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.

Genetic Modulation of Protein Expression in Rat Brain

“…The quantified proteins cover ∼70% of the range of transcripts detected by the transcriptomic data ( Figure S3A ). A moderate positive correlation between expression levels of mRNAs and proteins ( r = 0.35) was observed ( Figure S3B ), which is consistent with previous findings in human study 24 .…”

“…To investigate the genetic basis of trait variation in molecular endophenotypes, genetic reference populations, such as the mouse BXDs 17–19 , Collaborative Cross 20,21 , and the HXB/BXH recombinant inbred (RI) family 22,23 , have been used extensively over the past decade, but surprisingly never to study protein levels in the brain in any species other than humans 24 . The HXB/BXH family is the largest and most deeply phenotyped set of genetically diverse but fully inbred set of rats.…”

Efficient candidate drug target discovery through proteogenomics in a Scottish cohort

“…blood plasma sample storage time or co-ordinates on measurement plate). Technical artifacts, such as batch effects and some confounding factors can be accounted for to improve power and decrease the risk of false associations 53, 54 . For each aptamer, we performed multiple regression with the following covariates: biological sex, age, sample storage time in the freezer, season of the year when the plasma sample was taken, 96-well measurement plate number, row, and column.…”

The impact of common variants on gene expression in the human brain: from RNA to protein to schizophrenia risk

“…an eQTL) has been shown to be prevalent ( 19 ). In addition, QTLs specific to protein level have also been reported ( 19-21 ). Together, these observations indicated the importance and potential benefits of including downstream omics types, such as proteomics data, as information sources for fine mapping disease regulatory variants.…”

“…Indeed, recent studies using multi-omics approaches have demonstrated increased power for risk gene identification among other benefits ( 22 , 23 ). Of note, our recent work on genetic variants associated with protein level in prefrontal cortex of the human brain indicated the extent of contribution from non-synonymous coding variants to changes at the protein level, and the utility of these protein QTL variants in prioritizing GWAS risk genes for psychiatric disorders ( 21 ).…”