02155nas a2200349   4500000000100000000000100001008004100002260001500043653002400058653003000082653002000112100001900132700001200151700002700163700002400190700001400214700002000228700002300248700003000271700002300301700002100324700001700345700002100362700001900383700002500402700002000427245006000447856005500507300000800562520122100570022001401791       2023                            d  c2023-08-3110aAlzheimer's disease10aGene Expression Profiling10aGene regulation1 aAliza P. Wingo1 aYue Liu1 aEkaterina S. Gerasimov1 aSelina M. Vattathil1 aJiaqi Liu1 aDavid J. Cutler1 aMichael P. Epstein1 aGabriëlla A. M. Blokland1 aMadhav Thambisetty1 aJuan C. Troncoso1 aDuc M. Duong1 aDavid A. Bennett1 aAllan I. Levey1 aNicholas T. Seyfried1 aThomas S. Wingo00aSex differences in brain protein expression and disease  uhttps://www.nature.com/articles/s41591-023-02509-y  a1-93 aMost 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.  a1546-170X