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Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease.
Tuesday,2024-09-17 11:42 America/Los_Angeles — ecterry
| Title | Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Debette, S, Caro, I, Western, D, Namba, S, Sun, N, Kawaguchi, S, He, Y, Fujita, M, Roshchupkin, G, D'Aoust, T, Duperron, M-G, Sargurupremraj, M, Tsuchida, A, Koido, M, Ahmadi, M, Yang, C, Timsina, J, Ibanez, L, Matsuda, K, Suzuki, Y, Oda, Y, Kanai, A, Jandaghi, P, Munter, HMarkus, Auld, D, Astafeva, I, Puerta, R, Rotter, J, Psaty, B, Bis, J, Longstreth, W, Couffinhal, T, Garcia-Gonzalez, P, Pytel, V, Marquié, M, Cano, A, Boada, M, Joliot, M, Lathrop, M, Le Grand, Q, Launer, L, Wardlaw, J, Heiman, M, Ruiz, A, Matthews, P, Seshadri, S, Fornage, M, Adams, H, Mishra, A, Trégouët, D-A, Okada, Y, Kellis, M, De Jager, P, Tzourio, C, Kamatani, Y, Matsuda, F, Cruchaga, C |
| Journal | Res Sq |
| Date Published | 2024 Jul 02 |
| ISSN | 2693-5015 |
| Abstract | <p>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.</p> |
| DOI | 10.21203/rs.3.rs-4535534/v1 |
| Alternate Journal | Res Sq |
| PubMed ID | 39011113 |
| PubMed Central ID | PMC11247936 |
| Grant List | P30 AG066444 / AG / NIA NIH HHS / United States R01 HL103612 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States RF1 AG074007 / AG / NIA NIH HHS / United States R00 AG062723 / AG / NIA NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States N01HC85081 / HL / NHLBI NIH HHS / United States U01 AG058922 / AG / NIA NIH HHS / United States R01 AG044546 / AG / NIA NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States P30 AG066515 / AG / NIA NIH HHS / United States RF1 AG053303 / AG / NIA NIH HHS / United States U01 HL130114 / HL / NHLBI NIH HHS / United States P01 AG026276 / AG / NIA NIH HHS / United States RF1 AG058501 / AG / NIA NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States 75N92021D00006 / HL / NHLBI NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States |
ePub date:
24/07