Psychiatric disorders frequently co-occur with insulin resistance (IR)-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS). While genetic correlations have been reported, the genetics underlying this multimorbidity remains underexplored. Here, we investigate the joint genetic architecture of psychiatric-IR multimorbidity and explore links with the brain, tissue-specific gene expression, potential underlying biological mechanisms, and repurposable drugs. Genomic structural equation modeling (SEM) was applied to genome-wide association studies (GWAS) from five psychiatric disorders (attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), schizophrenia) and three IR-related conditions (MetS, obesity, T2DM) (N = 9725-933,970) previously showing pairwise genetic correlations. Factor analyses identified a latent genetic factor (Psych-IR factor) capturing shared genetics across psychiatric disorders (excluding schizophrenia) and IR-related conditions. Positive loadings were observed for ADHD, MDD, and IR-related conditions and negative loadings for AN and OCD. This factor showed genetic correlations with temporal, occipital, and total brain surface areas. A multivariate GWAS of the Psych-IR factor identified 150 associated loci and 366 genes (128 novel). Gene-set associations included insulin binding and Notch-signaling pathways, while gene-property analyses implicated the cerebellum, brain cortex, and pituitary gland, notably during prenatal development. Transcriptome-wide SEM (T-SEM) assessed tissue-specific gene expression associations and identified 499 genes (191 novel), including immune-related genes within the major histocompatibility complex (MHC) region. Drug repurposing analysis suggested six therapeutic candidates, including memantine and rosiglitazone. Enrichment of prioritized genes highlighted the chr16p11.2 region, BDNF-signaling, and lipid metabolism pathways. These findings advance understanding of the genetic and biological mechanisms underpinning psychiatric-IR multimorbidity, informing future research on precision medicine initiatives.

Abstract Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3 , and CELSR3 . Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.

One in five people attending services with a substance use disorder (SUD) also has comorbid attention-deficit/hyperactivity disorder (ADHD). While some evidence shows that shared heritability might partly explain this frequent comorbidity, studies on this topic are scarce. Therefore, the goal of this study was to test whether ADHD and SUD have shared genetic influences. A total of 1,513 SUD treatment-seeking individuals of European ancestry were included in the study. Polygenic risk scores (PRS) were applied to test a) the association of the PRS for ADHD with multiple SUD-related phenotypes, and b) the association of the PRS for SUDs (alcohol, cocaine, cannabis, opioid, and polysubstance use disorder) with ADHD-related phenotypes. Causality between ADHD traits and SUD-related phenotypes was tested by using one-sample Mendelian randomization analyses. PRS for ADHD significantly increased the likelihood of ever using heroin (R2 = 0.7 %, p < 0.001, ß = 0.20, SE = 0.06). PRS for opioid use disorder was significantly associated with ADHD inattentive symptoms (R2 = 0.6 %, p = 0.018, ß = 0.08, SE = 0.02) and with ADHD total symptom score (R2 = 0.6 %, p = 0.025, ß = 0.07, SE = 0.02). No evidence of causal relationships were found. The findings of this study highlight the genetic contribution to the relationship between ADHD and SUDs with some indication of overlap, particularly between ADHD and opioid use disorder.

Objectives Anterior cruciate ligament (ACL) rupture is a common and severe injury in athletes, influenced by both environmental and intrinsic factors. Genetic susceptibility has been suggested, but robust associations remain limited. We performed an exploratory genome-wide association study (GWAS) to identify genetic variants associated with ACL rupture in a well-characterised athlete cohort. Study design Case–control study. Methods A total of 607 participants of European ancestry were included: 401 patients with ACL rupture (293 unilateral, 108 bilateral) and 206 screened athlete controls with no history of ACL injury. Genotyping was performed using the Illumina Global Screening Array, and association analyses were conducted using logistic regression under an additive model, adjusting for population stratification. Results Several loci showed suggestive associations (p < 5×10⁻⁵), including variants in or near GALNT11, ITGAM, C10orf82, OR7E47P, HSPA12A, OPRD1, and NEK10. These genes are implicated in diverse biological processes, including inflammatory regulation, cellular stress responses, and ciliary function. No variants reached genome-wide significance (p < 5×10⁻⁸). Conclusions No genome-wide significant associations with ACL rupture were identified. However, several loci showed suggestive associations that highlight biological pathways related to inflammation, cellular stress responses, and ciliary function. These findings should be considered hypothesis-generating and require replication in larger independent cohorts before firm conclusions regarding their role in ACL injury susceptibility can be drawn.

