TY - JOUR
KW - Alzheimer's disease
KW - Gene Expression Profiling
KW - Gene regulation
AU - Aliza P. Wingo
AU - Yue Liu
AU - Ekaterina S. Gerasimov
AU - Selina M. Vattathil
AU - Jiaqi Liu
AU - David J. Cutler
AU - Michael P. Epstein
AU - Gabriëlla A. M. Blokland
AU - Madhav Thambisetty
AU - Juan C. Troncoso
AU - Duc M. Duong
AU - David A. Bennett
AU - Allan I. Levey
AU - Nicholas T. Seyfried
AU - Thomas S. Wingo
AB - 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.
BT - Nature Medicine
DA - 2023-08-31
DO - 10.1038/s41591-023-02509-y
LA - en
N2 - 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.
PY - 2023
SP - 1
EP - 9
T2 - Nature Medicine
TI - Sex differences in brain protein expression and disease
UR - https://www.nature.com/articles/s41591-023-02509-y
Y2 - 2023-09-15
SN - 1546-170X
ER -