Genetic variations in protein expression are implicated in a broad spectrum of common diseases and complex traits but remain less explored compared to mRNA and classical phenotypes. This study systematically analyzed brain proteomes in a rat family using tandem mass tag (TMT)-based quantitative mass spectrometry. We quantified 8,119 proteins across two parental strains (SHR/Olalpcv and BN-Lx/Cub) and 29 HXB/BXH recombinant inbred (RI) strains, identifying 597 proteins with differential expression and 464 proteins linked to cis-acting quantitative trait loci (pQTLs). Proteogenomics identified 95 variant peptides, and sex-specific analyses revealed both shared and distinct cis-pQTLs. We improved the ability to pinpoint candidate genes underlying pQTLs by utilizing the rat pangenome and explored the connections between pQTLs in rats and human disorders. Collectively, this study highlights the value of large proteo-genetic datasets in elucidating protein modulation in the brain and its links to complex central nervous system (CNS) traits.

Department of Developmental Neurobiology St Jude Children's Research Hospital Memphis TN 38105 USA

Department of Genetics Genomics and Informatics University of Tennessee Health Science Center Memphis TN 38163 USA

Department of Geriatrics School of Medicine and Health Sciences University of North Dakota Grand Forks ND 58202 USA

Department of Microbiology and Immunology Indiana University School of Medicine Indianapolis IN 46202 USA

Department of Neurology University of Tennessee Health Science Center Memphis TN 38163 USA

Department of Pediatrics and the Herman B Wells Center for Pediatric Research Indiana University School of Medicine Indianapolis IN 46202 USA

Department of Pharmaceutical Sciences University of Colorado Denver Aurora CO 80045 USA

Department of Pharmacology Addiction Science and Toxicology University of Tennessee Health Science Center Memphis TN 38103 USA

Department of Structural Biology St Jude Children's Research Hospital Memphis TN 38105 USA

Genomics of Regeneration of the Central Nervous System Center for Regenerative Therapies Dresden Dresden University of Technology 01307 Dresden Germany

Human Technopole Viale Rita Levi Montalcini 20157 Milan Italy

Institute of Physiology of the Czech Academy of Sciences Prague 14200 Czech Republic

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