Dynamic alterations in gene co-expression networks and gene-transcript associations characterize co-morbidities in cocaine use disorder.

Background-: Individuals with cocaine use disorder (CUD) who attempt abstinence experience craving and relapse, which poses challenges in treatment. Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome in living individuals are limited. Therefore, we investigated the connection between drug use behaviors during abstinence with blood transcriptomics. Methods-: We conducted a comprehensive longitudinal study involving 12 subjects (9 males, 3 females) with CUD and RNA sequencing on blood collected at a drug-free baseline, and 3, 6 & 9 months thereafter. We categorized subjects into 2 responder groups (high-low) based on scores of drug use variables, and 3 responder groups (low-intermediate-high) on days of abstinence. We investigated differential expression and gene-transcript associations across responder groups at each time point. Lastly, we examined genes that are both co-expressed and showed dynamic expression with time. Results-: Genes with significant transcript associations between high and. intermediate days of abstinence at 9 months were notably enriched for cannabis use disorder, drinks weekly, and coronary artery disease risk genes. Time-specific gene co-expression analysis prioritized transcripts related to immune processes, cell cycle, RNA-protein synthesis, and second messenger signaling for days of abstinence. Conclusion-: We demonstrate that abstinence reflects robust changes in drug use behaviors and the blood transcriptome in CUD. We also highlight the importance of longitudinal studies to capture complex biological processes during abstinence in CUD.

Genetic regulation of cell type-specific chromatin accessibility shapes brain disease etiology.

Nucleotide variants in cell type-specific gene regulatory elements in the human brain are risk factors for human disease. We measured chromatin accessibility in 1932 aliquots of sorted neurons and non-neurons from 616 human postmortem brains and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTLs). Only 10.4% of caQTLs are shared between neurons and non-neurons, which supports cell type-specific genetic regulation of the brain regulome. Incorporating allele-specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms that underlie disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs and identified the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides insights into disease etiology.

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.