Sex differences in neuropsychiatric genetics: progress in understanding mechanisms of risk and protection

Sex differences in the prevalence and clinical presentation of neuropsychiatric disorders suggest a corresponding divergence in underlying biological risk mechanisms between males and females. Advances in neuropsychiatric genetics have started to resolve these differences, defining sex-differential genetic architectures and risk loci across common and rare variants on the autosomes and sex chromosomes, with the study of major depressive disorder and neurodevelopmental disorders leading the way. As we look to translate sex-differential genetic signals into mechanistic understanding, emerging evidence highlights roles for sex chromosome dosage and gonadal hormone signaling. Sex-aware functional genomics approaches further provide genome-scale information for aligning genetic risk with these sex-differential biological drivers, baseline sex differences, and sex-differential disorder states. Moving forward, continued progress toward defining the biological basis for sex-biased neuropsychiatric risk will depend on purposeful integration of genetic and functional multi-omic datasets within a framework that incorporates established and developing principles of sex-differential neurobiology.