BackgroundExcessive alcohol consumption is a global health issue and a leading cause of disease, disability, and mortality. This study aimed to determine the effects of a 24-hour ethanol exposure, post-exposure withdrawal (cessation of alcohol intake), and post-exposure withdrawal relief on the sensorimotor performance of the nematode Caenorhabditis elegans.MethodsA modified kinetic chemotaxis assay (commonly referred as "diacetyl race") was conducted with worm populations subjected to three different doses of ethanol pre-exposure to assess the impact of ethanol on locomotion. Additionally, we employed lifespan, mobility, gene expression analysis and imaging assays to evaluate health status and molecular alterations occurring in the worms under different levels of ethanol exposure.ResultsWild-type, dopamine receptor mutant and serotonin biosynthesis null mutant worms presented different responses to ethanol in the kinetic chemotaxis assay. Furthermore, exposure to ethanol altered vesicle exocytosis in dopaminergic and serotonergic neurons and the expression of a panel of genes associated with stress responses. Additionally, 24-hour ethanol exposure differentially influenced the lifespan of wild-type and mutant worms.ConclusionsDifferent responses, which may be relevant to the pathogenesis of human alcohol use disorder, were observed in wild-type worms, a dopamine receptor mutant, and a serotonin biosynthesis null mutant in a variety of assays performed. Furthermore, we present a 3-step experimental model for drug tolerance, based on the well-established kinetic chemotaxis behavioral paradigm ("diacetyl race"). This model provides new insights into the effects of alcohol in worms, particularly regarding the roles of dopamine and serotonin neurotransmission. Importantly, this model holds potential for investigating the effects of other addictive substances beyond alcohol.

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

Background: Religiousness has been positively associated with better mental health and stronger self-control, including in patients with substance use disorders (SUDs) or attention deficit/hyperactivity disorder (ADHD). However, data on religiousness in patients with SUD and comorbid ADHD are lacking. Objectives: This study aims to test in patients with SUD and comorbid ADHD whether (1) religiousness is negatively associated with SUD and ADHD symptom severity, and (2) self-control mediates the assumed negative association of religiousness with SUD and ADHD symptom severity. Method: In an international cohort study, baseline religiousness, self-control, SUD and ADHD symptom severity, and craving were assessed with self-report questionnaires and structured clinical interviews in 578 treatment-seeking SUD patients with comorbid adult ADHD (SUD + ADHD). Data were analyzed using structural equation modeling (SEM). Results: Stronger self-control wad associated with lower severity of both ADHD and SUD, but higher religiousness was only associated with lower severity of ADHD. This association was not mediated by self-control. Conclusion: Religiousness may have a salutary relationship with ADHD severity, but not with SUD severity. While self-control was associated with lower symptom severity for both co-occurring conditions, it may not be involved in the potentially salutary effects of religiousness in patients with SUD + ADHD.

