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Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease.

Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease. Nature genetics Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Phillips, B., Wang, Y., Liu, M., Ali, M., Beric, A., Gorijala, P., Kohlfeld, P., Budde, J., Levey, A. I., Morris, J. C., Perrin, R. J., Ruiz, A., Marquié, M., Boada, M., de Rojas, I., Rutledge, J., Oh, H., Wilson, E. N., Le Guen, Y., Reus, L. M., Tijms, B., Visser, P. J., van der Lee, S. J., Pijnenburg, Y. A., Teunissen, C. E., Del Campo Milan, M., Alvarez, I., Aguilar, M., Greicius, M. D., Pastor, P., Pulford, D. J., Ibanez, L., Wyss-Coray, T., Sung, Y. J., Cruchaga, C. 2024

Abstract

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer's disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

View details for DOI 10.1038/s41588-024-01972-8

View details for PubMedID 39528825

View details for PubMedCentralID 9605867