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. 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 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 that may perturb membrane phospholipids and α-synuclein biology.
Competing Interest Statement
S.T. received a research grant from Nobelpharma Co., Ltd. S.W.S. serves on the Scientific Advisory Council of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. receives research support from Cerevel Therapeutics. S.W.S. is an editorial board member of the Journal of Parkinson's Disease and JAMA Neurology.
Funding Statement
This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas Nos. 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants-in-Aid [H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080] from the Ministry of Health, Welfare and Labour, Japan, and grants (15ek0108065h0002, 16kk0205001h0001, 17kk0205001h0002, 17ek0109279h0001, 18ek0109279h0002, 19ek0109279h0003, 20ek0109491h0001, 21ek0109491h0002, and 22ek0109491h0003) from the Japan Agency for Medical Research and Development (AMED) to S.T. This work was in part supported under the framework of international cooperation program managed by National Research Foundation of Korea (Grant Number: NRF-2015K2A1A2070274) to B. J. S.W.S. was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, U.S. National Institutes of Health (program #: 1ZIANS003154).
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The research project was approved by Research Ethics Committee of the Faculty of Medicine of the University of Tokyo.
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Data Availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.