A.R.), Mayo Clinic, Jacksonville, FL; Dublin Neurological Institute at the Mater Misericordiae University Hospital (A.M., T.L.), Conway; Institute of Biomolecular & Biomedical Research (A.M., T.L.), University College Dublin, Ireland; Department of Clinical Sciences (A.P.), Lund University, and Department of Neurology, Skåne University Hospital, Sweden; Department of Neurology (J.S., G.O.), Medical University of Silesia, Katowice; Department of Neurology (M.R., A.K.-W.), Jagiellonian University, Krakow; Department of Neurodegenerative Disorders (M.B.), Medical Research Centre, Polish Academy of Sciences, Warsaw; Department of Neurology (K.C.), Central Hospital of the Ministry of Interior and Administration, Warsaw, Poland; Lviv Regional Clinical Hospital (Y.S.), Ukraine; Department of Neurology and School of Medicine (I.R.), Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Departments of Neurology (A.H., J.E.A., B.F.B., R.C.P.) and Pathology and Laboratory Medicine (J.E.P.), Mayo Clinic, Rochester, MN; Department of Neurology (D.M.M.), NorthShore University Health System, Evanston, IL; and Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale, AZ. 2. From the Departments of Neuroscience (C.L., K.O., O.L.-B., A.I.S.-O., R.L.W., S.R., M.E.M., P.J.M., R.R., N.E.-T., D.W.D., O.A.R.), Neurology (S.F., N.E.-T., N.R.G.-R., R.J.U., Z.K.W.), and Psychiatry and Psychology (T.J.F.), Division of Biomedical Statistics and Informatics (M.G.H.), and Mayo Graduate School (P.J.M., O.A.R.), Mayo Clinic, Jacksonville, FL; Dublin Neurological Institute at the Mater Misericordiae University Hospital (A.M., T.L.), Conway; Institute of Biomolecular & Biomedical Research (A.M., T.L.), University College Dublin, Ireland; Department of Clinical Sciences (A.P.), Lund University, and Department of Neurology, Skåne University Hospital, Sweden; Department of Neurology (J.S., G.O.), Medical University of Silesia, Katowice; Department of Neurology (M.R., A.K.-W.), Jagiellonian University, Krakow; Department of Neurodegenerative Disorders (M.B.), Medical Research Centre, Polish Academy of Sciences, Warsaw; Department of Neurology (K.C.), Central Hospital of the Ministry of Interior and Administration, Warsaw, Poland; Lviv Regional Clinical Hospital (Y.S.), Ukraine; Department of Neurology and School of Medicine (I.R.), Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Departments of Neurology (A.H., J.E.A., B.F.B., R.C.P.) and Pathology and Laboratory Medicine (J.E.P.), Mayo Clinic, Rochester, MN; Department of Neurology (D.M.M.), NorthShore University Health System, Evanston, IL; and Department of Neurology (C.H.A.), Mayo Clinic, Scottsdale, AZ. ross.owen@mayo.edu.
Abstract
OBJECTIVE: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. METHODS: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. RESULTS: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution. CONCLUSIONS: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.
OBJECTIVE: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies. METHODS: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls. RESULTS: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63-2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62-20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04-12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85-25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution. CONCLUSIONS: Overall, our findings suggest that MAPTp.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.
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