Biology subjects

Weinberger, D.

Publications and source records attributed to Weinberger, D..

3 recordsLinked to original sources

bioRxiv2018

Differences in Pneumococcal Serotype Replacement in Individuals with and without Underlying Medical Conditions

BackgroundPneumococcal conjugate vaccines (PCVs) have had a well-documented impact on the incidence of invasive pneumococcal disease (IPD) worldwide. However, declines in IPD due to vaccine-targeted serotypes have been partially offset by increases in IPD due to non-vaccine serotypes. The goal of this study was to quantify serotype-specific changes in the incidence of IPD that occurred in different age groups, with or without certain co-morbidities, following the introduction of PCV7 and PCV13 in the childhood vaccination program in Denmark.\n\nMethodsWe used nationwide surveillance data for IPD in Denmark and a hierarchical Bayesian regression framework to estimate changes in the incidence of IPD associated with the introduction of PCV7 (2007) and PCV13 (2010) while controlling for serotype-specific epidemic cycles and unrelated secular trends.\n\nResults and ConclusionsFollowing the introduction of PCV7 and 13 in children, the net impact of serotype replacement varied considerably by age group and the presence of comorbid conditions. Serotype replacement offset a greater fraction of the decline in vaccine-targeted serotypes following the introduction of PCV7 compared with the period following the introduction of PCV13. Differences in the magnitude of serotype replacement were due to variations in the incidence of non-vaccine serotypes in the different risk groups before the introduction of PCV7 and PCV13. The relative increases in the incidence of IPD caused by non-vaccine serotypes did not differ appreciably in the post-vaccination period. Serotype replacement offset a greater proportion of the benefit of PCVs in strata in which the non-vaccine serotypes comprised a larger proportion of cases prior to the introduction of the vaccines. These findings could help to predict the impact of next-generation conjugate vaccines in specific risk groups.

epidemiology↗

bioRxiv2018

Long-read sequencing reveals the splicing profile of the calcium channel gene CACNA1C in human brain

RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show that CACNA1Cs transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.

neuroscience↗

bioRxiv2018

Association of a lincRNA postmortem with suicide by violent means and in vivo with aggressive phenotypes

ObjectivePrevious findings suggest that differences in brain expression of a human-specific long intergenic non-coding RNA (LINC01268; GRCh37/hg19: LOC285758) may be linked to aggressive behavior and suicide. The authors sought to replicate and extend these findings in a new sample, and translate the results to the behavioral level in living healthy subjects.\n\nMethodThe authors examined RNA sequencing data in human brain to confirm the prior postmortem association of the lincRNA specifically with suicide by violent means. In addition, they used a genetic variant associated with LINC01268 expression to detect association with in vivo prefrontal physiology related to behavioral control. They finally performed weighted gene co-expression network analysis (WGCNA) and gene-ontology analysis to identify biological processes associated with a LINC01268 co-expression network.\n\nResultsIn the replication sample, prefrontal expression of LINC01268 was again higher in suicides by violent means (N=65) than both non-suicides (N=78; 1.29e-06) and suicides by non-violent means (N=46; p=1.4e-06). In a living cohort, carriers of the minor allele of a SNP associated with increased LINC01268 expression in brain scored higher on a lifetime aggression questionnaire and show diminished engagement of prefrontal cortex (BA10) when viewing angry faces during fMRI. WGCNA highlighted the immune response.\n\nConclusionsThese results suggest that LINC01268 influences emotional regulation, aggressive behavior and suicide by violent means; the underlying biological dynamics may include modulation of genes potentially engaged in the immune response.

neuroscience↗