Sex differences in brain protein expression and disease

• Type of Material: Article
• Authors: Aliza Wingo, Emory University; Yue Liu, Emory University; Ekaterina Gerasimov, Emory University; Selina Vattathil, Emory University; Jiaqi Liu, Emory University; David J Cutler, Emory University; Michael Epstein, Emory University; Gabriëlla A. M. Blokland, Maastricht University; Madhav Thambisetty, National Institutes of Health; Juan C. Troncoso, Johns Hopkins Univeristy; Duc Duong, Emory University; David A. Bennett, Rush University Medical Center; Allan I Levey, Emory University; Nicholas Seyfried, Emory University; Thomas Wingo, Emory University
• Language: English
• Date: 2023-08-31
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038%2Fs41591-023-02509-y
• Title of Journal or Parent Work: Nature Medicine
• Volume: 29
• Issue: 9
• Start Page: 2224
• End Page: 2232
• Grant/Funding Information: This work was supported by grant nos. P30AG010161 (D.A.B.), P30AG072975 (D.A.B.), R01AG015819 (D.A.B.), R01AG017917 (D.A.B.), U01AG061356 (D.A.B.); I01 BX003853 (A.P.W.); IK4 BX005219 (A.P.W.); I01 BX005686 (A.P.W.); R01 AG072120 (A.P.W. and T.S.W.); R01 AG075827 (T.S.W. and A.P.W.); R01 AG056533 (T.S.W. and A.P.W.), RF1AG071170 (M.P.E. and D.J.C.), P30 AG066507 (J.C.T.), U19AG033655 (J.C.T.), P30 AG066511 (A.I.L.), U01 AG061357 (A.I.L., N.T.S.) and U54 AG065187 (A.I.L.), and in part by the intramural program of the National Institute on Aging.
• Keywords: Alzheimer's disease; Gene regulation; gene expression profiling
• Research Categories: Biology, Genetics

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.