Leveraging sex-genetic interactions to understand brain disorders: recent advances and current gaps

It is established that there are sex differences in terms of prevalence, age of onset, clinical manifestations, and response to treatment for a variety of brain disorders, including neurodevelopmental, psychiatric, and neurodegenerative disorders. Cohorts of increasing sample sizes with diverse data types collected, including genetic, transcriptomic and/or phenotypic data, are providing the building blocks to permit analytical designs to test for sex-biased genetic variant-trait associations, and for sex-biased transcriptional regulation. Such molecular assessments can contribute to our understanding of the manifested phenotypic differences between the sexes for brain disorders, offering the future possibility of delivering personalized therapy for females and males. With the intention of raising the profile of this field as a research priority, this review aims to shed light on the importance of investigating sex-genetic interactions for brain disorders, focusing on two areas: (i) variant-trait associations and (ii) transcriptomics (i.e. gene expression, transcript usage and regulation). We specifically discuss recent advances in the field, current gaps and provide considerations for future studies. In this review, the authors provide an overview of recent advances and current gaps related to studying sex differences for brain disorders at the level of the genetic code and transcription. They offer considerations to move research forward to account for sex differences. Graphical abstract