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

Yasuo Nakahara; Jun Mitsui; Hidetoshi Date; Kristine Joyce L. 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 Karl Gustavsson; Darren Christy; Melissa A. Maczis; Matthew James Farrer; Han‐Joon Kim; Sung Sup Park; Beomseok Jeon; Jin Zhang; Weihong Gu; Sonja W. Scholz; Andrew Singleton

doi:10.1101/2023.05.02.23289328

Genetic & Genomic MedicinemedRxivMay 2, 2023

Preprint

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

Yasuo Nakahara iD, Jun Mitsui iD, Hidetoshi Date, Kristine Joyce L. Porto iD, Yasuhiro Hayashi iD, Atsushi Yamashita iD, Yoshio Kusakabe iD, Takashi Matsukawa iD, Hiroyuki Ishiura iD, Tsutomu Yasuda, Atsushi Iwata iD, Jun Goto iD, Yaeko Ichikawa, Yoshio Momose, Yuji Takahashi iD, Tatsushi Toda iD, Rikifumi Ohta iD, Jun Yoshimura iD, Shinichi Morishita iD, Emil Karl Gustavsson iD, Darren Christy, Melissa A. Maczis iD, Matthew James Farrer iD, Han‐Joon Kim iD, Sung Sup Park iD, , Shoji Tsuji iD

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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