Brief Reports NR4A2 Genetic Variation in Sporadic Parkinson’s Disease: A Genewide Approach Daniel G. Healy, MRCPI, 1 * Patrick M. Abou-Sleiman, PhD, 1 Kourosh R. Ahmadi, PhD, 2 Sonia Gandhi, MRCP, 1 Miratul M. Muqit, MRCP, 1 Kailash P. Bhatia, MD, FRCP, 3 Niall P. Quinn, MD, FRCP, 3 Andrew J. Lees, MD, FRCP, 1,4 Janice L. Holton, MD, PhD, 1 Tamas Revesz, MD, 1 and Nicholas W. Wood, PhD, FRCP, FMed Sci 1 1 Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom; 2 Department of Biology, University College London, London, United Kingdom; 3 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London, United Kingdom; 4 Reta Lila Weston Institute for Neurological Studies, University of London, London, United Kingdom Abstract: The NR4A2 gene, which may cause autosomal dom- inant Parkinson’s disease (PD), has also been reported to be a susceptibility factor for sporadic PD. Here, we use a haplotype- tagging approach in 802 PD patients and 784 controls and demonstrate that common genetic variation, including NR4A2 haplotypes, does not influence the risk of PD in the Caucasian population. © 2006 Movement Disorder Society Key words: NR4A2; Parkinson’s disease; genewide study; haplotype tagging The NR4A2 gene (NURR1) functions as an orphan nuclear receptor of the steroid/thyroid superfamily. 1 This small gene spans 9.8 kb and contains eight exons. Evi- dence that the NR4A2 gene may be important in Parkin- son’s disease (PD) includes its role in the transcription of tyrosine hydroxylase and the dopamine transporter gene; NR4A2 knockout mice do not develop dopamine neu- rones in the substantia nigra; and heterozygous knock- outs have increased sensitivity to MPTP neurotox- icity. 2–4 In 2003, Le and colleagues 5 reported autosomal dominant mutations in NR4A2 in families with typical late-onset PD; however, the latter finding has not been replicated to date. There is conflicting data on the role of NR4A2 in sporadic PD. The hypothesis generating first study by Xu and colleagues 6 found a single nucleotide insertion (IVS6+16insG) that was associated with increased risk of PD. However, only 1 out of 5 follow-up studies has replicated this finding. 7–12 In this study, we aimed to clarify the role of NR4A2 in sporadic PD. This was performed using a sufficiently powerful case– control study and a haplotype-tagging strategy. Because the latter strategy has power to assess the genetic influence of any common (and potentially associated) variant in NR4A2, it minimizes the possibility of a false negative result. 13,14 PATIENTS AND METHODS Design A total of 802 PD patients were recruited after a clinical diagnosis was made by at least one consultant neurologist (n = 511) or after pathological confirmation (n = 291). 15,16 Unified diagnostic criteria (modified U.K. Queen Square Brain Bank criteria) were used. 15 PD was classified as either late-onset PD (LOPD; onset  50 years; n = 628) or young-onset PD (YOPD; onset  50 years; n = 174). To reduce the possibility of individuals with mendelian PD gene mutations overestimating any possible association, we excluded individuals with a known PD-affected relative. In addition, all patients were screened (and excluded) for mutations in the eight exons of NR4A2 and all YOPD were screened for parkin, PINK1, DJ-1, as well as the common G2019 mutation in LRRK2. Our controls (n = 784) consisted of healthy volunteers (n = 383) or patients’ spouses (n = 401). Control indi- viduals were matched by age ( 5 years) and sex. A consultant neurologist assessed 78% of control subjects and none exhibited parkinsonism at recruitment. For the total study, the mean age of onset for PD was 58.8 years and the mean age at recruitment for controls was 56.4 *Correspondence to: Dr. Daniel G. Healy, Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom. E-mail: d.healy@ion.ucl.ac.uk Received 3 September 2005; Revised 27 October 2005; Accepted 28 October 2005 Published online 14 September 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21018 Movement Disorders Vol. 21, No. 11, 2006, pp. 1960 –2025 © 2006 Movement Disorder Society 1960