Examining the shared etiology of psychopathology with genome-wide association studies

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(2), P. 1645 - 1665

Published: Jan. 12, 2023

Genome-wide association studies (GWASs) have ushered in a new era of reproducible discovery psychiatric genetics. The field has now identified hundreds common genetic variants that are associated with mental disorders, and many them influence more than one disorder. By advancing the understanding causal biology underlying psychopathology, GWAS results poised to inform development novel therapeutics, stratification at-risk patients, perhaps even revision top-down classification systems psychiatry. Here, we provide concise review findings an emphasis on elucidated shared etiology summarizing insights at three levels analysis: 1) genome-wide architecture; 2) networks, pathways, gene sets; 3) individual variants/genes. Three themes emerge from these efforts. First, all phenotypes heritable, highly polygenic, influenced by pleiotropic incomplete penetrance. Second, highlight broad etiological roles neuronal biology, system-wide effects over localized effects, early neurodevelopment as critical period. Third, loci robustly multiple forms psychopathology harbor genes involved synaptic structure function. Finally, conclude our discussing implications hold for psychiatry, well expected challenges future directions next stage

Language: Английский

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Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 111988 - 111988

Published: Jan. 1, 2023

The maturation of neurons and the development synapses, although emblematic neurons, also relies on interactions with astrocytes other glia. Here, to study role glia-neuron interactions, we analyze transcriptomes human pluripotent stem cell (hPSC)-derived from 80 donors, that were cultured or without contact glial cells. We find presence enhances synaptic gene-expression programs in when physical astrocytes. These changes correlate increased expression, cocultured glia, genes encode adhesion molecules. Both neuronal astrocyte are enriched for associated schizophrenia risk. Our results suggest astrocyte-expressed functions stronger expression genetic they a potential astrocyte-neuron schizophrenia.

Language: Английский

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Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk

European Heart Journal, Journal Year: 2023, Volume and Issue: 45(9), P. 707 - 721

Published: Dec. 8, 2023

Abstract Background and Aims RNA-based, antibody-based, genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, protein structure causally influence triglyceride apolipoprotein B (apoB) as well coronary artery (CAD), ischaemic stroke (IS), other cardiometabolic diseases. Methods RNA sequencing 246 explanted samples genome-wide genotyping performed identify single-nucleotide polymorphisms (SNPs) associated with expression ANGPTL3. Genome-wide summary statistics plasma from deCODE study (n = 35 359) were used. A total 647 carriers protein-truncating variants (PTVs) lower identified in UK Biobank. Two-sample MR using SNPs that or exposure diseases outcomes (CAD, IS, heart failure, non-alcoholic fatty disease, acute pancreatitis, type 2 diabetes). The impact rare PTVs on apoB CAD also investigated Results In two-sample studies, common hepatic had a very strong effect more modest low-density lipoprotein cholesterol, weaker no Biobank, providing lifelong reductions median [−0.37 (interquartile range 0.41) mmol/L] slightly (−0.06 ± 0.32 g/L) similar event rates compared non-carriers (10.2% vs. 10.9% non-carriers, P .60). Conclusions and/or exhibit circulating weak ASCVD. Near-complete function patients elevated may be required ASCVD

Language: Английский

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Review: Cancer and neurodevelopmental disorders: multi-scale reasoning and computational guide

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 2, 2024

The connection and causality between cancer neurodevelopmental disorders have been puzzling. How can the same cellular pathways, proteins, mutations lead to pathologies with vastly different clinical presentations? And why do individuals disorders, such as autism schizophrenia, face higher chances of emerging throughout their lifetime? Our broad review emphasizes multi-scale aspect this type reasoning. As these examples demonstrate, rather than focusing on a specific organ system or disease, we aim at new understanding that be gained. Within framework, our calls attention computational strategies which powerful in discovering connections, causalities, predicting outcomes, are vital for drug discovery. Thus, centering features, draw rapidly increasing data molecular level, including mutations, isoforms, three-dimensional structures, expression levels respective disease-associated genes. Their integrated analysis, together chromatin states, delineate how, despite being connected, differ, how symptoms. Here, seek uncover cancer, pediatric tumors, tantalizing questions raises.

Language: Английский

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Rare coding variant analysis for human diseases across biobanks and ancestries

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(9), P. 1811 - 1820

Published: Aug. 29, 2024

Language: Английский

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