Sex differences in brain protein expression and disease

Abstract

Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein expression and its genetic regulation in 1,277 human brain proteomes. We found that 13.2% (1,354) of brain proteins had sex-differentiated abundance and 1.5% (150) of proteins had sex-biased protein quantitative trait loci (sb-pQTLs). Among genes with sex-biased expression, we found 67% concordance between sex-differentiated protein and transcript levels; however, sex effects on the genetic regulation of expression were more evident at the protein level. Considering 24 psychiatric, neurologic and brain morphologic traits, we found that an average of 25% of their putatively causal genes had sex-differentiated protein abundance and 12 putatively causal proteins had sb-pQTLs. Furthermore, integrating sex-specific pQTLs with sex-stratified genome-wide association studies of six psychiatric and neurologic conditions, we uncovered another 23 proteins contributing to these traits in one sex but not the other. Together, these findings begin to provide insights into mechanisms underlying sex differences in brain protein expression and disease.

Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance

“…Intriguingly, the pathway enrichment analysis in schizophrenia also reveals shared proteins with neurodegenerative disorders such as Alzheimer’s and Parkinson’s Disease, consistent with a recent brain-based proteomic study 46 demonstrating unexpected overlap between schizophrenia and neurologic disorders. This raises the possibility of immune protein-mediated neurodegeneration as a potential contributing factor to the risk of schizophrenia.…”

Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia

“… 11 While we speculate that our analysis (using pQTLs from the general population) may more closely represent first-trimester biology, the genetic regulation of plasma proteins during pregnancy has not been studied at scale. Recent data suggest that between-sex differences in pQTLs are limited 41 , 42 with few sex-specific effects on protein-disease associations, 43 but whether sex-stratified pQTLs may yield additional insights warrants future investigation. However, our MR findings are consistent with observational associations between HDPs and first-trimester protein levels for NT-proBNP and HSP27, suggesting that pQTLs derived from non-pregnant individuals can recapitulate associations between proteins and outcomes in pregnancy.…”

Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

“…Lastly, translatability of findings is inevitably dependent on the characteristics of the study population. It becomes more and more evident that sex-differences are often overlooked but important in not only the genetics of psychiatric disorders but also their underlying neurobiology (Christiansen et al, 2022; Wingo et al, 2023). In the case of ZNF804A, there is evidence of a sex-specific SNP associated with schizophrenia (Zhang et al, 2011) as well as a mouse model indicating sex-dependent variations in schizophrenia-like phenotypes (Huang et al, 2020).…”