Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes

Cell Genomics, Год журнала: 2022, Номер 2(9), С. 100168 - 100168

Опубликована: Авг. 15, 2022

Язык: Английский

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New insights from the last decade of research in psychiatric genetics: discoveries, challenges and clinical implications

World Psychiatry, Год журнала: 2023, Номер 22(1), С. 4 - 24

Опубликована: Янв. 14, 2023

Psychiatric genetics has made substantial progress in the last decade, providing new insights into genetic etiology of psychiatric disorders, and paving way for precision psychiatry, which individual profiles may be used to personalize risk assessment inform clinical decision‐making. Long recognized heritable, recent evidence shows that disorders are influenced by thousands variants acting together. Most these commonly occurring, meaning every a each disorder, from low high. A series large‐scale studies have discovered an increasing number common rare robustly associated with major disorders. The most convincing biological interpretation findings implicates altered synaptic function autism spectrum disorder schizophrenia. However, mechanistic understanding is still incomplete. In line their extensive epidemiological overlap, appear exist on continua share large degree one another. This provides further support notion current diagnoses do not represent distinct pathogenic entities, ongoing attempts reconceptualize nosology. also influences range behavioral somatic traits diseases, including brain structures, cognitive function, immunological phenotypes cardiovascular disease, suggesting shared potential importance. Current polygenic score tools, predict susceptibility illness, yet provide clinically actionable information. likely improve coming years, they eventually become part practice, stressing need educate clinicians patients about use misuse. review discusses key possible applications, suggests future directions.

Язык: Английский

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Polygenic architecture of rare coding variation across 394,783 exomes

Nature, Год журнала: 2023, Номер 614(7948), С. 492 - 499

Опубликована: Фев. 8, 2023

Язык: Английский

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Diagnosis and management of bipolar disorders

BMJ, Год журнала: 2023, Номер unknown, С. e073591 - e073591

Опубликована: Апрель 12, 2023

Abstract Bipolar disorders (BDs) are recurrent and sometimes chronic of mood that affect around 2% the world’s population encompass a spectrum between severe elevated excitable states (mania) to dysphoria, low energy, despondency depressive episodes. The illness commonly starts in young adults is leading cause disability premature mortality. clinical manifestations bipolar disorder can be markedly varied within individuals across their lifespan. Early diagnosis challenging misdiagnoses frequent, potentially resulting missed early intervention increasing risk iatrogenic harm. Over 15 approved treatments exist for various phases disorder, but outcomes often suboptimal owing insufficient efficacy, side effects, or lack availability. Lithium, first treatment continues most effective drug overall, although full remission only seen subset patients. Newer atypical antipsychotics increasingly being found depression; however, long term tolerability safety uncertain. For many with combination therapy adjunctive psychotherapy might necessary treat symptoms different illness. Several classes medications treating predicting which medication likely tolerable not yet possible. As pathophysiological insights into causes revealed, new era targeted aimed at causal mechanisms, they pharmacological psychosocial, will hopefully developed. time being, judgment, shared decision making, empirical follow-up remain essential elements care. This review provides an overview features, diagnostic subtypes, major modalities available people highlighting recent advances ongoing therapeutic challenges.

Язык: Английский

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Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice

Nature Aging, Год журнала: 2023, Номер 3(9), С. 1067 - 1078

Опубликована: Авг. 16, 2023

Platelet factors regulate wound healing and can signal from the blood to brain

Язык: Английский

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Structure–function coupling in macroscale human brain networks

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(10), С. 688 - 704

Опубликована: Авг. 5, 2024

Язык: Английский

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Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, role of cell type-specific transcript-isoform diversity during human development not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing deeply profile full-length transcriptome germinal zone cortical plate regions developing neocortex at tissue single-cell resolution. We identified 214,516 distinct isoforms, which 72.6% were novel (not previously annotated Gencode version 33), uncovered a substantial contribution diversity-regulated by binding proteins-in defining cellular identity neocortex. comprehensive isoform-centric gene annotation reprioritize thousands rare de novo risk variants elucidate genetic mechanisms for disorders.

Язык: Английский

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Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

Science, Год журнала: 2024, Номер 384(6698)

Опубликована: Май 23, 2024

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment regulatory elements in the developing brain. However, prioritizing risk genes mechanisms is challenging without a unified atlas. Across 672 diverse human brains, we identified 15,752 harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing heterogeneity intrinsic properties of neuronal maturation. Isoform-level regulation, particularly second trimester, mediated largest proportion GWAS heritability. Through colocalization, prioritized about 60% loci across five disorders, exceeding adult brain findings. Finally, contextualized results within gene isoform coexpression networks, revealing comprehensive landscape transcriptome regulation development disease.

Язык: Английский

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Genomics yields biological and phenotypic insights into bipolar disorder

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Язык: Английский

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Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations

Nature Genetics, Год журнала: 2023, Номер 55(3), С. 369 - 376

Опубликована: Март 1, 2023

Abstract Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of protein-coding regions genome identified causal role for ten genes concentration rare variant signals evolutionarily constrained 1 . This study—and other large-scale human genetics studies—was mainly composed individuals European (EUR) ancestry, generalizability findings non-EUR populations remains unclear. To address this gap, we designed custom sequencing panel 161 selected based on current knowledge sequenced new cohort 11,580 cases 10,555 controls diverse ancestries. Replicating earlier work, found that carried significantly higher burden protein-truncating variants (PTVs) (odds ratio = 1.48; P 5.4 × 10 −6 ). In meta-analyses with existing datasets totaling up to 35,828 107,877 controls, excess was largely consistent across five ancestral populations. Two ( SRRM2 AKAP11 ) were newly implicated as risk genes, one gene PCLO shared by those autism. Overall, our results lend robust support allelic spectrum genetic architecture being conserved

Язык: Английский

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