LRRK2 exonic variants and risk of multiple system atrophy

Michael G. Heckman, Lucia Schottlaender, Alexandra I. Soto-Ortolaza, Nancy N. Diehl, Sruti Rayaprolu, Kotaro Ogaki, Shinsuke Fujioka, Melissa E. Murray, William P. Cheshire, Ryan J. Uitti, Zbigniew K. Wszolek, Matthew J. Farrer, Anna Sailer, Andrew B. Singleton, Patrick F. Chinnery, Michael J. Keogh, Steve M. Gentleman, Janice L. Holton, Kiely Aoife, David M.A. MannSafa Al-Sarraj, Claire Troakes, Dennis W. Dickson, Henry Houlden, Owen A. Ross

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Objective: The aim of this study was to evaluate the association between common exonic variants in the leucine-rich repeat kinase 2 (LRRK2) gene and risk of multiple system atrophy (MSA). Methods: One series from the United States (92 patients with pathologically confirmed MSA, 416 controls) and a second series from the United Kingdom (85 patients with pathologically confirmed MSA, 352 controls) were included in this case-control study.We supplemented these data with those of 53 patients from the United States with clinically probable or possible MSA. Seventeen common LRRK2 exonic variants were genotyped and assessed for association withMSA. Results: In the combined series of 177 patients with pathologically confirmed MSA and 768 controls, there was a significant association between LRRK2 p.M2397T and MSA (odds ratio [OR] = 0.60, p = 0.002). This protective effect was observed more strongly in the US series (OR = 0.46, p = 0.0008) than the UK series (OR = 0.82, p = 0.41). We observed other noteworthy associations with MSA for p.G1624G (OR = 0.63, p = 0.006) and p.N2081D (OR = 0.15, p = 0.010). The p.G1624G-M2397T haplotype was significantly associated with MSA in the US series (p < 0.0001) and combined series (p = 0.003) but not the UK series (p = 0.67). Results were consistent when additionally including the US patients with clinical MSA, where the strongest singlevariant association was again observed for p.M2397T (OR = 0.59, p = 0.0005). Conclusions: These findings provide evidence that LRRK2 exonic variants may contribute to susceptibility to MSA. Validation in other series and meta-analytic studies will be important.

Original languageEnglish (US)
Pages (from-to)2256-2261
Number of pages6
JournalNeurology
Volume83
Issue number24
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Clinical Neurology

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    Heckman, M. G., Schottlaender, L., Soto-Ortolaza, A. I., Diehl, N. N., Rayaprolu, S., Ogaki, K., Fujioka, S., Murray, M. E., Cheshire, W. P., Uitti, R. J., Wszolek, Z. K., Farrer, M. J., Sailer, A., Singleton, A. B., Chinnery, P. F., Keogh, M. J., Gentleman, S. M., Holton, J. L., Aoife, K., ... Ross, O. A. (2014). LRRK2 exonic variants and risk of multiple system atrophy. Neurology, 83(24), 2256-2261. https://doi.org/10.1212/WNL.0000000000001078