Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders

• Published in: Nature neuroscience Vol. 24; no. 9; pp. 1302 - 1312
• Main Authors: Yang, Chengran, Farias, Fabiana H. G., Ibanez, Laura, Suhy, Adam, Sadler, Brooke, Fernandez, Maria Victoria, Wang, Fengxian, Bradley, Joseph L., Eiffert, Brett, Bahena, Jorge A., Budde, John P., Li, Zeran, Dube, Umber, Sung, Yun Ju, Mihindukulasuriya, Kathie A., Morris, John C., Fagan, Anne M., Perrin, Richard J., Benitez, Bruno A., Rhinn, Herve, Harari, Oscar, Cruchaga, Carlos
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2021; Nature Publishing Group
• Subjects: 631/378/2583; 692/53/2423; 692/699/375/132/1283; Acetylation; Aged; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Blood plasma; Brain; Brain - metabolism; Causes of; Cerebrospinal fluid; Cerebrospinal Fluid - metabolism; Cerebrospinal fluid proteins; Deoxyribonucleic acid; DNA; DNA methylation; Female; Gene expression; Gene Expression Regulation; Gene mapping; Gene regulation; Genetic aspects; Genetics; Genome-wide association studies; Genomics; Health aspects; High-Throughput Screening Assays - methods; Histones; Humans; Male; Medical research; Medicine, Experimental; Middle Aged; Movement disorders; Nervous system diseases; Neurobiology; Neurodegenerative diseases; Neurological diseases; Neurological disorders; Neurosciences; Parkinson's disease; Plasma; Plasma - metabolism; Post-transcription; Proteins; Proteome; Proteomes; Proteomics - methods; Quantitative Trait Loci; Resource; Target recognition; Therapeutic targets; Tissues; United States
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-021-00886-6

Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer’s disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer’s disease, Parkinson’s disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases. Yang et al. generated a genomic atlas of protein levels in brain, cerebrospinal fluid and plasma and used human genetics approaches to identify proteins implicated in neurological diseases as well as druggable targets.