The General Factor of Psychopathology (p): Choosing Among Competing Models and Interpreting p

Clinical Psychological Science, Journal Year: 2023, Volume and Issue: 12(1), P. 53 - 82

Published: May 3, 2023

Over the past 10 years, general factor of psychopathology, p, has attracted interest and scrutiny. We review history idea that all mental disorders share something in common, p; how we arrived at this idea; it became conflated with a statistical representation, Bi-Factor Model. then leverage Environmental Risk (E-Risk) longitudinal twin study to examine properties nomological network different representations p. find p performed similarly regardless was modelled, suggesting if sample content are same resulting will be similar. suggest meaning is not found by dueling over models but conducting well-specified criterion-validation studies developing new measurement approaches. outline directions refresh research efforts uncover what have common.

Language: Английский

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Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging

Nature Aging, Journal Year: 2023, Volume and Issue: 3(8), P. 1020 - 1035

Published: Aug. 7, 2023

Abstract The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits multivariate genome-wide association study methods, we modeled their underlying genetic factor (‘mvAge’). mvAge (effective n = ~1.9 million participants European ancestry) identified 52 independent variants in 38 genomic loci. Twenty were novel (not reported input studies). Transcriptomic imputation age-relevant genes, VEGFA PHB1 . Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on ( P value 8.41 × 10 −5 ). Similarly, genetically proxied thiazolidinediones 3.50 −10 ), proprotein convertase subtilisin/kexin 9 inhibition 1.62 −6 angiopoietin-like protein 4, beta blockers calcium channel also had estimates. Extending the drug-target framework to 3,947 protein-coding prioritized 122 targets. Together, findings will inform future studies aimed at improving healthy aging.

Language: Английский

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Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 18, 2024

Language: Английский

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Neurogenetic and multi‐omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder

Addiction Biology, Journal Year: 2024, Volume and Issue: 29(2)

Published: Jan. 29, 2024

Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples, shared neurobiological genetic influences may part explain these associations. Links between sensation use disorder (AUD) primarily manifest via increased rather than through direct effects on increasing problems consequences. Here the overlap among seeking, consumption, AUD was examined using multivariate modelling approaches for genome-wide association study (GWAS) summary statistics conjunction neurobiologically informed analyses at multiple investigation. Meta-analytic genomic structural equation (GenomicSEM) were used to conduct GWAS AUD. Resulting downstream examine brain tissue enrichment heritability evidence (e.g., stratified GenomicSEM, RRHO, correlations neuroimaging phenotypes), identify regions likely contributing observed across traits H-MAGMA LAVA). Across approaches, results supported neurogenetic architecture characterised by overlapping genes expressed midbrain striatal tissues variants cortical surface area. Alcohol evidenced relation decreased frontocortical thickness. Finally, mediation models provided mediating associations This extends previous research examining critical sources multi-omic which underlie phenotypic

Language: Английский

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Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(8), P. 2399 - 2407

Published: March 15, 2024

Language: Английский

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Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome

Nature Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 30, 2024

Language: Английский

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Cross-trait multivariate GWAS confirms health implications of pubertal timing

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 18, 2025

Pubertal timing is highly variable and associated with long-term health outcomes. Phenotypes pubertal include age at menarche, voice break, first facial hair growth spurt, seems to have a shared genetic architecture between the sexes. However, puberty phenotypes primarily been assessed separately, failing account for genetics, which limits reliability of purported implications. Here, we model common using multivariate GWAS, an effective population 514,750 European participants. We find 266 independent variants in 197 loci, including 18 novel variants. Transcriptomic, proteome imputation fine-mapping analyses reveal genes causal timing, KDM4C, LEPR, CCNC, ACP1, PCSK1. Linkage disequilibrium score regression Mendelian randomisation analysis establish associations earlier both accelerated ageing risk developing cardiovascular disease osteoporosis. that alanine aminotransferase, glycated haemoglobin, high-density lipoprotein cholesterol Parabacteroides levels are mediators these relationships, controlling oily fish retinol intake may be beneficial promoting healthy development.

