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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The schizophrenia syndrome, circa 2024: What we know and how that informs its nature

Schizophrenia Research, Год журнала: 2023, Номер 264, С. 1 - 28

Опубликована: Дек. 12, 2023

Язык: Английский

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Genomic findings in schizophrenia and their implications

Molecular Psychiatry, Год журнала: 2023, Номер 28(9), С. 3638 - 3647

Опубликована: Сен. 1, 2023

Abstract There has been substantial progress in understanding the genetics of schizophrenia over past 15 years. This revealed a highly polygenic condition with majority currently explained heritability coming from common alleles small effect but additional contributions rare copy number and coding variants. Many specific genes loci have implicated that provide firm basis upon which mechanistic research can proceed. These point to disturbances neuronal, particularly synaptic, functions are not confined brain regions circuits. Genetic findings also nature schizophrenia’s close relationship other conditions, bipolar disorder childhood neurodevelopmental disorders, provided an explanation for how risk persist population face reduced fecundity. Current genomic approaches only potentially explain around 40% heritability, proportion this is attributable robustly identified loci. The extreme polygenicity poses challenges biological mechanisms. high degree pleiotropy points need more transdiagnostic shortcomings current diagnostic criteria as means delineating biologically distinct strata. It inferring causality observational experimental studies both humans model systems. Finally, Eurocentric bias needs be rectified maximise benefits ensure these felt across diverse communities. Further advances likely come through application new emerging technologies, such whole-genome long-read sequencing, large samples. Substantive will require parallel functional genomics proteomics applied developmental stages. For efforts succeed identifying disease mechanisms defining novel strata they combined sufficiently granular phenotypic data.

Язык: Английский

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Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Shared genetic architecture between irritable bowel syndrome and psychiatric disorders reveals molecular pathways of the gut-brain axis

Genome Medicine, Год журнала: 2023, Номер 15(1)

Опубликована: Авг. 1, 2023

Abstract Background Irritable bowel syndrome (IBS) often co-occurs with psychiatric and gastrointestinal disorders. A recent genome-wide association study (GWAS) identified several genetic risk variants for IBS. However, most of the heritability remains unidentified, overlap somatic disorders is not quantified beyond correlations. Here, we characterize architecture IBS, further, investigate its phenotypes, identify novel genomic loci. Methods Using GWAS summary statistics IBS (53,400 cases 433,201 controls), performed bivariate casual mixture model analysis to between these phenotypes. We leveraged boost discovery loci associated specific shared both using conditional/conjunctional false rate (condFDR/conjFDR) framework. used functional mapping gene annotation (FUMA) analyses. Results was highly polygenic 12k trait-influencing variants. found extensive a lesser extent diseases. 132 independent IBS-associated (condFDR < 0.05) by conditioning on ( n = 127) diseases 24). conjFDR, 70 unique were Functional analyses revealed enrichment biological pathways nervous immune systems. Genetic correlations subtypes different. Conclusions phenotypes what Leveraging overlap, discovered which implicate wide range gut-brain axis. differences may underlie clinical subtype These results increase our understanding pathophysiology form basis development individualized interventions.

Язык: Английский

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Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy

Nature Human Behaviour, Год журнала: 2023, Номер 7(9), С. 1584 - 1600

Опубликована: Июнь 26, 2023

Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex as distinct constructs. We applied the 'pleiotropy-informed' multivariate omnibus statistical test to genome-wide association of 35 measures neuroticism from UK Biobank (n = 336,993). identified 431 significantly associated loci with evidence abundant shared associations, personality domains. Functional characterization implicated genes significant tissue-specific expression in all tested tissues brain-specific gene sets. conditioned independent Big 5 on our findings, boosting discovery other improving polygenic prediction. These findings advance understanding architecture traits, indicating a prominence pleiotropic effects higher order domains such function. Hindley et al. used genetics tools examine underpinnings find they functioning.

Язык: Английский

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Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease

Nature Cardiovascular Research, Год журнала: 2024, Номер 3(6), С. 754 - 769

Опубликована: Июнь 17, 2024

Язык: Английский

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The genetic architecture of differentiating behavioral and emotional problems in early life

Biological Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Early in life, behavioral and cognitive traits associated with risk for developing a psychiatric condition are broad undifferentiated. As children develop, these differentiate into characteristic clusters of symptoms behaviors that ultimately form the basis diagnostic categories. Understanding this differentiation process - context genetic conditions, which is highly generalized can improve early detection intervention. We modeled emotional problems from age 1.5-5 years (behavioral = score) pre-registered study ∼79,000 population-based Norwegian Mother, Father, Child Cohort Study. used genomic structural equation modeling to identify signal total problems, investigating their links 11 neurodevelopmental conditions. examined associations polygenic scores (PGS) both outcomes assessed relative contributions direct indirect effects ∼33,000 family trios. Differentiation was primarily genetically correlated conditions via "neurodevelopmental" factor. Total were factor "p"-factor. PGS analyses revealed an association between liability ADHD (β=0.11 [0.10,0.12]), weaker (β=0.06 [0.04,0.07]). Trio-PGS showed predominantly on outcomes. uncovered process, mostly related common variants Investigating life may enhance our understanding developmental emergence different

Язык: Английский

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The relationship between cannabis use, schizophrenia, and bipolar disorder: a genetically informed study

The Lancet Psychiatry, Год журнала: 2023, Номер 10(6), С. 441 - 451

Опубликована: Май 17, 2023

Язык: Английский

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Dissociation of Cognitive Effort–Based Decision Making and Its Associations With Symptoms, Cognition, and Everyday Life Function Across Schizophrenia, Bipolar Disorder, and Depression

Biological Psychiatry, Год журнала: 2023, Номер 94(6), С. 501 - 510

Опубликована: Апрель 19, 2023

Язык: Английский

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