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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Genetics of circadian rhythms and sleep in human health and disease

Nature Reviews Genetics, Год журнала: 2022, Номер 24(1), С. 4 - 20

Опубликована: Авг. 26, 2022

Язык: Английский

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From variant to function in human disease genetics

Science, Год журнала: 2021, Номер 373(6562), С. 1464 - 1468

Опубликована: Сен. 23, 2021

Over the next decade, primary challenge in human genetics will be to understand biological mechanisms by which genetic variants influence phenotypes, including disease risk. Although scale of this is daunting, better methods for functional variant interpretation have transformative consequences diagnosis, risk prediction, and development new therapies. An array characterizing impact at scale, using patient tissue samples as well vitro models, are already being applied dissect across a range cell types environments. These approaches also increasingly deployed clinical settings. We discuss rationale, approaches, applications, future outlook molecular cellular effects variants.

Язык: Английский

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Precise modulation of transcription factor levels identifies features underlying dosage sensitivity

Nature Genetics, Год журнала: 2023, Номер 55(5), С. 841 - 851

Опубликована: Апрель 6, 2023

Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation craniofacial morphology; we therefore developed an approach precisely modulate levels facial progenitor cells applied it SOX9, a associated with disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases SOX9 dosage, REs directly primarily regulated by show heightened dosage; these RE responses partially predict gene expression responses. Sensitive genes preferentially affect functional chondrogenesis PRS-like shape variation. We propose that underlie the specific phenotypes while buffering other leads robust, nonlinear dosage-to-phenotype relationships.

Язык: Английский

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PRSet: Pathway-based polygenic risk score analyses and software

PLoS Genetics, Год журнала: 2023, Номер 19(2), С. e1010624 - e1010624

Опубликована: Фев. 7, 2023

Polygenic risk scores (PRSs) have been among the leading advances in biomedicine recent years. As a proxy of genetic liability, PRSs are utilised across multiple fields and applications. While numerous statistical machine learning methods developed to optimise their predictive accuracy, these typically distil liability single number based on aggregation an individual’s genome-wide alleles. This results key loss information about profile, which could be critical given functional sub-structure genome heterogeneity complex disease. In this manuscript, we introduce ‘pathway polygenic’ paradigm disease risk, liabilities underlie diseases, rather than liability. We describe method accompanying software, PRSet, for computing analysing pathway-based PRSs, polygenic calculated genomic pathways each individual. evaluate potential pathway two distinct ways, creating major sections: (1) first section, benchmark PRSet as enrichment tool, evaluating its capacity capture GWAS signal pathways. find that target sample sizes >10,000 individuals, similar power MAGMA LD score regression, with advantage providing individual-level estimates -opening up range PRS applications, (2) second performance stratification. show using supervised stratification approach, (computed by PRSet) outperform standard C+T lassosum) classifying subtypes 20 21 scenarios tested. definition annotation becomes increasingly refined, expect offer insights into treatment response, generate biologically tractable therapeutic targets from signal, and, ultimately, provide powerful path precision medicine.

Язык: Английский

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Genetics of multiple sclerosis: lessons from polygenicity

The Lancet Neurology, Год журнала: 2022, Номер 21(9), С. 830 - 842

Опубликована: Авг. 10, 2022

Язык: Английский

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Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders

Brain, Год журнала: 2023, Номер 146(8), С. 3392 - 3403

Опубликована: Фев. 9, 2023

Psychiatric disorders and common epilepsies are heritable with a high comorbidity overlapping symptoms. However, the causative mechanisms underlying this relationship poorly understood. Here we aimed to identify genetic loci between epilepsy psychiatric gain better understanding of their shared clinical features. We analysed genome-wide association study data for all (n = 44 889), generalized 33 446), focal 39 348), schizophrenia 77 096), bipolar disorder 406 405), depression 500 199), attention deficit hyperactivity 53 293) autism spectrum 46 350). First, applied MiXeR tool estimate total number causal variants influencing disorders. Next, used conjunctional false discovery rate statistical framework improve power discover genomic loci. Additionally, assessed validity findings in independent cohorts, functionally characterized identified The phenotypes were considerably less polygenic (1.0 K 3.4 variants) than (5.6 13.9 variants), being least having highest polygenicity (13.9 variants). observed cross-trait enrichment depression. Using analysis, 40 distinct jointly associated at <0.05, four which epilepsy. Most risk 31). Among loci, 32 novel epilepsy, two epilepsies. There was mixture concordant discordant allelic effects sign concordance highly consistent datasets disorders, supporting findings. Gene-set analysis implicated biological processes related cell cycle regulation, protein phosphatase activity, membrane vesicle function; gene-set analyses other underpowered. extensive overlap mixed effect directions demonstrates complex these line bi-directional relationship, indicates that may contribute pathophysiological features

Язык: Английский

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Frequency, morbidity and equity — the case for increased research on male fertility

Nature Reviews Urology, Год журнала: 2023, Номер 21(2), С. 102 - 124

Опубликована: Окт. 12, 2023

Язык: Английский

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The transition from genomics to phenomics in personalized population health

Nature Reviews Genetics, Год журнала: 2023, Номер 25(4), С. 286 - 302

Опубликована: Дек. 13, 2023

Язык: Английский

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Schizophrenia genomics: genetic complexity and functional insights

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(9), С. 611 - 624

Опубликована: Июль 19, 2024

Язык: Английский

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