Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy.

Abstract

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association (P = 6.5 x 10-7) that was replicated in additional Japanese samples (P = 2.9 x 10-6. OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data (P = 5.0 x 10-15. Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples (P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2{gamma} lysophospholipase/transacylase. The cPLA2{gamma}-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2{gamma}-Val143 isoform that may perturb membrane phospholipids and -synuclein biology.