Genome-wide association study identifies a new susceptibility locus inPLA2G4Cfor Multiple System Atrophy

• DOI: 10.1101/2023.05.02.23289328
• Publication Date: 2023-05-05T17:15:27Z
• Authors: Yasuo Nakahara; Jun Mitsui; Hidetoshi Date; Kristine Joyce Porto; Yasuhiro Hayashi; Atsushi Yamashita; Yoshio Kusakabe; Takashi Matsukawa; Hiroyuki Ishiura; Tsutomu Yasuda; Atsushi Iwata; Jun Goto; Yaeko Ichikawa; Yoshio Momose; Yuji Takahashi; Tatsushi Toda; Rikifumi Ohta; Jun Yoshimura; Shinichi Morishita; Emil K Gustavsson; Darren Christy; Melissa Maczis; Matthew J. Farrer; Han-Joon Kim; Sung-Sup Park; Beomseok Jeon; Jin Zhang; Weihong Gu; Sonja W. Scholz; Andrew B. Singleton; Henry Houlden; Ichiro Yabe; Hidenao Sasaki; Masaaki Matsushima; Hiroshi Takashima; Akio Kikuchi; Masashi Aoki; Kenju Hara; Akiyoshi Kakita; Mitsunori Yamada; Hitoshi Takahashi; Osamu Onodera; Masatoyo Nishizawa; Hirohisa Watanabe; Mizuki Ito; Gen Sobue; Kinya Ishikawa; Hidehiro Mizusawa; Kazuaki Kanai; Satoshi Kuwabara; Kimihito Arai; Shigeru Koyano; Yoshiyuki Kuroiwa; Kazuko Hasegawa; Tatsuhiko Yuasa; Kenichi Yasui; Kenji Nakashima; Hijiri Ito; Yuishin Izumi; Ryuji Kaji; Takeo Kato; Susumu Kusunoki; Yasushi Osaki; Masahiro Horiuchi; Ken Yamamoto; Mihoko Shimada; Taku Miyagawa; Yosuke Kawai; Nao Nishida; Katsushi Tokunaga; Alexandra Dürr; Alexis Brice; Alessandro Filla; Thomas Klockgether; Ullrich Wüllner; Caroline M. Tanner; Walter A. Kukull; Virginia M.-Y. Lee; Eliezer Masliah; Phillip A. Low; Paola Sandroni; Laurie Ozelius; Tatiana Foroud; Shoji Tsuji
• Keywords: Genome-wide Association Study; Genetic Association

Abstract To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted genome-wide association study (GWAS) in Japanese MSA case/control series followed by replication studies Japanese, Korean, Chinese, European and North American samples. In GWAS stage rs2303744 on chromosome 19 showed suggestive ( P = 6.5 × 10 −7 ) that was replicated additional samples 2.9 −6 . OR 1.58; 95% confidence interval, 1.30 to 1.91), then confirmed as highly significant meta-analysis East Asian population data 5.0 -15 Odds ratio= 1.49; CI 1.35 1.72). The with remained combined European/North =0.023. ratio=1.14; 1.02 1.28) despite allele frequencies being quite different between these populations. leads an amino acid substitution PLA2G4C encodes cPLA2γ lysophospholipase/transacylase. cPLA2γ-Ile143 isoform encoded risk has significantly decreased transacylase activity compared alternate cPLA2γ-Val143 may perturb membrane phospholipids α-synuclein biology.