Language: Английский

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Systematic dissection of pleiotropic loci and critical regulons in excitatory neurons and microglia relevant to neuropsychiatric and ocular diseases

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 25, 2025

Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between eye and brain, we integrated bulk multiomic profiles with GWAS summary statistics for eight neuropsychiatric five ocular diseases. Our analysis uncovered latent factors explaining 61.7% genetic variance across these 13 diseases, revealing diverse correlational patterns among them. We 45 pleiotropic 91 candidate genes that contribute to disease risk. By integrating profiles, implicated excitatory neurons microglia as key contributors eye-brain connections. Polygenic enrichment further 15 regulons 16 were linked comorbid conditions. Functionally, neuron-specific involved axon guidance synaptic activity, while microglia-specific associated immune response cell activation. In sum, findings underscore link psychiatric disorders

Language: Английский

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Genome data based deep learning identified new genes predicting pharmacological treatment response of attention deficit hyperactivity disorder

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 7, 2025

Although the efficacy of pharmacy in treatment attention deficit/hyperactivity disorder (ADHD) has been well established, lack predictors response poses great challenges for personalized treatment. The current study employed a comprehensive approach, combining genome-wide association analyses (GWAS) and deep learning (DL) methods, to elucidate genetic underpinnings pharmacological ADHD. Based on genotype data medication-naïve patients with ADHD who received treatments 12 weeks, performed GWAS using percentage changes ADHD-RS score as phenotype. Then, DL models were constructed predict symptom scores variants selected based four different P thresholds (E-02, E-03, E-04, E-05) inputs. results identified two significant loci (rs10880574, = 2.39E-09; rs2000900, 3.31E-09) which implicated genes, TMEM117 MYO5B, that primarily associated both brain- gut-related disorders. convolutional neural network (CNN) model, values less than E-02 (5516 SNPs), demonstrated best performance mean squared error (MSE) equals 0.012 (Accuracy 0.83; Sensitivity 0.90; Specificity 0.75) validation dataset, 0.081 an independent test dataset (Acc 0.61, 0.81; 0.26). Notably, variant contributed most CNN model was NKAIN2, ADHD-related gene, is also metabolic processes. To conclude, integration methods revealed new genes contribute responses, underscored interplay between systems processes, potentially providing critical insights into precision Furthermore, our exhibited good encouraged future studies implied potential clinical applications.

Language: Английский

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Impact of life adversity and gene expression on psychiatric symptoms in children and adolescents: findings from the Brazilian high risk cohort study

Frontiers in Psychiatry, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 13, 2025

Introduction While the influence of both genetic and environmental factors on development psychiatric symptoms is well-recognized, precise nature their interaction throughout remains a subject ongoing debate. This study investigated association between expression 78 candidate genes, previously associated with phenotypes, in peripheral blood adversity psychopathology sample 298 young individuals assessed at two time points from Brazilian High Risk Cohort Study for Mental Conditions (BHRCS). Methods Psychopathology was using Child Behavior Checklist (CBCL), considering total CBCL, p-factor (i.e. general factor psychopathology), internalizing externalizing as clinical variables. The life adversities considered this includes four composite variables: child maltreatment, stressful events, threat deprivation. Gene measured next-generation sequencing target genes differential gene analyzed DESeq2 package. Results Mixed models revealed six symptoms: NR3C1, HSPBP1, SIN3A, SMAD4, CRLF3 exhibited negative correlation these symptoms, while FAR1 showed positive correlation. Additionally, we also found USP38 symptoms. Finally, DENND11 PRRC1 were negatively deprivation, latent characterized by neglect, parental absence, measures material forms No mediation or moderation effect observed meaning that they might distinct pathways. Discussion Among nine which encodes glucocorticoid receptor, far most investigated, being depressive early adversity, stress. further research needed to fully understand complex relationship expression, adversities, psychopathology, our findings provide valuable insights into molecular mechanisms underlying mental disorders.

Language: Английский

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