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Am J Neurodegener Dis 2013;2(4):287-299

Original Article
GWAS risk factors in Parkinson’s disease: LRRK2 coding variation and
genetic interaction with PARK16

Alexandra I Soto-Ortolaza, Michael G Heckman, Catherine Labbé, Daniel J Serie, Andreas Puschmann, Sruti
Rayaprolu, Audrey Strongosky, Magdalena Boczarska-Jedynak, Grzegorz Opala, Anna Krygowska-Wajs, Maria
Barcikowska, Krzysztof Czyzewski, Timothy Lynch, Ryan J Uitti, Zbigniew K Wszolek, Owen A Ross

Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA; Section of Biostatistics, Mayo Clinic, Jacksonville,
Florida, USA; Department of Neurology, Lund University, Sweden; Department of Neurology, Mayo Clinic, Jacksonville,
Florida, USA; Department of Neurology, Medical University of Silesia, Katowice, Poland; Department of Neurology,
Jagiellonian University, Krakow, Poland; Department of Neurodegenerative Disorders, Medical Research Centre,
Polish Academy of Sciences, Warsaw, Poland; Department of Neurology, Central Hospital of The Ministry of Interior
and Administration, Warsaw, Poland; Dublin Neurological Institute at The Mater Misericordiae University Hospital,
Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland. Equal contributors.

Received September 3, 2013; Accepted October 15, 2013; Epub November 29, 2013; Published December 15, 2013

Abstract: Parkinson’s disease (PD) is a multifactorial movement disorder characterized by progressive
neurodegeneration. Genome-wide association studies (GWAS) have nominated over fifteen distinct loci associated
with risk of PD, however the biological mechanisms by which these loci influence disease risk are mostly unknown.
GWAS are only the first step in the identification of disease genes: the specific causal variants responsible for the risk
within the associated loci and the interactions between them must be identified to fully comprehend their impact on the
development of PD. In the present study, we first attempted to replicate the association signals of 17 PD GWAS loci in
our series of 1381 patients with PD and 1328 controls. BST1, SNCA, HLA-DRA, CCDC62/HIP1R and MAPT all showed
a significant association with PD under different models of inheritance and LRRK2 showed a suggestive association.
We then examined the role of coding LRRK2 variants in the GWAS association signal for that gene. The previously
identified LRRK2 risk mutant p.M1646T and protective haplotype p.N551K-R1398H-K1423K did not explain the
association signal of LRRK2 in our series. Finally, we investigated the gene-gene interaction between PARK16 and
LRRK2 that has previously been proposed. We observed no interaction between PARK16 and LRRK2 GWAS variants,
but did observe a non-significant trend toward interaction between PARK16 and LRRK2 variants within the protective
haplotype. Identification of causal variants and the interactions between them is the crucial next step in making
biological sense of the massive amount of data generated by GWAS studies. Future studies combining larger sample
sizes will undoubtedly shed light on the complex molecular interplay leading to the development of PD.
(AJND1309001).

Keywords: Association studies in genetics, Parkinson’s disease/Parkinsonism

Address correspondence to: Dr. Owen A Ross, Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San
Pablo Road, Jacksonville, FL 32224, USA. Tel: 904-953-6280; Fax: 904-953-7370; E-mail: ross.owen@mayo.edu