Convergence of the dysregulated regulome in schizophrenia with polygenic risk and evolutionarily constrained enhancers.

Enhancers play an essential role in the etiology of schizophrenia; however, the dysregulation of enhancer activity and its impact on the regulome in schizophrenia remains understudied. To address this gap in our knowledge, we assessed enhancer and gene expression in 1,382 brain samples comprising cases with schizophrenia and unaffected controls. Dysregulation of enhancer expression was concordant with changes in gene expression, and was more closely associated with schizophrenia polygenic risk, suggesting that enhancer dysregulation is proximal to the genetic etiology of the disease. Modeling the shared variance of cis-coordinated genes and enhancers revealed a gene regulatory program that was highly associated with genetic vulnerability to schizophrenia. By integrating coordinated factors with evolutionary constraints, we found that enhancers acquired during human evolution are more likely to regulate genes that are implicated in neuropsychiatric disorders and, thus, hold potential as therapeutic targets. Our analysis provides a systematic view of regulome dysregulation in schizophrenia and highlights its convergence with schizophrenia polygenic risk and human-gained enhancers.

Alzheimer's disease transcriptional landscape in ex-vivo human microglia.

Microglia are resident immune cells of the brain and are implicated in the etiology of Alzheimer's Disease (AD) and other diseases. Yet the cellular and molecular processes regulating their function throughout the course of the disease are poorly understood. Here, we present the transcriptional landscape of primary microglia from 189 human postmortem brains, including 58 healthy aging individuals and 131 with a range of disease phenotypes, including 63 patients representing the full spectrum of clinical and pathological severity of AD. We identified transcriptional changes associated with multiple AD phenotypes, capturing the severity of dementia and neuropathological lesions. Transcript-level analyses identified additional genes with heterogeneous isoform usage and AD phenotypes. We identified changes in gene-gene coordination in AD, dysregulation of co-expression modules, and disease subtypes with distinct gene expression. Taken together, these data further our understanding of the key role of microglia in AD biology and nominate candidates for therapeutic intervention.

Single-cell multi-cohort dissection of the schizophrenia transcriptome.

The complexity and heterogeneity of schizophrenia have hindered mechanistic elucidation and the development of more effective therapies. Here, we performed single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across 140 individuals in two independent cohorts. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Transcriptional alterations included known genetic risk factors, suggesting convergence of rare and common genomic variants on neuronal population-specific alterations in schizophrenia. Based on the magnitude of schizophrenia-associated transcriptional change, we identified two populations of individuals with schizophrenia marked by expression of specific excitatory and inhibitory neuronal cell states. This single-cell atlas links transcriptomic changes to etiological genetic risk factors, contextualizing established knowledge within the human cortical cytoarchitecture and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.

Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits.

OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. The objective of this study was to perform a well-powered genetic study of TRD. METHODS: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks. RESULTS: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. CONCLUSIONS: This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD.