Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits Understanding the tissue-specific genetic architecture of protein levels is instrumental to understand the biology of health and disease. We generated a genomic atlas of protein levels in multiple neurologically relevant tissues (380 brain, 835 cerebrospinal fluid (CSF) and 529 plasma), by profiling thousands of proteins (713 CSF, 931 plasma and 1079 brain) in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. cis-pQTL were more likely to be shared across tissues but trans-pQTL tend to be tissue-specific. Between 44% to 68.2% of the pQTL do not colocalize with expression, splicing, methylation or histone QTLs, indicating that protein levels have a different genetic architecture to those that regulate gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. Here we present the first multi-tissue study yielding hundred of novel pQTLs. This data will be instrumental to identify the functional gene from GWAS signals, identify novel biological protein-protein interactions, identify novel potential biomarkers and drug targets for complex traits. Chengran Yang1,2,3, Fabiana G. Farias1,2,3, Laura Ibanez1,2,3, Brooke Sadler4, Maria Victoria Fernandez1,2,3, Fengxian Wang1,2,3, Joseph L. Bradley1,2,3, Brett Eiffert1,2,3, Jorge A. Bahena1,2,3, John P. Budde1,2,3, Zeran Li1,2,3, Umber Dube1,2,3, Yun Ju Sung1,2,3, Kathie A. Mihindukulasuriya1,2,3, John C. Morris3,5,6, Anne Fagan3,5,6, Richard J. Perrin3,5,6, Bruno Benitez1,2,3, Herve Rhinn7, Oscar Harari1,2,3,6† and Carlos Cruchaga1,2,3,6†* 1. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA 2. NeuroGenomics and Informatics, Washington University School of Medicine, St Louis, MO, USA 3. Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA 4. Pediatrics Hematology/Oncology, Washington University School of Medicine, St Louis, MO, USA 5. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA 6. The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, USA. 7. Department of Bioinformatics. Alector, Inc. 151 Oyster Point Blvd. #300 South San Francisco, CA, USA.