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 Mann; Safa Al-Sarraj; Claire Troakes; Dennis W. Dickson; Henry Houlden; Owen A. Ross

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

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

38 Citations (Scopus)

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 language	English
Pages (from-to)	2256-2261
Number of pages	6
Journal	Neurology
Volume	83
Issue number	24
Publication status	Published - 1 Dec 2014

Cite this

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.

@article{de340407f50a4f82b2ae87b7364d2305,

title = "LRRK2 exonic variants and risk of multiple system atrophy",

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.",

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

year = "2014",

month = dec,

day = "1",

language = "English",

volume = "83",

pages = "2256--2261",

journal = "Neurology",

issn = "0028-3878",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "24",

}

Heckman, MG, Schottlaender, L, Soto-Ortolaza, AI, Diehl, NN, Rayaprolu, S, Ogaki, K, Fujioka, S, Murray, ME, Cheshire, WP, Uitti, RJ, Wszolek, ZK, Farrer, MJ, Sailer, A, Singleton, AB, Chinnery, PF, Keogh, MJ, Gentleman, SM, Holton, JL, Aoife, K, Mann, DMA, Al-Sarraj, S , Troakes, C, Dickson, DW, Houlden, H & Ross, OA 2014, 'LRRK2 exonic variants and risk of multiple system atrophy', Neurology, vol. 83, no. 24, pp. 2256-2261.

TY - JOUR

T1 - LRRK2 exonic variants and risk of multiple system atrophy

AU - Heckman, Michael G.

AU - Schottlaender, Lucia

AU - Soto-Ortolaza, Alexandra I.

AU - Diehl, Nancy N.

AU - Rayaprolu, Sruti

AU - Ogaki, Kotaro

AU - Fujioka, Shinsuke

AU - Murray, Melissa E.

AU - Cheshire, William P.

AU - Uitti, Ryan J.

AU - Wszolek, Zbigniew K.

AU - Farrer, Matthew J.

AU - Sailer, Anna

AU - Singleton, Andrew B.

AU - Chinnery, Patrick F.

AU - Keogh, Michael J.

AU - Gentleman, Steve M.

AU - Holton, Janice L.

AU - Aoife, Kiely

AU - Mann, David M A

AU - Al-Sarraj, Safa

AU - Troakes, Claire

AU - Dickson, Dennis W.

AU - Houlden, Henry

AU - Ross, Owen A.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84925940317&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:84925940317

SN - 0028-3878

VL - 83

SP - 2256

EP - 2261

JO - Neurology

JF - Neurology

IS - 24

ER -

LRRK2 exonic variants and risk of multiple system atrophy

Abstract

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