MAPT haplotype diversity in multiple system atrophy.

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.