Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population

• Published in: Human molecular genetics Vol. 20; no. 3; pp. 615 - 627
• Main Authors: Saad, M., Lesage, S., Saint-Pierre, A., Corvol, J.-C., Zelenika, D., Lambert, J.-C., Vidailhet, M., Mellick, G. D., Lohmann, E., Durif, F., Pollak, P., Damier, P., Tison, F., Silburn, P. A., Tzourio, C., Forlani, S., Loriot, M.-A., Giroud, M., Helmer, C., Portet, F., Amouyel, P., Lathrop, M., Elbaz, A., Durr, A., Martinez, M., Brice, A., Agid, Y., Anheim, M., Bonnet, A.- M., Borg, M., Broussolle, E., Corvol, J.- C., Destee, A., Klebe, S., Penet, C., Rascol, O., Tranchant, C., Verin, M., Viallet, F.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2011
• Subjects: ADP-ribosyl Cyclase - genetics; Adult; Aged; Antigens, CD - genetics; Biological and medical sciences; Brain; Case-Control Studies; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 4; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Europe - epidemiology; Female; Fundamental and applied biological sciences. Psychology; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genotype; GPI-Linked Proteins - genetics; Humans; Male; Medical sciences; Middle Aged; Molecular and cellular biology; Neurology; Parkinson Disease - epidemiology; Parkinson Disease - genetics; Polymorphism, Single Nucleotide; Risk Factors; Transcription Factors; Europe; Human; Nervous system diseases; Parkinson disease; Risk; Chromosome C12; European; Cerebral disorder; Association; Central nervous system disease; Risk factor; Genetics; Degenerative disease; Locus; Extrapyramidal syndrome
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddq497

We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a French sample of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study sample (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third sample of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.