Citations 1
Genome-wide association analysis identifies PLA2G4C as a susceptibility locus for Multiple System Atrophy
Tsuji, Shoji , Nakahara, Yasuo , Mitsui, Jun , Date, Hidetoshi, Porto, Kristine Joyce L. , Hyashi, Y., Kusakabe, Yoshio , Matsukawa, Takashi , Ishiura, Hiroyuki , Yasuda, Tsutomu , Goto, Jun , Ichikawa, Yaeko, Momose, Yoshio, Takahashi, Yuji , Ohta, Rikifumi , Yoshimura, Jun , Gustavsson, Emil K. , Christy, Darren, Maczis, Melisa, Gu, Weihong, Scholz, Sonja W. , Houlden, Henry , Sasaki, Hidenao , Kikuchi, Akio , Hara, Kenju , Kakita, Akiyoshi , Yamada, Mitsunori , Nishizawa, Masatoyo , Ito, Mizuki , Sobue, Gen , Ishikawa, Kinya , Mizusawa, Hidehiro, Kanai, Kazuaki , Arai, Kimihito , Koyano, Shigeru , Kuroiwa, Yoshiyuki , Hasegawa, Kazuko, Yuasa, Tatsuhiko, Yasui, Kenichi, Ito, Hijiri, Izumi, Yuishin , Kaji, Ryuji , Kato, Takeo , Kusunoki, Susumu , Osaki, Yasushi , Horiuchi, Masahiro , Yamamoto, Ken , Shimada, Mihoko , Miyagawa, Taku , Nishida, Nao , Tokunaga, Katsushi , Filla, Alessandro , Klockgether, Thomas , Wuellner, Ullrich, Kukull, Walter A. , Masliah, Eliezer , Low, Phillip A. , Sandroni, Paola , Ozelius, Laurie J. , Trojanowski, John Q. , Scholz, Sonja W , Houlden, Henry , Yamashita, Atsushi , Yasuda, Tsutomu, Iwata, Atsushi , Toda, Tatsushi , Morishita, Shinichi , Kim, Han‐Joon , Park, Sung Sup , Zhang, Jin , Chelban, Viorica , Mok, Kin Ying , Yabe, Ichiro , Matsushima, Masaaki , Takashima, Hiroshi , Aoki, Masashi , Takahashi, Hitoshi , Onodera, Osamu , Watanabe, Hirohisa , Kuwabara, Satoshi , Nakashima, Kenji , Horiuchi, Masahiro, Kawai, Yosuke , Dürr, Alexandra , Brice, Alexis , Tanner, Caroline M. , Lee, Virginia M.‐Y. , Foroud, Tatiana , Farrer, Matthew J.
No container title available | February 6, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
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 × 10− 7) that was replicated in additional Japanese samples (P = 2.9 × 10− 6, odds ratio (OR) = 1.58; 95% confidence interval (CI), 1.30–1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data (P = 5.0 × 10− 15, OR = 1.49; 95% CI 1.35–1.65). The association of rs2303744 with MSA remained significant in combined European/North American samples (P = 0.017, OR = 1.12; 95% CI 1.02–1.23) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that 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, and may perturb membrane phospholipids and promote oligodendroglial pathology.