American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

Obsessive-compulsive disorder (OCD) is a chronic, serious psychiatric disorder that affects 2-3% of the population and is associated with high personal and societal costs. Genetic factors are estimated to explain roughly half the risk of developing OCD, and genomic studies are just beginning to identify common and rare genetic variants mediating this risk. A major goal of genomic studies is to yield insights into the etiology of OCD and identify molecular targets for the development of novel the...

ImportanceObsessive-compulsive disorder (OCD) affects 2-3% of the population with often disabling obsessions and compulsions. Despite its high heritability, genetic studies of OCD have lagged other psychiatric disorders, particularly in understanding the role of rare genetic variants. ObjectiveTo identify rare coding genetic variants contributing to OCD risk and examine genetic overlap with chronic tic disorders (CTD) and other psychiatric conditions. DesignFamily-based and case-control whole-...

BackgroundTransdiagnostic genetic factor models organize shared liability across psychiatric disorders, but they may leave systematic pairwise genetic overlap unexplained. MethodsUsing publicly available PGC cross-disorder LD score regression genetic correlations and published five-factor genomic SEM parameters, we computed model-implied disorder correlations and derived edge-level residual genetic correlations (observed minus model-implied) for all disorder pairs. We summarized residual misfit...

Externalizing spectrum disorders--spanning attention-deficit/hyperactivity disorder, conduct disorder, substance use disorders, and other disorders characterized by disinhibition--frequently co-occur within individuals due, in part, to shared genetic etiology. To advance understanding of this genetic architecture, we conducted a multi-ancestry, multivariate genome-wide association analysis of more than 4 million individuals, identifying 1,294 genomic regions linked to an externalizing factor. Fi...

Major psychiatric disorders typically emerge in youth and exhibit shared and disorder-specific behavioral phenotypes and neuroanatomical alterations, yet the transdiagnostic neurobehavioral gradients and environmental interactions contributing to this heterogeneity remain poorly understood. Here, we present a transdiagnostic cohort of 1,755 youths aged 10-24 years, including 1,040 patients with bipolar disorder (BD), major depressive disorder (MDD), or schizophrenia spectrum disorder, and 715 he...

BackgroundWhile previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposition underlying suicidal behaviors in diverse populations. This study aimed to conduct a large-scale investigation of the suicidality spectrum (SP) to generate new insights into its biology and epidemiology. MethodsLeveraging ancestrally diverse participants (SI Ncase/control=179 881/1 01...

Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to "any anxiety diagnosis". Additional genome-wide evidence to discern genetic differences between fear ...

BackgroundSchizophrenia (SCZ) is a highly heritable and heterogeneous disorder with diverse clinical presentations and cognitive deficits. The specific genetic variants contributing to this variability remain largely unknown. This study aims to uncover the genetic bases of various clinical phenotypes such as age at onset (AAO), positive/negative symptoms, self-harm and aggression in SCZ using genome-wide association studies (GWAS). Few large-scale GWAS have explored these phenotypes, especially ...

Major depression (MD) is a disorder class that exhibits substantial phenotypic and clinical heterogeneity, yet many large-scale molecular genetic investigations treat MD as a unitary outcome. Here, we applied Genomic Structural Equation Modeling (Genomic SEM) to characterize the genetic variation in two clinically relevant MD subtypes, childhood-onset (child-onset) and treatment-resistant MD, that are independent of the field-standard GWAS of MD in all its forms. In addition, we fit a complement...

BackgroundBipolar disorder (BIP) frequently co-occurs with heightened substance use (SU) and substance use disorders (SUDs). Although the strong co-occurrence of these heritable traits points to shared genetic susceptibility, the extent to which there are differences in how SU and SUD overlap with BIP genetic architecture remains unclear. MethodsWe quantified the polygenic overlap between BIP and SUDs (alcohol, cannabis, opioid, and tobacco), and BIP and SU traits (drinks per week, lifetime can...

BackgroundLipidomic alterations have been reported across schizophrenia (SCZ) and bipolar disorder (BD), but findings are heterogeneous and often overlap across diagnoses, limiting diagnostic specificity. Associations between lipid profiles and illness severity have also been inconsistent when assessed using single symptom scales, raising the possibility that unidimensional measures fail to capture biologically relevant variation. Whether plasma lipidomic alterations relate to multidimensional p...

Prenatal alcohol exposure (PAE) disrupts embryonic development and gives rise to a variable fetal alcohol spectrum disorder (FASD) phenotype characterized by neurodevelopmental and dysmorphological defects. We investigated the effects of PAE on placental gene regulation by performing genome-wide DNA methylation (DNAm) microarray and gene expression (mRNA sequencing) analyses in 87 PAE, 77 unexposed control, and 11 smoking-exposed-only placentas. Significant alterations were identified in genes i...

BackgroundNeuropsychological deficits are common in obsessive-compulsive disorder (OCD) and may influence functional and treatment outcomes. Only a few studies have effectively targeted these deficits, with most failing to show broad transfer of training. This study aimed to evaluate the efficacy of an integrated cognitive control training (ICCT) program on neuropsychological functioning in OCD patients and assess related changes in clinical and socio-occupational functions. MethodA single-grou...

Neuroticism is a core personality trait linked to emotional instability and increased risk for anxiety, depression, and schizophrenia. Most genome-wide association studies (GWAS) have focused on European populations, limiting the discovery of ancestry-specific genetic influences. To address this gap, we conducted the most diverse multi-ancestry GWAS meta-analysis of neuroticism to date, analyzing 668,780 individuals across African (AFR), European (EUR), East Asian (EAS), and South Asian (SAS) po...

ImportanceLarge language models (LLMs) have demonstrated diagnostic potential in several medical specialties, but their application to psychiatry - where diagnosis relies heavily on clinical judgment, narrative interpretation, and reasoning under uncertainty - remains insufficiently evaluated. ObjectiveTo evaluate diagnostic accuracy and clinician-judged reasoning quality of multiple large language models using psychiatric case vignettes. DesignMixed-methods evaluation study of diagnostic accu...

BackgroundNegative symptoms (NS) such as anhedonia, avolition, asociality, blunted affect and alogia are associated with poor functional outcomes in psychiatric and neurological disorders and are an unmet treatment need. ObjectiveThis protocol describes the design of an observational, single-center study aimed at characterizing negative symptoms across a transdiagnostic sample of individuals with mental disorders and related conditions, with a particular focus on avolition, its biological corre...

BackgroundThe prevalences of suicidal ideation (SI) and suicide attempt (SA) are influenced by genetic, behavioral, and environmental factors. Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may mediate or moderate genetic liability for suicidality. MethodsUsing data from 10,275 participants (43.8% female; 47.2% African-like genetic ancestry [AFR], 52.8% European-like genetic ancestry [EUR]), we tested whether polygenic scores (PGS) for SI and SA predicted lifetime SI or SA....

Background and AimsSubstance use disorders (SUDs) are heritable and share genetic variance with externalizing and internalizing psychopathology. Although recent gene identification efforts have demonstrated the value of modeling the shared genetic architecture among SUDs and externalizing, most research has thus far failed to account for overlap with internalizing. In this study, we aim to characterize the genetic relationships of both externalizing and internalizing with SUDs. Design and setti...

BackgroundImpairments in cognitive functioning (CF) contribute to the onset, severity, and persistence of psychiatric symptoms. While specific CF domains may relate differentially to psychopathology, evidence also supports a general factor of cognitive impairment (the C-factor). We aimed to examine how general and domain-specific CF impairments relate to psychopathology using both diagnosis-specific and transdiagnostic symptom frameworks. MethodsData were drawn from five cognitive tasks adminis...

Obsessive-compulsive symptoms, characterized by intrusive thoughts and repetitive behaviors, are prevalent among youth. These symptoms are known to be moderately heritable and linked to structural brain changes involved in their pathophysiology. This study investigates the connections between structural brain alterations (cortical thickness, surface area and subcortical volume), genetic variation, and childhood obsessive-compulsive symptom scores within 143 samples of healthy control participant...