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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Psychosis superspectrum I: Nosology, etiology, and lifespan development

Molecular Psychiatry, Год журнала: 2024, Номер 29(4), С. 1005 - 1019

Опубликована: Янв. 10, 2024

Язык: Английский

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Persistent PTSD symptoms are associated with plasma metabolic alterations relevant to long-term health: A metabolome-wide investigation in women

Psychological Medicine, Год журнала: 2025, Номер 55

Опубликована: Янв. 1, 2025

Abstract Background Post-traumatic stress disorder (PTSD) is characterized by severe distress and associated with cardiometabolic diseases. Studies in military clinical populations suggest that dysregulated metabolomic processes may be a key mechanism. Prior work identified validated metabolite-based score (MDS) linked depression anxiety subsequent Here, we assessed whether PTSD shares metabolic alterations if additional metabolites are related to PTSD. Methods We leveraged plasma metabolomics data from three subsamples nested within the Nurses’ Health Study II, including 2835 women 2950 blood samples collected across time points (1996–2014) 339 known assayed mass spectrometry-based techniques. Trauma exposures were 2008 as follows: lifetime trauma without PTSD, remission, persistent symptoms. Associations between MDS or individual estimated each subsample adjusting for potential confounders combined random-effects meta-analyses. Results Persistent symptoms higher levels of previously developed MDS. Out metabolites, 29 (primarily elevated glycerophospholipids glycerolipids) (false discovery rate < 0.05; technical covariates). No metabolite associations found other PTSD-related exposures. Conclusions As first large-scale, population-based analysis our study highlighted shared distinct differences versus anxiety. novel markers symptom persistence, suggesting further connections dysregulation have downstream consequences health.

Язык: Английский

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Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 10, 2024

Abstract The etiology of substance use disorders (SUDs) and psychiatric reflects a combination both transdiagnostic (i.e., common) disorder-level independent) genetic risk factors. We applied genomic structural equation modeling to examine these factors across SUDs, psychotic, mood, anxiety using genome-wide association studies (GWAS) European-(EUR) African-ancestry (AFR) individuals. In EUR individuals, represented SUDs (143 lead single nucleotide polymorphisms [SNPs]), psychotic (162 SNPs), mood/anxiety (112 SNPs). identified two novel SNPs for that have probable regulatory roles on FOXP1 , NECTIN3 BTLA genes. AFR (1 SNP) (no significant SUD factor SNP, although previously in EUR- cross-ancestry GWAS, is finding Shared variance accounted overlap between their comorbidities, with second-order GWAS identifying up 12 not significantly associated either first-order Finally, common independent effects showed different associations psychiatric, sociodemographic, medical phenotypes. For example, the components schizophrenia bipolar disorder had distinct affective risk-taking behaviors, phenome-wide conditions tobacco broader factor. Thus, combining approaches can improve our understanding co-occurring increase specificity discovery, which critical demonstrate considerable symptom etiological overlap.

Язык: Английский

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Transdiagnostic biomarkers of mental illness across the lifespan: A systematic review examining the genetic and neural correlates of latent transdiagnostic dimensions of psychopathology in the general population

Neuroscience & Biobehavioral Reviews, Год журнала: 2023, Номер 155, С. 105431 - 105431

Опубликована: Окт. 26, 2023

This systematic review synthesizes evidence from research investigating the biological correlates of latent transdiagnostic dimensions psychopathology (e.g., p-factor, internalizing, externalizing) across lifespan. Eligibility criteria captured genomic and neuroimaging studies general and/or specific in population samples all age groups. MEDLINE, Embase, PsycINFO were searched for relevant published up to March 2023 46 selected inclusion. The results revealed several consistently associated with psychopathology, including polygenic scores ADHD neuroticism, global surface area gray matter volume. Shared unique associations between symptom are highlighted, as potential age-specific differences associations. Findings interpreted reference key methodological studies. included provide compelling that dimension reflects common underlying genetic neurobiological vulnerabilities shared diverse manifestations mental illness. Substantive interpretations context discussed.