BACKGROUND:Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS:We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS:We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS:Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Background: Treatment of attention-deficit/ hyperactivity disorder (ADHD) in patients with a substance use disorder (SUD) and comorbid ADHD (SUD +ADHD) may have positive effects on the outcome of both conditions, but controversy exists regarding the preferred ADHDtreatment in these patients. Little is known about the treatments that are provided for these patients in routine addiction care practice and the factors that are associated with treatment provision. Objective: To describe the treatments provided in everyday clinical practice and to explore factors associated with ADHD treatment provision in patients with SUD + ADHD. Methods: An international multicenter observational prospective cohort design was employed. Patients with moderate to severe SUD and comorbid ADHD according to DSM-5 were invited to participate at the start of a new SUD treatment episode between June 2017 and May 2021. Clinical and sociodemographic data were collected at 12 study sites in 9 countries through patient interviews, interviews with treatment providers, and patient files. Treatment variation across studies was described, and mixed-effect logistic regression was used to identify factors associated with ADHD treatment provision. Results: A total of 578 treatment-seeking patients with SUD + ADHD (274 inpatients, 303 outpatients, and 1 unknown) were recruited. About twothirds received some kind of ADHD treatment (62.8%), with 54.0% receiving pharmacologic, 34.0% receiving psychological treatment, and 25.1% receiving combined pharmacologic and psychological treatment. The treatment site explained more of the variation in ADHD treatment provision than individual patient factors. In addition, higher ADHD symptom severity and sobriety at intake were associated with receiving ADHD treatment. Conclusion: These findings suggest that treatment of SUD + ADHD patients is suboptimal even in specialized centers with substantial practice variation. Further research is needed to better understand the barriers to implement treatment guidelines for ADHD + SUD and, thus, to improve quality of care. Trial Registration: ISRCTN: 15998989 20/12/2019 (https://doi.org/10.1186/ ISRCTN15998989)

Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

The PRIME (Prevention and Remediation of Insulin Multimorbidity in Europe) project aims to investigate the correlation between insulin-related somatic disorders and brain disorders. Previous research within the project has demonstrated shared genetic factors among these disorders. Besides genetic factors, environmental factors may also contribute to their development. Cells can respond and adapt to environmental changes by modifying their gene expression, a process influenced by epigenetic mechanisms like chromatin remodeling. We utilized the H-MAGMA software to conduct gene-based analysis incorporating chromatin interaction profiles (Hi-C data) from human brain tissues. This approach allowed us to extract valuable biological insights from genome-wide association study (GWAS) summary statistics. Epigenetic analyses were performed on 21 pairs of three insulin-related somatic diseases and seven neuropsychiatric disorders using cross-disorder GWAS summary statistics and chromatin interaction profiles from human brain tissues. Our analysis revealed significant gene-based associations for all pairs of disorders. We identified several genes that were shared across multiple disorders, which are known to have relevant neurobiological functions and have previously been associated with the investigated disorders. Notable genes among the frequently overlapping ones include RHOA, IHO1, NDUFAF3, PKHD1, CCDC71, TMEM219, AMT, ARIH2, NPIPB11, QRICH1, TAOK2, and BANK1, showing significant associations across various disorder pairs. RHOA, CCDC71, and TAOK2 have previously been linked to both somatic insulin-related disorders and neurodevelopmental disorders. Subsequently, we performed a Gene Ontology analysis on genes that were significant in at least three disorder pairs in our cross-disorder analyses (n=420 genes). The Gene Ontology analysis indicated enrichment in three major biological process domains ("epigenetics," immune system, and mitochondrial organization), as well as a few minor domains. These findings suggest the potential involvement of these processes in the multimorbidity between somatic and brain insulin-related disorders. In the ``epigenetics'' domain specifically, we identified genes associated with covalent chromatin modifications, histone modifications, lysine acetylation, and various protein modifications. Importantly, the enrichment of genes in the epigenetics-related domain is independent of the original use of the H-MAGMA method. Our findings provide valuable insights into the intricate relationship between somatic and brain insulin-related disorders, emphasizing the significance of epigenetic factors. The results support previous findings within the PRIME project and contribute to the understanding of shared genetic and environmental factors underlying these disorders. Further research is necessary to validate these findings and explore the mechanisms behind the comorbidity observed between somatic and brain insulin-related disorders. The insights gained from this study have the potential to aid in the development of targeted interventions and personalized medicine approaches for individuals with co-occurring somatic and psychiatric disorders.

