Eva C. Beins

Epstein-Barr virus (EBV) is a herpes virus that infects around 90-95% of the global population, and is associated with numerous autoimmune and neoplastic diseases. EBV persists in B cells as a life-long latent infection. Despite its relevance to disease development, the biological basis of host control during EBV latent infection remains unknown. Here, we report the identification of genetic and non-genetic factors that contribute to latent EBV infection control. In the genome sequence (GS) data of blood from 486,315 UK Biobank and 336,123 All of Us participants, we identified short-reads mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. The detection of EBV-reads (EBVread+) reflected increased viral load, and was associated with HIV infection, intake of immunosuppressive drugs, and current, but not former, smoking. Genome-wide association analyses identified strong associations at the Major Histocompatibility Complex (MHC), including 54 independent HLA-alleles of MHC class I and II, and at 27 genomic regions outside MHC (e.g., loci encompassing ERAP2, CTLA4). Associated genes included genes underlying monogenic susceptibility to EBV infection (e.g., CD70), and novel candidates thereof (e.g., CD226). In an analysis of individuals with EBV-associated diseases, we observed a higher polygenic burden of EBVread+ for HLA-alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01), and at MHC class II in rheumatoid arthritis (RA). A phenome-wide association analysis identified a polygenic overlap of EBVread+ with inflammatory bowel disease, hypothyroidism, and type I diabetes (T1D). Mendelian randomization analyses suggested potential causal effects of EBVread+ on RA and T1D. Our results will inform mechanistic studies and therapeutic approaches in EBV-associated diseases. More broadly, our study illustrates how by-products of human GS data can be used to investigate persistent viral infections.

Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

Purpose: BioMD-Y is a comprehensive biobank study of children and adolescents with major depression (MD) and their healthy peers in Germany, collecting a host of both biological and psychosocial information from the participants and their parents with the aim of exploring genetic and environmental risk and protective factors for MD in children and adolescents.Participants: Children and adolescents aged 8–18 years are recruited to either the clinical case group (MD, diagnosis of MD disorder) or the typically developing control group (absence of any psychiatric condition).Findings to date: To date, four publications on both genetic and environmental risk and resilience factors (includingFKBP5, glucocorticoid receptor activation, polygenic risk scores, psychosocial and sociodemographic risk and resilience factors) have been published based on the BioMD-Y sample.Future plans: Data collection is currently scheduled to continue into 2026. Research questions will be further addressed using available measures.

Bipolar disorder (BD) is a complex mood disorder with a strong genetic component. Recent studies suggest that microRNAs contribute to psychiatric disorder development. In BD, specific candidate microRNAs have been implicated, in particular miR-137, miR-499a, miR-708, miR-1908 and miR-2113. The aim of the present study was to determine the contribution of these five microRNAs to BD development. For this purpose, we performed: (i) gene-based tests of the five microRNA coding genes, using data from a large genome-wide association study of BD; (ii) gene-set analyses of predicted, brain-expressed target genes of the five microRNAs; (iii) resequencing of the five microRNA coding genes in 960 BD patients and 960 controls and (iv) in silico and functional studies for selected variants. Gene-based tests revealed a significant association with BD for MIR499A, MIR708, MIR1908 and MIR2113. Gene-set analyses revealed a significant enrichment of BD associations in the brain-expressed target genes of miR-137 and miR-499a-5p. Resequencing identified 32 distinct rare variants (minor allele frequency < 1%), all of which showed a non-significant numerical overrepresentation in BD patients compared to controls (p = 0.214). Seven rare variants were identified in the predicted stem-loop sequences of MIR499A and MIR2113. These included rs142927919 in MIR2113 (p_nom = 0.331) and rs140486571 in MIR499A (p_nom = 0.297). In silico analyses predicted that rs140486571 might alter the miR-499a secondary structure. Functional analyses showed that rs140486571 significantly affects miR-499a processing and expression. Our results suggest that MIR499A dysregulation might contribute to BD development. Further research is warranted to elucidate the contribution of the MIR499A regulated network to BD susceptibility.

Frequent testing of large population groups combined with contact tracing and isolation measures will be crucial for containing Coronavirus Disease 2019 outbreaks. Here we present LAMP-Seq, a modified, highly scalable reverse transcription loop-mediated isothermal amplification (RT–LAMP) method. Unpurified biosamples are barcoded and amplified in a single heat step, and pooled products are analyzed en masse by sequencing. Using commercial reagents, LAMP-Seq has a limit of detection of ~2.2 molecules per µl at 95% confidence and near-perfect specificity for severe acute respiratory syndrome coronavirus 2 given its sequence readout. Clinical validation of an open-source protocol with 676 swab samples, 98 of which were deemed positive by standard RT–qPCR, demonstrated 100% sensitivity in individuals with cycle threshold values of up to 33 and a specificity of 99.7%, at a very low material cost. With a time-to-result of fewer than 24 h, low cost and little new infrastructure requirement, LAMP-Seq can be readily deployed for frequent testing as part of an integrated public health surveillance program.

Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with AD and in corresponding animal models. Dendritic cells (DCs) represent a heterogeneous population of myeloid cells that orchestrate innate and adaptive immune responses and self-tolerance. Upon sensing exogenous and endogenous danger signals, mature DCs secrete proinflammatory factors, acquire migratory and antigen presenting capacities and thus contribute to neuroinflammation in trauma, autoimmunity, and neurodegenerative diseases. However, little is known about the involvement of DCs in the pathogenesis of AD. In this review, we summarize the current knowledge on DCs in peripheral immune responses and neuroinflammation in MDD and BD. In addition, we consider the impact of DCs on neuroinflammation and behavior in animal models of AD. Finally, we will discuss therapeutic perspectives targeting DCs and their effector molecules in mood disorders.