Язык: Английский

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Generalized genetic liability to substance use disorders

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(11)

Опубликована: Июнь 2, 2024

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common compared with individual SUDs characterized by greater severity, additional psychiatric comorbidities, worse outcomes. Here, we review evidence for the role generalized genetic liability to various SUDs. Coaggregation has familial contributions, twin studies suggesting a strong contribution additive influences undergirding variety substances (including alcohol, nicotine, cannabis, others). GWAS have documented similarly large correlations between opioid disorders. Extending these findings, recent identified multiple genomic loci that contribute risk problematic tobacco use, implicating dopaminergic regulatory neuronal development mechanisms in pathophysiology SUD liability, certain signals demonstrating cross-species translational validity. Overlap other externalizing behaviors, while substantial, does not explain entirety signal SUD. Polygenic scores (PGS) derived from outperform PGS prediction serious mental health medical comorbidities. Going forward, it will be important further elucidate etiology incorporating SUDs, evaluating clinical presentation across lifespan, increasing granularity investigation (e.g., specific transdiagnostic criteria) ultimately improve nosology, prevention, treatment

Язык: Английский

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An Honest Reckoning With the Amygdala and Mental Illness

American Journal of Psychiatry, Год журнала: 2024, Номер 181(12), С. 1059 - 1075

Опубликована: Дек. 1, 2024

Anxiety disorders are a leading source of human misery, morbidity, and premature mortality. Existing treatments far from curative for many, underscoring the need to clarify underlying neural mechanisms. Although many brain regions contribute, amygdala has received most intense scientific attention. Over past several decades, this scrutiny yielded detailed understanding function, but it failed produce new clinical assays, biomarkers, or cures. Rising urgent public health challenge demands an honest reckoning with functional-neuroanatomical complexity shift theories anchored on "the amygdala" models centered specific nuclei cell types. This review begins by examining evidence studies rodents, monkeys, humans "canonical model," idea that plays central role in fear- anxiety-related states, traits, disorders. Next, authors selectively highlight work indicating canonical model, while true, is overly simplistic fails adequately capture actual state evidentiary record, breadth amygdala-associated functions illnesses, amygdala's functional architecture. The describe implications these facts basic neuroimaging research. concludes some general recommendations grappling accelerating efforts understand more effectively treat amygdala-related psychopathology.

Язык: Английский

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A Systematic Review of the Etiology and Neurobiology of Intermittent Explosive Disorder

Psychiatry Research, Год журнала: 2025, Номер 347, С. 116410 - 116410

Опубликована: Фев. 22, 2025

Язык: Английский

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Major depressive disorder on a neuromorphic continuum

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 11, 2025

The heterogeneity of major depressive disorder (MDD) has hindered clinical translation and neuromarker identification. Biotyping facilitates solving the problems heterogeneity, by dissecting MDD patients into discrete subgroups. However, interindividual variations suggest that depression may be conceptualized as a "continuum," rather than "category." We use Bayesian model to decompose structural MRI features from multisite cross-sectional cohort three latent disease factors (spatial pattern) continuum factor compositions (individual expression). are associated with distinct neurotransmitter receptors/transporters obtained open PET sources. Increases cortical thickness in sensory decreases orbitofrontal cortices (Factor 1) associate norepinephrine 5-HT2A density, cingulo-opercular network subcortex 2) 5-HTT increases social affective brain systems 3) relate density. Disease patterns can also used predict symptom improvement longitudinal cohort. Moreover, individual expressions stable over time cohort, differentially expressed controls transdiagnostic Collectively, our data-driven reveal organize along continuous dimensions affect sets regions. Li et al. identify abnormalities using an unsupervised machine learning technique, quantify their expression level for each patient.

Язык: Английский

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Transdiagnostic and Disorder-Level GWAS Enhance Precision of Substance Use and Psychiatric Genetic Risk Profiles in African and European Ancestries

Biological Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

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