Additional file 1. Age adjusted prevalence data of the 14 disorders in 24 global populations.

Complex disorders are caused by a combination of genetic, environmental and lifestyle factors, and their prevalence can vary greatly across different populations. The extent to which genetic risk, as identified by Genome Wide Association Study (GWAS), correlates to disease prevalence in different populations has not been investigated systematically. Here, we studied 14 different complex disorders and explored whether polygenic risk scores (PRS) based on current GWAS correlate to disease prevalence within Europe and around the world. A clear variation in GWAS-based genetic risk was observed based on ancestry and we identified populations that have a higher genetic liability for developing certain disorders. We found that for four out of the 14 studied disorders, PRS significantly correlates to disease prevalence within Europe. We also found significant correlations between worldwide disease prevalence and PRS for eight of the studied disorders with Multiple Sclerosis genetic risk having the highest correlation to disease prevalence. Based on current GWAS results, the across population differences in genetic risk for certain disorders can potentially be used to understand differences in disease prevalence and identify populations with the highest genetic liability. The study highlights both the limitations of PRS based on current GWAS but also the fact that in some cases, PRS may already have high predictive power. This could be due to the genetic architecture of specific disorders or increased GWAS power in some cases.

The Prevention and Remediation of Insulin Multimorbidity in Europe (PRIME) project aims to investigate the comorbidity of brain and somatic disorders, with a particular focus on metabolic conditions. Previous studies carried out as part of this project have provided evidence of genetic factors common to these disorders. This study delves into the cellular aspects of these disorders and their shared biological underpinnings using single-cell data and multi-omics. In this study, we leveraged the sc-linker framework to integrate single-cell RNA-sequencing (scRNA-seq) data, epigenomic SNP-to-gene maps, and genome-wide association study (GWAS) summary statistics to identify relevant cell types and processes associated with comorbid brain and metabolic disorders, emphasizing insulin multimorbidity. We examined type 2 diabetes (T2D) and several brain disorders in brain tissue, as well as in the liver, which plays a critical role in metabolism, and the colon to explore the association between these tissues and brain/metabolic disorders using single-cell data. The analysis revealed intriguing associations between type 2 diabetes (T2D) and γ-aminobutyric acid-ergic (GABAergic) inhibitory neurons within the brain. GABAergic neurons, known for their role in neural signaling and inhibitory control, were associated with T2D, suggesting the involvement of neural circuitry dysregulation in insulin-related metabolic disorders. Furthermore, the investigation of liver scRNA-seq data shed light on a specific association between major depressive disorder (MDD) and T2D with dendritic cells in the liver. Dendritic cells are involved in immune response modulation, highlighting the connection between immune dysregulation and T2D multimorbidity. Additionally, the analysis of colon tissue provided evidence linking colonel adipocytes to MDD and T2D, indicating potential shared molecular signatures and underlying biological mechanisms in adipose tissue. The findings contribute to understanding the cellular mechanisms underlying brain-metabolic disorder comorbidity, particularly in T2D. By integrating scRNA-seq, epigenomic information, and GWAS summary statistics, GABAergic inhibitory neurons were identified as potential cellular components of T2D within the brain. Furthermore, the study suggests a disease-specific involvement of dendritic cells in both MDD and T2D in the liver, emphasizing the contribution of immune-related processes to metabolic dysfunction. Additionally, the adipose-related results highlight the significance of lipid metabolism in the shared biology of T2D and brain disorders. The integration of multi-omics data through the sc-linker framework provides valuable insights into the shared biology of brain and metabolic disorders, paving the way for targeted therapeutic interventions. The results highlight the potential importance of neural circuitry dysregulation, immune-related processes, and lipid metabolism in the pathogenesis and comorbidity of brain and metabolic disorders. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847879.