Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Biological insights from 108 schizophrenia-associated genetic loci

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia

Литература о Свердловской области: [указатель]. 1954. Вып. 3-4

0|5|Предисловие [c. 5]0|6|Схема классификации летописи литературы о Свердловской области [c. 6]0|9|Коммунистическая партия Советского Союза [c. 9]1|9|Партийное строительство. Руководство партии хозяйственным и культурным строительством [c. 9]1|15|Пропаганда и агитация. Партийное просвещение [c. 15]1|17|История Коммунистической партии Советского Союза [c. 17]0|18|ВЛКСМ. [c. 18]0|21|Пионерские организации и внешкольная работа [c. 21]0|22|История гор. Свердловска и Свердловской области [c. 22]0|23|Социалистическое строительство в Свердловской области [c. 23]0|23|Финансы [c. 23]0|24|Труд [c. 24]1|26|Профессиональные союзы [c. 26]1|27|Социалистическое соревнование. Общие материалы [c. 27]1|28|Соревнование городов [c. 28]0|28|Советское строительство [c. 28]1|28|Выборы в Верховный Совет РСФСР [c. 28]1|28|Местные органы государственной власти [c. 28]1|29|Органы юстиции. Суд и прокуратура [c. 29]0|31|Природа Свердловской области [c. 31]1|31|Геология. Палеонтология. Археология [c. 31]1|32|География [c. 32]1|32|Животный и растительный мир [c. 32]0|32|Техника. Промышленность [c. 32]1|32|История техники и промышленности [c. 32]1|33|Общие вопросы [c. 33]1|34|Производство предметов народного потребления [c. 34]1|35|Строительство. Строительные материалы. Строительная промышленность [c. 35]1|35|Строительство заводов железобетонных изделий [c. 35]1|40|Энергетическая промышленность [c. 40]1|41|Горная промышленность [c. 41]1|44|Металлургическая промышленность [c. 44]1|51|Машиностроительная промышленность [c. 51]1|57|Химическая промышленность [c. 57]1|58|Лесная промышленность [c. 58]1|60|Легкая промышленность [c. 60]1|60|Камнерезное дело [c. 60]1|61|Местная и кооперативная промышленность [c. 61]0|62|Транспорт. Связь [c. 62]1|62|Транспорт [c. 62]1|65|Связь [c. 65]0|65|Сельское хозяйство [c. 65]1|65|Свердловская область на сельскохозяйственной выставке [c. 65]1|69|Трудящиеся города — сельскому хозяйству [c. 69]1|70|Общие вопросы. Колхозы. Совхозы [c. 70]1|72|Освоение целинных и залежных земель [c. 72]1|73|Механизация. Электрификация. МТС [c. 73]1|77|Агротехника. Общее растениеводство. Почвоведение [c. 77]1|79|Частное растениеводство [c. 79]2|79|Зерновые и бобовые культуры [c. 79]2|79|Кормовые культуры . Луга. Пастбища [c. 79]2|79|Садоводство. Плодоводство [c. 79]2|80|Овощеводство [c. 80]1|82|Животноводство [c. 82]0|86|Охота. Рыбоводство [c. 86]0|86|Торговля. Общественное питание [c. 86]0|89|Гражданское строительство. Коммунальное хозяйство. Бытовое обслуживание населения [c. 89]0|91|Здравоохранение. Медицина [c. 91]0|92|Физическая культура. Спорт. Игры [c. 92]0|94|Культура. Просвещение. Наука [c. 94]1|94|Общие вопросы культуры и просвещения. Наука [c. 94]1|95|Семья и быт [c. 95]1|96|Дошкольное воспитание [c. 96]1|96|Начальное и среднее образование [c. 96]1|98|Политехническое обучение в школах [c. 98]1|98|Высшее и среднее специальное образование [c. 98]1|101|Ремесленные училища. Фабрично-заводское обучение. Технические училища [c. 101]1|102|Культурно-просветительная работа [c. 102]0|105|Литературоведение. Художественная литература. Фольклор [c. 105]1|105|Литературная критика и библиография [c. 105]1|107|Художественная литература [c. 107]2|107|Проза [c. 107]2|108|Поэзия [c. 108]2|109|Драматургия [c. 109]2|109|Фельетоны [c. 109]0|111|Искусство [c. 111]1|111|Архитектура [c. 111]1|111|Изобразительное искусство [c. 111]1|112|Театр. Зрелищные предприятия [c. 112]1|114|Музыка [c. 114]1|114|Художественная самодеятельность [c. 114]1|115|Кино [c. 115]1|115|Религия. Наука и религия. Атеизм [c. 115]1|116|Печать [c. 116

Biological insights from 108 schizophrenia-associated genetic loci

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.</p

Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders