Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy.
Nakahara, Y.; Mitsui, J.; Date, H.; Porto, K. J.; Hayashi, Y.; Yamashita, A.; Kusakabe, Y.; Matsukawa, T.; Ishiura, H.; Yasuda, T.; Iwata, A.; Goto, J.; Ichikawa, Y.; Momose, Y.; Takahashi, Y.; Toda, T.; Ohta, R.; Yoshimura, J.; Morishita, S.; Gustavsson, E. K.; Christy, D.; Maczis, M.; Farrer, M. J.; Kim, H.-J.; Park, S.-S.; Jeon, B.; Zhang, J.; Gu, W.; Scholz, S. W.; Singleton, A. B.; Houlden, H.; Yabe, I.; Sasaki, H.; Matsushima, M.; Takashima, H.; Kikuchi, A.; Aoki, M.; Hara, K.; Kakita, A.; Yamada, M.; Takahashi, H.; Onodera, O.; Nishizawa, M.; Watanabe, H.; Ito, M.; Sobue, G.; Ishikawa,
Show 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.
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