A cross-disorder analysis of CNVs finds novel loci and dose-dependent relationships of genes to psychiatric traits.

Rare copy number variants (CNVs) are a key component of the genetic basis of psychiatric conditions, but have not been well characterized for most. We conducted a genome-wide CNV analysis across six diagnostic categories (N = 574,965): autism (ASD), ADHD, bipolar disorder (BD), major depressive disorder (MDD), PTSD, and schizophrenia (SCZ). We identified 35 genome-wide significant associations at 18 loci, including novel associations in SCZ ( - ) and in the combined cross-disorder analysis ( ).

Genome-wide study of somatic symptom and related disorders identifies novel genomic loci and map genetic architecture.

Somatic symptom and related disorders (SSRD) are characterized by a mixture of neurological and psychiatric features and include functional neurological (FND) and somatic symptom disorders (SomD). While these complex neuropsychiatric disorders show evidence of genetic susceptibility, there are no genome-wide association studies (GWAS) of SSRD, and the heritability is unknown. We did a GWAS of a total of 22,203 patients with SSRD, and 1,831,107 controls of European ancestry.

Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects.

Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions.

Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap with metabolic markers.

Metabolic dysfunction is increasingly implicated in neurodegenerative diseases, yet the genetic architecture linking metabolic markers with Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear. We systematically analysed phenotypic and genetic relationships between 249 circulating metabolites with AD and PD, comparing patterns to body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD) and stroke. Using linkage disequilibrium score regression and bivariate Gaussian mixture modeling, we identified distinct genetic overlap.

Immune, Developmental, and Synaptic Pathways Define Bipolar Disorder Clinical Heterogeneity.

Importance: The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity.

Dissecting the Genetic Relationship Between Severe Mental Disorders and Autoimmune Diseases.

Severe mental disorders have been linked to immune system dysfunction. While a genetic association between mental disorders and autoimmune diseases has been suggested, their genetic relationship remains incompletely understood. Utilizing a complementary set of statistical analyses, we conducted a comprehensive investigation of the genetic architecture between severe mental disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and seven autoimmune diseases (autoimmune thyroiditis, celiac disease, inflammatory bowel disease (IBD), multiple sclerosis, psoriasis, rheumatoid arthritis, and type 1 diabetes), involving a total of 667,518 cases from 10 genome-wide association studies.

The Psychiatric Genomics Consortium: discoveries and directions.

Research by the Psychiatric Genomics Consortium (PGC) has advanced the discovery of common and rare genetic variations that contribute to the susceptibility to many psychiatric disorders and neurodevelopmental conditions. This Review reflects on major findings from the past 5 years of research by the PGC in five priority areas: discovery of common variants using genome-wide association studies; rare variation and its interplay with polygenic risk; using genetics to go beyond diagnostic boundaries; ascribing functional attributes to genomic discoveries; and developing and implementing processes for data sharing, outreach to various communities, and training. The insights gained in these domains frame the agenda for the next phase of PGC research.

The Landscape of Shared and Divergent Genetic Influences across 14 Psychiatric Disorders.

Psychiatric disorders display high levels of comorbidity and genetic overlap. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct, the majority of genetic signal is shared. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci shared across eight disorders.

Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder.

Mapping genetic convergence across brain structure, mental health, and cardiometabolic disease.

Individuals with psychiatric disorders frequently experience comorbid cardiometabolic conditions, complicating treatment and worsening health outcomes. Both psychiatric and cardiometabolic disorders have been individually associated with alterations in brain structure. Yet, it remains unclear whether these associations reflect a shared genetic basis that also contributes to their frequent co-occurrence.

Optimizing Genetic Ancestry Adjustment in DNA Methylation Studies: A Comparative Analysis of Approaches.

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs.

New Genomics Discoveries Across the Bipolar Disorder Spectrum Implicate Neurobiological and Developmental Pathways.

Bipolar disorder (BD) is a highly heritable mental disorder that affects millions of people worldwide. Our understanding of the genetic etiology and biological processes that underlie BD have greatly increased in recent years. Extensive progress has been made in identifying common variant signals for BD, and the polygenic score from the latest genome-wide association study (GWAS) may provide some clinical utility if combined with other risk factors for BD.

Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers.

Metabolites in plasma form biosignatures of a range of common complex human diseases. Discovering variants with pleiotropic effects across metabolites can reveal underlying biological mechanisms. We therefore performed uni- and multivariate genome-wide association studies (GWAS) on 249 circulating metabolic markers across 328,006 UK Biobank and Estonian Biobank participants.

Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region.

Relationship Between Problematic Alcohol Use and Various Psychiatric Disorders: A Genetically Informed Study.

Objective: Problematic alcohol use (PAU) adversely affects the clinical course of psychiatric disorders. Genetic studies have suggested that genetic factors underlie the co-occurrence of PAU with psychiatric disorders. This study aimed to elucidate shared genetic architectures, prioritizing genes that disorders may have in common.

Identification of risk variants and cross-disorder pleiotropy through multi-ancestry genome-wide analysis of alcohol use disorder.

Alcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies (GWASs) can provide new evidence regarding the aetiology of AUD. We report a multi-ancestry GWAS focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals [102,079 cases; European, 75,583; African, 20,689 (mostly African-American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent].

Polygenic overlap between subjective well-being and psychiatric disorders and cross-ancestry validation.

Subjective well-being (SWB) is important for understanding human behaviour and health. Although the connection between SWB and psychiatric disorders has been studied, common genetic mechanisms remain unclear. This study aimed to explore the genetic relationship between SWB and psychiatric disorders.

Recommendations for defining treatment outcomes in major psychiatric disorders using real-world data.

Although information from real-world data can be used to identify factors that aid treatment choice, there are no guidelines for the use of such data. The aim of this Review is to summarise and evaluate definitions of treatment outcomes for antidepressants, antipsychotics, and mood stabilisers when using real-world data, and to suggest standards for the field. Given that no standards for the use of these data in estimating treatment outcomes exist, variability is high for treatment outcome definitions.

Genetic insights into psychotic major depressive disorder: bridging the mood-psychotic disorder spectrum.

Background: Psychotic major depressive disorder (MDD), a subtype of MDD characterised by psychotic symptoms that occur exclusively during mood episode, is clinically significant yet underexplored genetically due to its rarity. This study comprehensively examines the genetic basis of psychotic MDD and elucidates its position within the mood-psychotic spectrum.

Methods: This population-based cohort study used Swedish and Danish registry data for over 5.

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.

Polygenic overlap with granulocyte counts identifies novel loci for clozapine metabolism and clozapine-induced agranulocytosis.

While clozapine is the most effective antipsychotic drug, its use is limited due to hematological adverse effects involving the reduction of granulocyte counts with potential life-threatening agranulocytosis. It is not yet possible to predict or prevent the risk of agranulocytosis, and the mechanisms are unknown but likely related to clozapine metabolism. Genome-wide association studies (GWASs) of clozapine metabolism and clozapine-induced agranulocytosis have identified few genetic loci.

Charting the shared genetic architecture of Alzheimer's disease, cognition, and educational attainment, and associations with brain development.

The observation that the risk of developing Alzheimer's disease is reduced in individuals with high premorbid cognitive functioning, higher educational attainment, and occupational status has led to the 'cognitive reserve' hypothesis. This hypothesis suggests that individuals with greater cognitive reserve can tolerate a more significant burden of neuropathological changes before the onset of cognitive decline. The underpinnings of cognitive reserve remain poorly understood, although a shared genetic basis between measures of cognitive reserve and Alzheimer's disease has been suggested.

Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder.

Background: Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified.

Methods: We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes.

Leveraging the Genetics of Psychiatric Disorders to Prioritize Potential Drug Targets and Compounds.

Background: Genetics has the potential to inform biologically relevant drug treatment and repurposing which may ultimately improve patient care. In this study, we combine methods which leverage the genetics of psychiatric disorders to prioritize potential drug targets and compounds.

Methods: We used the largest available genome-wide association studies, in European ancestry, of four psychiatric disorders [i.