Sex differences in brain cell-type specific chromatin accessibility in schizophrenia.

Background: Our understanding of the sex-specific role of the non-coding genome in serious mental illnesses, particularly schizophrenia (SCZ), remains largely incomplete.

Methods: To address this gap, we explored sex differences in 1,393 chromatin accessibility profiles, derived from neuronal and non-neuronal nuclei of two distinct cortical regions from 234 cases with serious mental illness and 235 controls.

Results: We identified sex-specific enhancer-promoter interactions and showed that they regulate genes involved in X-chromosome inactivation (XCI). Additionally, examining chromosomal conformation allowed us to identify sex-specific cis- and trans-regulatory domains (CRDs and TRDs). Co-localization of sex-specific TRDs with schizophrenia common risk variants pinpointed male-specific regulatory regions controlling a number of metabolic pathways. Moreover, enhancers from female-specific TRDs were associated with two genes known to escape XCI-XIST, which encodes a long non-coding RNA (lncRNA) that coats the X chromosome and initiates XCI, and JPX, a regulatory lncRNA that activates XIST transcription-underlying the importance of TRDs in deciphering sex differences in schizophrenia.

Conclusions: Overall, these findings provide extensive characterization of sex differences in the brain epigenome and disease-associated regulomes.