AN INDEPENDENT REPLICATION OF PARK16 IN ASIAN SAMPLES

Parkinson disease (PD) is the most common neurodegenerative movement disorder with age-related prevalence. Approximately 1% of the population is affected at 65 years, which increases to 4%-5% in 85-year-olds.¹ To date, several loci containing pathogenic or risk variants have been identified; the most recent, PARK16, was nominated through 2 genome-wide association studies (GWAS) using samples of Japanese and European ancestry.^2,3 This new locus, located in 1q32, was originally identified in the Asian study with p values ranging from 10⁻⁷ to 10⁻¹². PARK16 did not reach significance level in the European GWAS or its replication (p value >10⁻⁴); however, combining samples from stage I and II indicated an association. The most significant SNP in the European study (rs823128) showed a 1% difference in minor allele frequency (MAF) between patients with PD (4%) and control subjects (3%), resulting in an odds ratio (OR) of 0.66 (p value = 7.3 × 10⁻⁸) (of note, the allele frequencies seem to have been mistakenly switched in the combined analysis).³ In contrast, the MAF of rs823128 appears to be more common in the Japanese population, with a lower frequency in patients with PD (10%) vs control subjects (14%), resulting in an OR of 1.41 (confidence interval 1.26-1.58; p value = 4.9 × 10⁻⁷). Interestingly, rs947211 presents the highest level of significance in the Asian study (p value = 1.5 × 10⁻¹²); however, it did not replicate in the European GWAS (uncorrected p value = 0.01, OR = 0.93).

In this study, we attempted to replicate this association in 7 independent patient-control series from Asia, Europe, North Africa, and North America (table e-1 on the Neurology® Web site at www.neurology.org). Genotyping of rs823128 was performed on the Sequenom platform with a call rate of >95% for all series. All genotypes were in Hardy-Weinberg equilibrium; allele and genotype frequencies for each series and a combined analysis are displayed in table 1.

Table 1 Association of rs823128 with Parkinson disease in populations of Asian, Arab-Berber, and European ancestry

We could replicate the association observed in the Japanese population in our Taiwanese series of ethnic Chinese ancestry (OR = 1.46 modeled over the major allele, confidence interval 1.05-2.04; p value = 0.015) despite the relatively small sample size of this series (n = 751). In contrast, neither the Tunisian series nor any of the Caucasian samples of European ancestry from North America or Europe, individually or combined, showed evidence for association (p value >0.05). The allele frequency for rs823128 is similar in the Taiwanese and Tunisian samples (13%), but low in all the Caucasian series (2%-5%), resulting in decreased statistical power to identify true associations.

This study confirmed the presence of PARK16 in Taiwanese ethnic Chinese samples. Additional population studies are needed to discern whether PARK16 is a global risk locus, and to identify the functional variants responsible in Asia.

Supplemental data at www.neurology.org

Author Contributions: Statistical analysis was conducted by Dr. Carles Vilariño-Güell.

Study funding: Supported by NIH NINDS P50 NS40256 and the Michael J. Fox Foundation.

Disclosure: Dr. Vilarino-Guell reports no disclosures. Dr. Ross serves on the editorial board of Open Longevity Science. Dr. Aasly serves on the editorial boards of Parkinsonism & Related Disorders, Tidsskrift Norske Lægeforening, and Parkinson Disease; and is coauthor on a patent re: LRRK2 G2019S. Dr. White reports no disclosures. Dr. Alex Rajput has served on scientific advisory boards for Novartis and UCB; has received funding for travel and speaker honoraria from Novartis; serves on the editorial board of the Canadian Journal of Neurological Sciences; and has received research support from Novartis, Allergan Inc., the NIH (NINDS U01 NS050324-01A1 [local PI]), CIHR, International Essential Tremor Foundation, Regina Curling Classic for Parkinson's research, and Parkinson's disease and movement disorders endowment through RUH Foundation. Dr. Ali Rajput receives research support from the Saskatchewan Parkinson's Disease Foundation, Curling Classic, and PrintWest Golf Classic. Dr. Lynch serves/has served on scientific advisory boards for Merck Serono, the UK Parkinson's Disease Association, the Dublin Neurological Institute at the Mater Misericordiae University Hospital, the Irish Institute of Clinical Neuroscience, and Neuroscience Ireland; has received speaker honoraria from Lundbeck Inc. and Boehringer Ingelheim; and has received unrestricted educational grants from Orion Corporation, Lundbeck Inc., Boehringer Ingelheim, Bayer Schering Pharma, Biogen Idec, and GlaxoSmithKline for opening of the Dublin Neurological Institute, Ireland. Dr. Krygowska-Wajs reports no disclosures. Dr. Jasinska-Myga has received research support from the Robert and Clarice Smith Fellowship Program, the Pacific Alzheimer Research Foundation, and the Polish Foundation for Development of Neurology, Degenerative and Cerebrovascular Diseases. Dr. Opala serves on the editorial board of Neurologia i Neurochirurgia Polska, Polski Przegląd Neurologiczny, Neurologia po Dyplomie, and Psychogeriatria Polska. Dr. Barcikowska has received speaker honoraria from Novartis. Dr. Lee and Dr. Hentati report no disclosures. Dr. Uitti serves as an Associate Editor of Neurology®; has received research support from Advanced Neuromodulations Systems and the NIH/NINDS (P50NS 40256 [coinvestigator]); and his institution receives annual royalties from Lundbeck Inc. from the licensing of the technology related to PARK8/LRRK2. Dr. Wszolek serves as Co-Editor-in-Chief of Parkinsonism and Related Disorders, Regional Editor of the European Journal of Neurology, and on the editorial boards of Neurologia i Neurochirurgia Polska, Advances in Rehabilitation, the Medical Journal of the Rzeszow University, and Clinical and Experimental Medical Letters; holds and has contractual rights for receipt of future royalty payments from patents re: A novel polynucleotide involved in heritable Parkinson's disease; receives royalties from publishing Parkinsonism and Related Disorders (Elsevier, 2007, 2008, 2009) and the European Journal of Neurology (Wiley-Blackwell, 2007, 2008, 2009); receives research support from Allergan, Inc., the NIH (NIA P01AG017216-1 [coinvestigator], NIA R01AG015866-1 [coinvestigator], and NINDS P50NS 40256 [coinvestigator]), the Pacific Alzheimer Research Foundation (Canada), and the CIHR. Dr. Farrer serves on a scientific advisory board for the Michael J. Fox Foundation; serves/has served on the editorial boards of Neurobiology of Disease and Parkinsonism and Related Disorders; is coinventor on patents re: LRRK2 gene and mutations; receives institutional research support from Lundbeck Inc.; has received research support from the NIH (NS40256 [Project and Core PI]), the Pacific Alzheimer Research Foundation, and the Michael J. Fox Foundation; and his institution receives annual royalties from Lundbeck Inc. from the licensing of the technology related to PARK8/LRRK2. Dr. Wu reports no disclosures.

Received March 5, 2010. Accepted in final form June 29, 2010.

Address correspondence and reprint requests to Dr. Carles Vilarino-Guell, Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, 950 West 28th Avenue, University of British Columbia, Vancouver, BC V5Z 4H4 Canada; carles@cmmt.ubc.ca; or Dr. Ruey-Meei Wu, Department of Neurology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan; robinwu@ntu.edu.tw