DEBETTE, Stephanie; CARO, Ilana; WESTERN, Daniel; NAMBA, Shinichi; SUN, Na; KAWAGUCHI, Shuji; HE, Yunye; FUJITA, Masashi; ROSHCHUPKIN, Gennady; D'AOUST, Tim; DUPERRON, Marie-Gabrielle; SARGURUPREMRAJ, Murali; TSUCHIDA, Ami; KOIDO, Masaru; AHMADI, Marziehsadat; YANG, Chengran; TIMSINA, Jigyasha; IBANEZ, Laura; MATSUDA, Koichi; SUZUKI, Yutaka; ODA, Yoshiya; KANAI, Akinori; AULD, Dan; JANDAGHI, Pouria; MUNTER, Hans Markus; ASTAFEVA, Iana; PUERTA, Raquel; ROTTER, Jerome; JOLIOT, Marc; PSATY, Bruce; BIS, Joshua; LONGSTRETH, Will; COUFFINHAL, Thierry; GARCIA-GONZALEZ, Pablo; PYTEL, Vanesa; CANO, Amanda; BOADA, Mercè; LATHROP, Mark; LE GRAND, Quentin; LAUNER, Lenore; WARDLAW, Joanna; HEIMAN, Myriam; RUIZ, Agustin; MATTHEWS, Paul; SESHADRI, Sudha; FORNAGE, Myriam; ADAMS, Hieab; MISHRA, Aniket; TRÉGOUËT, David-Alexandre; OKADA, Yukinori; KELLIS, Manolis; DE JAGER, Philip; TZOURIO, Christophe; KAMATANI, Yoichiro; MATSUDA, Fumihiko; CRUCHAGA, Carlos

doi:10.21203/rs.3.rs-4535534/v1

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Research Square - Preprint. 2024-07-02

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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.< Réduire

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

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