Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease-Reference-Cited by-同舟云学术

Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease

Published:2024-07-02 Issue: Volume: Page:
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Debette Stephanie¹^ORCID,Caro Ilana¹^ORCID,Western Daniel²^ORCID,Namba Shinichi³^ORCID,Sun Na⁴,Kawaguchi Shuji⁵,He Yunye⁶,Fujita Masashi⁷,Roshchupkin Gennady⁸^ORCID,D'Aoust Tim⁹,Duperron Marie-Gabrielle¹⁰^ORCID,Sargurupremraj Murali¹¹,Tsuchida Ami^ORCID,Koido Masaru⁶^ORCID,Ahmadi Marziehsadat¹²,Yang Chengran¹³^ORCID,Timsina Jigyasha²,Ibanez Laura¹³,Matsuda Koichi¹⁴,Suzuki Yutaka¹⁵^ORCID,Oda Yoshiya¹⁶,Kanai Akinori¹⁵^ORCID,Jandaghi Pouria^ORCID,Munter Hans Markus¹⁷^ORCID,Auld Dan¹²^ORCID,Astafeva Iana¹⁸,Puerta Raquel¹⁹^ORCID,Rotter Jerome²⁰^ORCID,Psaty Bruce²¹^ORCID,Bis Joshua²²^ORCID,Longstreth Will²²,Couffinhal Thierry²³^ORCID,Garcia-Gonzalez Pablo¹⁹^ORCID,Pytel Vanesa²⁴,Marquié Marta¹⁹^ORCID,Cano Amanda¹⁹,Boada Mercè²⁵^ORCID,Joliot Marc²⁶^ORCID,Lathrop Mark²⁷,Grand Quentin Le¹⁰^ORCID,Launer Lenore²⁸^ORCID,Wardlaw Joanna²⁹^ORCID,Heiman Myriam³⁰^ORCID,Ruiz Agustin³¹,Matthews Paul³²^ORCID,Seshadri Sudha³³^ORCID,Fornage Myriam³⁴^ORCID,Adams Hieab³⁵,Mishra Aniket¹^ORCID,Trégouët David-Alexandre³⁶^ORCID,Okada Yukinori³⁷,Kellis Manolis³⁸^ORCID,De Jager Philip⁷^ORCID,Tzourio Christophe^ORCID,Kamatani Yoichiro¹⁵^ORCID,Matsuda Fumihiko⁵,Cruchaga Carlos³⁹^ORCID

Affiliation:

1. University of Bordeaux

2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

3. Osaka University

4. MIT Computer Science and Artificial Intelligence Laboratory; Broad Institute of MIT and Harvard

5. Kyoto University Graduate School of Medicine

6. Graduate School of Frontier Sciences, The University of Tokyo

7. Columbia University Irving Medical Center

8. Erasmus Medical Center

9. Bordeaux Population Health, Inserm U1219, University of Bordeaux

10. University of Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219

11. University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, F-33000 Bordeaux, France; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases Unive

12. Victor Phillip Dahdaleh Institute of Genomic Medicine, McGill University

13. Washington University in St. Louis

14. Department of Computational Biology and Medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo

15. The University of Tokyo

16. Graduate School of Medicine, The University of Tokyo

17. McGill University

18. Bordeaux Population Health, Inserm U1219, University of Bordeaux; Institute of Neurodegenerative Diseases

19. Ace Alzheimer Center Barcelona

20. The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

21. Cardiovascular Health Research Unit

22. University of Washington

23. University of Bordeaux, The clinical unit of Exploration, Prevention and Care Center for Atherosclerosis (CEPTA), CHUB, Inserm U1034

24. Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III

25. Universitat Internacional de Catalunya

26. GIN, IMN/UMR5293 UB/CNRS/CEA

27. Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada

28. National Institute on Aging, National Institutes of Health

29. University of Edinburgh

30. Massachusetts Institute of Technology

31. Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center; Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya;CIBERN

32. UK Dementia Research Institute Centre at Imperial College London

33. University of Texas Health Science Center

34. 1. Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center 2. Human Genetics Center, Department of Epidemiology, School of Public Health

35. Department of Human Genetics, Radboud University Medical Center; Latin American Brain Health (BrainLat), Universidad Adolfo Ibáñez

36. INSERM

37. Department of Genome Informatics, Graduate School of Medicine, The Univ. of Tokyo; Department of Statistical Genetics, Osaka Univ. Graduate School of Medicine; Laboratory for Systems Genetic, RIKEN

38. MIT

39. Washington University

Abstract

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific mechanism-based treatment. We used Mendelian randomization to combine a unique cerebrospinal fluid (CSF) and plasma pQTL resource with the latest European-ancestry GWAS of MRI-markers of cSVD (white matter hyperintensities, perivascular spaces). We describe a new biological fingerprint of 49 protein-cSVD associations, predominantly in the CSF. We implemented a multipronged follow-up, across fluids, platforms, and ancestries (Europeans and East-Asian), including testing associations of direct plasma protein measurements with MRI-cSVD. We highlight 16 proteins robustly associated in both CSF and plasma, with 24/4 proteins identified in CSF/plasma only. cSVD-proteins were enriched in extracellular matrix and immune response pathways, and in genes enriched in microglia and specific microglial states (integration with single-nucleus RNA sequencing). Immune-related proteins were associated with MRI-cSVD already at age twenty. Half of cSVD-proteins were associated with stroke, dementia, or both, and seven cSVD-proteins are targets for known drugs (used for other indications in directions compatible with beneficial therapeutic effects. This first cSVD proteogenomic signature opens new avenues for biomarker and therapeutic developments.

Publisher

Research Square Platform LLC

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