Genome-wide association study identifies a new susceptibility locus inPLA2G4Cfor Multiple System Atrophy
Author:
Nakahara Yasuo, Mitsui Jun, Date Hidetoshi, Porto Kristine Joyce, Hayashi Yasuhiro, Yamashita Atsushi, Kusakabe Yoshio, Matsukawa Takashi, Ishiura Hiroyuki, Yasuda Tsutomu, Iwata Atsushi, Goto Jun, Ichikawa Yaeko, Momose Yoshio, Takahashi Yuji, Toda Tatsushi, Ohta Rikifumi, Yoshimura Jun, Morishita Shinichi, Gustavsson Emil K, Christy Darren, Maczis Melissa, Farrer Matthew J., Kim Han-JoonORCID, Park Sung-Sup, Jeon Beomseok, Zhang Jin, Gu Weihong, Scholz Sonja W., Singleton Andrew B., Houlden HenryORCID, Yabe Ichiro, Sasaki Hidenao, Matsushima Masaaki, Takashima Hiroshi, Kikuchi Akio, Aoki Masashi, Hara Kenju, Kakita Akiyoshi, Yamada Mitsunori, Takahashi Hitoshi, Onodera OsamuORCID, Nishizawa Masatoyo, Watanabe Hirohisa, Ito Mizuki, Sobue Gen, Ishikawa Kinya, Mizusawa Hidehiro, Kanai Kazuaki, Kuwabara Satoshi, Arai Kimihito, Koyano Shigeru, Kuroiwa Yoshiyuki, Hasegawa Kazuko, Yuasa Tatsuhiko, Yasui Kenichi, Nakashima Kenji, Ito Hijiri, Izumi Yuishin, Kaji Ryuji, Kato Takeo, Kusunoki Susumu, Osaki Yasushi, Horiuchi Masahiro, Yamamoto Ken, Shimada Mihoko, Miyagawa Taku, Kawai Yosuke, Nishida Nao, Tokunaga Katsushi, Dürr AlexandraORCID, Brice Alexis, Filla Alessandro, Klockgether Thomas, Wüllner Ullrich, Tanner Caroline M., Kukull Walter A., Lee Virginia M.-Y., Masliah Eliezer, Low Phillip A., Sandroni Paola, Ozelius Laurie, Foroud Tatiana, Tsuji Shoji
Abstract
AbstractTo 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 × 10−7) that was replicated in additional Japanese samples (P= 2.9 × 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 × 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 inPLA2G4Cthat encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.
Publisher
Cold Spring Harbor Laboratory
|
|