期刊
PARKINSONISM & RELATED DISORDERS
卷 30, 期 -, 页码 40-45出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.parkreldis.2016.06.010
关键词
Multiple system atrophy; MAPT; Association study; Genetics
资金
- NINDS [R01 NS078086, P01 NS44233, U54 NS065736, K23 NS075141, UL1 RR24150, R01 NS092625, R01FD478, P50 AG016574, U01 AG006786]
- Mayo Clinic Center for Regenerative Medicine
- Mayo Clinic Center for Individualized Medicine
- Mayo Clinic Neuroscience Focused Research Team
- Cure MSA Foundation
- FRSQ postdoctoral fellowship
- Mayo Clinic Alzheimer's Disease and Related Dementias Genetics program
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 HIE (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. (C) 2016 Elsevier Ltd. All rights reserved.
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