Genetic regulation of human brain proteome reveals proteins implicated in psychiatric disorders

Abstract Psychiatric disorders are highly heritable yet polygenetic, potentially involving hundreds of risk genes. Genome-wide association studies (GWAS) have identified hundreds of genomic susceptibility loci for psychiatric disorders, but how these loci contribute to the underlying psychopathology and etiology remains elusive. Here we generated a deep human brain proteome by quantifying 11,672 proteins across 288 subjects using 11-plex tandem mass tag (TMT) coupled with two-dimensional liquid chromatography-tandem mass spectrometry (LC/LC-MS/MS). We identified 788 cis-acting protein quantitative trait loci (cis-pQTLs) associated with 883 proteins at a genome-wide false discovery rate (FDR) < 5%. In contrast to expression at transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 487 shared regulatory signals between gene expression (i.e., eQTL) and protein abundance (i.e., pQTLs). Mediation analysis revealed that for most (64%) of the colocalized genes, the expression level of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Causality analysis by Mendelian Randomization (MR) revealed 4 cis-pQTLs and 19 cis-eQTLs causally controlling schizophrenia (SCZ) GWAS loci, respectively. We further integrated multiple omic data together with network analysis to prioritize candidate genes for SCZ GWAS loci. Collectively, our results underscore the potential of proteome-wide linkage analysis for mechanistic understanding of psychiatric disorders.