A common missense variant in SLC39A8 is convincingly associated with schizophrenia and several additional phenotypes. Homozygous loss-of-function mutations in SLC39A8 result in undetectable serum manganese (Mn) and a Congenital Disorder of Glycosylation (CDG) due to the exquisite sensitivity of glycosyltransferases to Mn concentration. Here, we identified several Mn-related changes in human carriers of the common SLC39A8 missense allele. Analysis of structural brain MRI scans showed a dose-dependent change in the ratio of T2w to T1w signal in several regions. Comprehensive trace element analysis confirmed a specific reduction of only serum Mn, and plasma protein N-glycome profiling revealed reduced complexity and branching. N-glycome profiling from two individuals with SLC39A8-CDG showed similar but more severe alterations in branching that improved with Mn supplementation, suggesting that the common variant exists on a spectrum of hypofunction with potential for reversibility. Characterizing the functional impact of this variant will enhance our understanding of schizophrenia pathogenesis and identify novel therapeutic targets and biomarkers.

Gene expression is orchestrated by a complex array of gene regulatory elements that govern transcription in a cell-type-specific manner. Though previously studied, the ability to utilize regulatory elements to identify disrupting variants remains largely elusive. To identify important factors within these regions, we generated enhancer–promoter interaction (EPI) networks and investigated the presence of disease-associated variants that fall within these regions. Our study analyzed six neuronal cell types across neural differentiation, allowing us to examine closely related cell types and across differentiation stages. Our results expand upon previous findings of cell-type specificity of enhancer, promoter, and transcription factor binding sites. Notably, we find that regulatory regions within EPI networks can identify the enrichment of variants associated with neuropsychiatric disorders within specific cell types and network sub-structures. This enrichment within sub-structures can allow for a better understanding of potential mechanisms by which variants may disrupt transcription. Together, our findings suggest that EPIs can be leveraged to better understand cell-type-specific regulatory architecture and used as a selection method for disease-associated variants to be tested in future functional assays. Combined with these future functional characterization assays, EPIs can be used to better identify and characterize regulatory variants’ effects on such networks and model their mechanisms of gene regulation disruption across different disorders. Such findings can be applied in practical settings, such as diagnostic tools and drug development.