biostudies-literature00470Labbe COARAlzheimer’s Disease Research CenterNIA NIH HHSNCRR NIH HHSMayo Clinic Neuroscience Focused Research TeamMayo Clinic Center for Regenerative MedicineNINDSFDA HHSMayo Clinic Center for Individualized MedicinePALNINDS NIH HHSWSCure MSA FoundationMayo Clinic Study of Aging40-5https://www.ebi.ac.uk/biostudies/studies/S-EPMC5007155biostudies-literatureUnknown30<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%,<h4>Controls</h4>22.7%, p = 0.024) and H1E (MSA:3.0%,<h4>Controls</h4>9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%,<h4>Controls</h4>1.3%, p = 0.030) and H1J (MSA:3.0%,<h4>Controls</h4>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).<h4>Conclusions</h4>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.Parkinsonism & related disordersMAPT haplotype diversity in multiple system atrophy.PMC5007155R01 FD478R01 NS078086UL1 RR24150P01 NS44233P50 NS072187U01 AG006786R01 NS092625R01 FD004789P50 AG016574U54 NS065736K23 NS075141P01 NS044233UL1 RR024150Dickson DWLabbe CMurray MEHeckman MGFujioka SRoss OAOgaki KSandroni PCoon EASinger WGraff-Radford NRPetersen RCYounkin SGWszolek ZKLorenzo-Betancor OCheshire WPUitti RJvan Gerpen JASoto-Ortolaza AIKoga SBoeve BFWalton RLLow PA47falseMAPT haplotype diversity in multiple system atrophy.<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>We identified four significant association signals in our pathologically confirmed cases, two from the protective haplotypes H2 (MSA:16.2%,<h4>Controls</h4>22.7%, p = 0.024) and H1E (MSA:3.0%,<h4>Controls</h4>9.0%, p = 0.014), and two from the rare risk haplotypes H1x (MSA:3.7%,<h4>Controls</h4>1.3%, p = 0.030) and H1J (MSA:3.0%,<h4>Controls</h4>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).<h4>Conclusions</h4>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.2016-01-01T00:00:00Z2016 Sep2024-11-12T12:31:23.677Z2019-03-27T02:23:11ZS-EPMC50071552737497810.1016/j.parkreldis.2016.06.010