Hum Genet (2009) 126:425–430 DOI 10.1007/s00439-009-0678-x 123 ORIGINAL INVESTIGATION Non-synonymous GIGYF2 variants in Parkinson’s disease from two Asian populations Eng-King Tan · Chin-Hslen Lin · Chun-Hwei Tai · Louis C. Tan · Meng-Ling Chen · R. Li · Hui-Qin Lim · Ratnagopal Pavanni · Yih Yuen · K. M. Prakash · Yi Zhao · Ruey-Meei Wu Received: 5 April 2009 / Accepted: 29 April 2009 / Published online: 16 May 2009  Springer-Verlag 2009 Abstract Mutations in the GIGYF2 gene at the PARK11 locus have recently been reported in Parkinson’s disease (PD). However, the pathogenicity of some of these muta- tions has been debated. We conducted a comprehensive genetic analysis of the entire GIGYF2 gene in a cohort of young onset and familial PD patients, followed up with screening of speciWc variants in a separate group of PD and healthy controls. A total of 850 study subjects [450 Parkin- son’s disease (PD) patients and 400 controls] from two Asian countries were included. Our analysis revealed 17 variants distributed across the entire GIGYF2 gene. Ten of these were novel variants out of which eight were non-syno- nymous (all heterozygous). Out of these eight, half were novel polymorphic variants (0.2–2%) whereas four were novel non-synonymous variants which were not detected in healthy controls. The seven PD patients with non-synony- mous variants had a mean age and age at onset of 55.3 and 50.9 years. All had typical features of PD and only one had a positive family history. The collective frequency of these non-synonymous variants was higher in PD compared to controls (1.6 vs. 0%, P = 0.016, relative risk 1.9, 95% CI 1.2, 1.9). None of the previously reported pathogenic mutations in Italian and French patients were present in our cohort. Our data suggest that GIGYF2 is unlikely to play a major role in our Asian populations. Rare non-synonymous variants appeared to be enriched in our PD patients compared to healthy controls. However, in vivo functional studies and segregation analysis in large pedigrees will be needed to determine if these single heterozygous variants represent rare mutations, risk alleles or benign polymorphisms. Introduction PD is a common neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Genetic contribution in PD has created considerable excite- ment as at least 14 loci (PARK1–PARK14) have been assigned and numerous causative genes have been reported to associate with either typical PD and/or atypical levodopa responsive parkinsonism (PARK1 and PARK4 OMIM #168601 (SNCA), PARK2 OMIM #602544 (PRKN), PARK6 OMIM #605909 (PINK1), PARK7 OMIM #606324 (DJ-1), PARK8 OMIM #609007 (LRRK2), PARK9 OMIM #610513 (ATP13A2), and PARK14 OMIM #603604 (PLA2G6) (Tan and Skipper 2007; Polymeropoulos et al. 1997; Kitada et al. 1998; Leroy et al. 1998; Valente et al. 2004; Bonifati et al. 2003; Paisan-Ruiz et al. 2004; E.-K. Tan · R. Li · H.-Q. Lim · R. Pavanni · K. M. Prakash Department of Neurology, Singapore General Hospital, Singapore, Singapore e-mail: gnrtek@sgh.com.sg Y. Zhao Department of Clinical Research, Singapore General Hospital, Singapore, Singapore Y. Yuen Department of Health Screening, Singapore General Hospital, Singapore, Singapore E.-K. Tan · L. C. Tan National Neuroscience Institute, Singhealth, Singapore, Singapore E.-K. Tan · R. Pavanni · K. M. Prakash Duke-NUS Graduate Medical School, Singapore, Singapore C.-H. Lin · C.-H. Tai · M.-L. Chen · R.-M. Wu (&) Department of Neurology, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan e-mail: robinwu@ntu.edu.tw