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

doi:10.1212/WNL.0000000000001078

LRRK2 exonic variants and risk of multiple system atrophy

Neurology. 2014 Dec 9;83(24):2256-61. doi: 10.1212/WNL.0000000000001078. Epub 2014 Nov 5.

Authors

Michael G Heckman¹, Lucia Schottlaender², Alexandra I Soto-Ortolaza², Nancy N Diehl², Sruti Rayaprolu², Kotaro Ogaki², Shinsuke Fujioka², Melissa E Murray², William P Cheshire², Ryan J Uitti², Zbigniew K Wszolek², Matthew J Farrer², Anna Sailer², Andrew B Singleton², Patrick F Chinnery², Michael J Keogh², Steve M Gentleman², Janice L Holton², Kiely Aoife², David M A Mann², Safa Al-Sarraj², Claire Troakes², Dennis W Dickson², Henry Houlden², Owen A Ross²

Affiliations

¹ From the Section of Biostatistics (M.G.H., N.N.D.) and Departments of Neuroscience (A.I.S.-O., S.R., K.O., M.E.M., D.W.D., O.A.R.) and Neurology (S.F., W.P.C., R.J.U., Z.K.W.), Mayo Clinic, Jacksonville, FL; Department of Molecular Neuroscience (L.S., A.S., H.H.), Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Department of Medical Genetics (M.J.F.), University of British Columbia, Vancouver, Canada; Laboratory of Neurogenetics (A.B.S.), National Institute on Aging, Bethesda, MD; Institute of Genetic Medicine (P.F.C., M.J.K.), Newcastle University, Central Parkway, Newcastle upon Tyne; Neuropathology Unit (S.M.G.), Department of Medicine, Imperial College London; Queen Square Brain Bank for Neurological Disorders (J.L.H., K.A.), Department of Molecular Neuroscience, UCL Institute of Neurology, University College London; Clinical and Cognitive Sciences Research Group (D.M.A.M.), Institute of Brain, Behavior and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford; and MRC London Neurodegenerative Diseases Brain Bank (S.A.-S., C.T.), King's College London, UK. heckman.michael@mayo.edu.
² From the Section of Biostatistics (M.G.H., N.N.D.) and Departments of Neuroscience (A.I.S.-O., S.R., K.O., M.E.M., D.W.D., O.A.R.) and Neurology (S.F., W.P.C., R.J.U., Z.K.W.), Mayo Clinic, Jacksonville, FL; Department of Molecular Neuroscience (L.S., A.S., H.H.), Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Department of Medical Genetics (M.J.F.), University of British Columbia, Vancouver, Canada; Laboratory of Neurogenetics (A.B.S.), National Institute on Aging, Bethesda, MD; Institute of Genetic Medicine (P.F.C., M.J.K.), Newcastle University, Central Parkway, Newcastle upon Tyne; Neuropathology Unit (S.M.G.), Department of Medicine, Imperial College London; Queen Square Brain Bank for Neurological Disorders (J.L.H., K.A.), Department of Molecular Neuroscience, UCL Institute of Neurology, University College London; Clinical and Cognitive Sciences Research Group (D.M.A.M.), Institute of Brain, Behavior and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford; and MRC London Neurodegenerative Diseases Brain Bank (S.A.-S., C.T.), King's College London, UK.

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 with MSA.

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 single-variant 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Case-Control Studies
Exons
Female
Genetic Predisposition to Disease*
Genetic Variation*
Genotyping Techniques
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Male
Middle Aged
Multiple System Atrophy / genetics*
Protein Serine-Threonine Kinases / genetics*
Risk
United Kingdom
United States

Substances

LRRK2 protein, human
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding