TY - JOUR
T1 - MAPT haplotype diversity in multiple system atrophy
AU - Labbé, Catherine
AU - Heckman, Michael G.
AU - Lorenzo-Betancor, Oswaldo
AU - Murray, Melissa E.
AU - Ogaki, Kotaro
AU - Soto-Ortolaza, Alexandra I.
AU - Walton, Ronald L.
AU - Fujioka, Shinsuke
AU - Koga, Shunsuke
AU - Uitti, Ryan J.
AU - van Gerpen, Jay A.
AU - Petersen, Ronald C.
AU - Graff-Radford, Neill R.
AU - Younkin, Steven G.
AU - Boeve, Bradley F.
AU - Cheshire, William P.
AU - Low, Phillip A.
AU - Sandroni, Paola
AU - Coon, Elizabeth A.
AU - Singer, Wolfgang
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
AU - Ross, Owen A.
N1 - Funding Information:
Dr. Boeve has served as an investigator for clinical trials sponsored by GE Healthcare and FORUM Pharmaceuticals. He receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009). He serves on the Scientific Advisory Board of the Tau Consortium. He has consulted for Isis Pharmaceuticals. Dr Ross is a member of the editorial board of PLoS ONE, American Journal of Neurodegenerative disease, Molecular Neurodegeneration and Parkinsonism and Related Disorders, and he is funded by NIH grants NS078086 and NS072187 and the Michael J. Fox Foundation. All authors have approved the final version of this paper.
Funding Information:
The authors thank those who contributed to their research, particularly the patients and families who donated DNA samples and brain tissue for this work. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson’s Disease Research Center of Excellence (NINDS P50 NS072187, neuropathology core: DWD, clinical core PI: ZKW, genetic core PI: OAR). This work is also supported by NINDS R01 NS078086 ( OAR ), P01 NS44233 ( PAL ), U54 NS065736 ( PAL ), K23 NS075141 ( WS ), UL1 RR24150 ( PAL ), R01 NS092625 ( PAL ), R01 FD478 ( PAL ), P50 AG016574 ( Alzheimer’s Disease Research Center ), U01 AG006786 ( Mayo Clinic Study of Aging ), Mayo Clinic Center for Regenerative Medicine , Mayo Clinic Center for Individualized Medicine , Mayo Clinic Neuroscience Focused Research Team , Cure MSA Foundation , and a gift from Carl Edward Bolch, Jr. and Susan Bass Bolch (SF, OAR, ZKW). CL is the recipient of a FRSQ postdoctoral fellowship and is a 2015 Younkin Scholar supported by the Mayo Clinic Alzheimer’s Disease and Related Dementias Genetics program.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - Association study
KW - Genetics
KW - MAPT
KW - Multiple system atrophy
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U2 - 10.1016/j.parkreldis.2016.06.010
DO - 10.1016/j.parkreldis.2016.06.010
M3 - Article
C2 - 27374978
AN - SCOPUS:84979695272
VL - 30
SP - 40
EP - 45
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
SN - 1353-8020
ER -