Genome-wide association analysis identifies PLA2G4C as a susceptibility locus for Multiple System Atrophy-Reference-Cited by-同舟云学术

Genome-wide association analysis identifies PLA2G4C as a susceptibility locus for Multiple System Atrophy

Published:2024-02-06 Issue: Volume: Page:
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Tsuji Shoji¹^ORCID,Nakahara Yasuo¹,Mitsui Jun¹^ORCID,Date Hidetoshi²,Porto Kristine Joyce²,Hyashi Yasuhiro³,Yamashita Atsushi³,Kusakabe Yoshio³,Matsukawa Takashi¹^ORCID,Ishiura Hiroyuki⁴^ORCID,Yasuda Tsutomu²,Iwata Atsushi²,Goto Jun²,Ichikawa Yaeko⁵,Momose Yoshio²,Takahashi Yuji²,Toda Tatsushi¹^ORCID,Ohta Rikifumi²^ORCID,Yoshimura Jun²,Morishita Shinichi¹^ORCID,Gustavsson Emil⁶^ORCID,Christy Darren⁷,Maczis Melisa⁷,Kim Han-Joon⁸,Park Sung-Sup⁹,Zhang Jin¹⁰,Gu Weihong¹⁰,Scholz Sonja¹¹^ORCID,Chelban Viorica¹²^ORCID,Mok Kin⁶,Houlden Henry¹³^ORCID,Yabe Ichiro¹⁴,Sasaki Hidenao¹⁴,Matsushima Masaaki¹⁴,Takashima Hiroshi¹⁵,Kikuchi Akio¹⁶,Aoki Masashi¹⁷,Hara Kenju¹⁸,Kakita Akiyoshi¹⁹,Yamada Mitsunori²⁰,Takahashi Hitoshi¹⁸,Onodera Osamu¹⁸^ORCID,Nishizawa Masatoyo¹⁸,Watanabe Hirohisa²¹,Ito Mizuki²²,Sobue Gen²¹^ORCID,Ishikawa Kinya²³^ORCID,Mizusawa Hidehiro²⁴,Kanai Kazuaki²⁵,Kuwabara Satoshi²⁶,Arai Kimihito²⁷,Koyano Shigeru²⁸,Kuroiwa Yoshiyuki²⁹,Hasegawa Kazuko³⁰,Yuasa Tatsuhiko³¹,Yasui Kenichi³²,Nakashima Kenji³²,Ito Hijiri³²,Izumi Yuishin³³,Kaji Ryuji³³,kato Takeo³⁴,Kusunoki Susumu³⁵,Osaki Yasushi³⁶,Horiuchi Masahiro³⁷,Yamamoto Ken³⁸^ORCID,Shimada Mihoko³⁹,Miyagawa Taku²,Kawai Yosuke⁴⁰^ORCID,Nishida Nao⁴⁰^ORCID,Tokunaga Katsushi⁴⁰^ORCID,Durr Alexandra⁴¹,Brice Alexis⁴²,Filla Alessandro⁴³,Klockgether Thomas⁴⁴,Wuellner Ullrich⁴⁵^ORCID,Tanner Caroline⁴⁶,Kukull Walter⁴⁷,Lee Virginia⁴⁸^ORCID,Masliah Eliezer⁴⁹,Low Phillip⁵⁰,Sandroni Paola⁵⁰,Ozelius Laurie⁵¹,Foroud Tatiana^ORCID,Farrer Matthew⁵²,Trojanowski John⁵³

Affiliation:

1. The University of Tokyo

2. University of Tokyo

3. Teikyo University

4. Okayama University

5. Kyorin University School of Medicine

6. University College London

7. University of British Columbia

8. Seoul National University College of Medicine

9. Seoul National University Hospital

10. China-Japan Friendship Hospital

11. National Institute of Neurological Disorders and Stroke

12. UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.

13. UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery

14. Hokkaido University

15. Kagoshima University

16. Tohoku University School of Medicine

17. Tohoku University Graduate School of Medicine

18. Niigata University

19. Brain Research Institute, Niigata University

20. Shinshu University School of Medicine

21. Nagoya University

22. Nagoya University Graduate School of Medicine

23. Tokyo Medical and Dental University

24. National Center of Neurology and Psychiatry

25. Juntendo University

26. Chiba University

27. Chiba East Hospital

28. Yokohama City University

29. Teikyo University School of Medicine University Hospital

30. Sagamihara National Hospital

31. Kamagaya General Hospital

32. Tottori University

33. University of Tokushima Graduate School

34. Yamagata University Faculty of Medicine

35. Kindai University Faculty of Medicine

36. Kochi Medical School

37. St. Marianna University School of Medicine

38. Kurume University School of Medicine

39. Genome Medical Science Project (Toyama), National Center for Global Health and Medicine (NCGM), Tokyo, Japan

40. National Center for Global Health and Medicine

41. INSERM

42. INSERM U679

43. Federico II University

44. University of Bonn

45. University Hospital Bonn

46. Parkinson's Institute

47. University of Washington

48. University of Pennsylvania

49. National Institute on Aging

50. Mayo Clinic

51. The Collaborative Center for X-linked Dystonia Parkinsonism, Department of Neurology, Massachusetts General Hospital, Charlestown

52. University of Florida

53. University of Pennsylvania School of Medicine

Abstract

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.

Publisher

Research Square Platform LLC

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