Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date,... Show moreLung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by & GE;2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.Multi-ancestry genome-wide association analyses and systematic variant-to-gene mapping strategies implicate new genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Show less
Colangeli, R.; Morena, M.; Werner, A.; Thompson, R.J.; Stelt, M. van der; Pittman, Q.J.; ... ; Teskey, G.C. 2022
Repeated seizures result in a persistent maladaptation of endocannabinoid signaling, mediated in part by anandamide signaling deficiency in the basolateral amygdala (BLA) that manifests as aberrant... Show moreRepeated seizures result in a persistent maladaptation of endocannabinoid signaling, mediated in part by anandamide signaling deficiency in the basolateral amygdala (BLA) that manifests as aberrant synaptic function and altered emotional behaviour. Here, we determined the effect of repeated seizures (kindling) on 2-AG signaling on GABA transmission by directly measuring tonic and phasic eCB-mediated retrograde signaling in an in vitro BLA slice preparation from male rats. We report that both activity-dependent and muscarinic receptor (mAChR)-mediated depression of GABA synaptic transmission was reduced following repeated seizure activity. These effects were recapitulated in sham rats by preincubating slices with the 2-AG synthesising enzyme inhibitor DO34. Conversely, preincubating slices with the 2-AG degrading enzyme inhibitor KML29 rescued activity-dependent 2-AG signaling, but not mAChR-mediated synaptic depression, over GABA transmission in kindled rats. These effects were not attributable to a change in CB1 receptor sensitivity or altered 2-AG tonic signaling since the application of the highly selective CB1 receptor agonist CP55,940 provoked a similar reduction in GABA synaptic activity in both sham and kindled rats, while no effect of either DO34 or of the CB1 inverse agonist AM251 was observed on frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in either sham or kindled rats. Collectively, these data provide evidence that repeated amygdala seizures persistently alter phasic 2-AG mediated-retrograde signaling at BLA GABAergic synapses, probably by impairing stimulus-dependent 2-AG synthesis/release, which contributes to the enduring aberrant synaptic plasticity associated with seizure activity.SIGNIFICANT STATEMENT: The plastic reorganization of endocannabinoid (eCB) signaling after seizures and during epileptogenesis may contribute to the negative neurobiological consequences associated with seizure activity. Therefore, a deeper understanding of the molecular basis underlying the pathologic long-term eCB signaling remodelling following seizure activity will be crucial to develop novel therapies for epilepsy which not only target seizure activity, but, most importantly, the epileptogenesis and the comorbid conditions associated with epilepsy. Show less
Objective: Network analysis allows us to identify the most interconnected (i.e., central) symptoms, and multiple authors have suggested that these symptoms might be important treatment targets.... Show moreObjective: Network analysis allows us to identify the most interconnected (i.e., central) symptoms, and multiple authors have suggested that these symptoms might be important treatment targets. This is because change in central symptoms (relative to others) should have greater impact on change in all other symptoms. It has been argued that networks derived from cross-sectional data may help identify such important symptoms. We tested this hypothesis in social anxiety disorder. Method: We first estimated a state-of-the-art regularized partial correlation network based on participants with social anxiety disorder (n = 910) to determine which symptoms were more central. Next, we tested whether change in these central symptoms were indeed more related to overall symptom change in a separate dataset of participants with social anxiety disorder who underwent a variety of treatments (n = 244). We also tested whether relatively superficial item properties (infrequency of endorsement and variance of items) might account for any effects shown for central symptoms. Results: Centrality indices successfully predicted how strongly changes in items correlated with change in the remainder of the items. Findings were limited to the measure used in the network and did not generalize to three other measures related to social anxiety severity. In contrast, infrequency of endorsement showed associations across all measures. Conclusions: The transfer of recently published results from cross-sectional network analyses to treatment data is unlikely to be straightforward. (PsycINFO Database Record (c) 2018 APA, all rights reserved) Show less
