Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

• MeSH
• alely MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci genetika   MeSH
• genomika MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• schizofrenie * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in people with cystic fibrosis (pwCF) can lead to severe outcomes. METHODS: In this observational study, the European Cystic Fibrosis Society Patient Registry collected data on pwCF and SARS-CoV-2 infection to estimate incidence, describe clinical presentation and investigate factors associated with severe outcomes using multivariable analysis. RESULTS: Up to December 31, 2020, 26 countries reported information on 828 pwCF and SARS-CoV-2 infection. Incidence was 17.2 per 1000 pwCF (95% CI: 16.0-18.4). Median age was 24 years, 48.4% were male and 9.4% had lung transplants. SARS-CoV-2 incidence was higher in lung-transplanted (28.6; 95% CI: 22.7-35.5) versus non-lung-transplanted pwCF (16.6; 95% CI: 15.4-17.8) (p≤0.001).SARS-CoV-2 infection caused symptomatic illness in 75.7%. Factors associated with symptomatic SARS-CoV-2 infection were age >40 years, at least one F508del mutation and pancreatic insufficiency.Overall, 23.7% of pwCF were admitted to hospital, 2.5% of those to intensive care, and regretfully 11 (1.4%) died. Hospitalisation, oxygen therapy, intensive care, respiratory support and death were 2- to 6-fold more frequent in lung-transplanted versus non-lung-transplanted pwCF.Factors associated with hospitalisation and oxygen therapy were lung transplantation, cystic fibrosis-related diabetes (CFRD), moderate or severe lung disease and azithromycin use (often considered a surrogate marker for Pseudomonas aeruginosa infection and poorer lung function). CONCLUSION: SARS-CoV-2 infection yielded high morbidity and hospitalisation in pwCF. PwCF with forced expiratory volume in 1 s <70% predicted, CFRD and those with lung transplants are at particular risk of more severe outcomes.

• Publikační typ
• časopisecké články MeSH

Intravenous thrombolysis (IVT) is a standard treatment for anterior (ACS) and posterior circulation stroke (PCS). However, due to the low occurrence of PCS and of intracranial hemorrhage (ICH) in PCS, the knowledge about ICH predictors following IVT in PCS is sparse. Our aim was to identify predictors for ICH following IVT in PCS. The set consisted of 1281 consecutive ischemic stroke (IS) patients treated with IVT, out of which 158 (103 males; mean age 65.6 ± 12.3 years) had PCS. Collected data include baseline characteristics, common stroke risk factors, pre-medication, stroke severity, admission blood glucose level, blood pressure and treatment with intravenous antihypertensive therapy before and during IVT, occlusion of arteries, recanalization rate, time to treatment, and clinical outcome at day 90. Overall, 11 (7%) patients had ICH. Atrial fibrillation (p = 0.004), neurological deficit at time of treatment in the National Institutes of Health Stroke Scale (p = 0.016), decreased level of consciousness (p = 0.003), occlusion of basilar artery (p = 0.007), occlusion of PCA (p = 0.001), and additional endovascular therapy (p = 0.001) were identified by logistic regression analysis as significant predictors for ICH in PCS. Patients with ischemic lesion in the brainstem, occlusion of vertebral artery, or absence of basilar and posterior cerebral artery occlusion might be considered for treatment with IVT even in borderline cases. Those patients seem to have less frequently favorable outcomes without an increase in ICH rate. Time to IVT in PCS seems not to influence ICH risk or chances for favorable outcomes as significantly as it does in ACS.

• Klíčová slova
• Intracranial hemorrhage, Intravenous thrombolysis, Ischemic stroke, Posterior circulation,
• MeSH
• cévní mozková příhoda etiologie   terapie   MeSH
• fibrinolytika škodlivé účinky   MeSH
• intrakraniální krvácení chemicky indukované   diagnóza   MeSH
• intravenózní podání MeSH
• ischemie mozku komplikace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční angiografie MeSH
• magnetická rezonanční tomografie MeSH
• prediktivní hodnota testů MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tkáňový aktivátor plazminogenu škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrinolytika MeSH
• tkáňový aktivátor plazminogenu MeSH