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.

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 therapeutics. However, the overwhelming majority of subjects in existing genetic studies are of European ancestry, limiting the generalizability of these findings. To address this gap in understanding, we established the Black EquaLity in OCD NeuroGenomics (BELONG) study ( https://belongocd.com/ ). BELONG aims to collect DNA and clinical data from 1,250 richly phenotyped OCD cases of African ancestry in a culturally sensitive manner. In addition, BELONG includes the collection of parental DNA samples for trio-based analyses and unrelated matched controls for case-control analysis. DNA samples will be sequenced using optimized approaches that will allow us to examine both rare and common genome-wide variation to identify OCD risk genes. We will also meta-analyze these data with other existing OCD genomic data. Overall, BELONG will increase the representation of Black Americans in OCD genetic research, which is necessary to generalize precision medicine discoveries in psychiatric genetics.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by symptoms that emerge in childhood and often improve or even disappear in adulthood, providing a model for understanding how altered brain development shapes neural structure and function. We investigate brain structural alterations in TS and Chronic Tic Disorders (TS/CTD) across development, presenting the largest structural neuroimaging analysis for TS/CTD to date (1,803 individuals from the ENIGMA-TS Working Group), and integrating with large-scale genomewide association studies. Nonlinear age effects were observed in cortical thickness across development and in thalamic volume in children, indicating altered trajectories of brain maturation. Pediatric and adult TS/CTD showed distinct structural patterns, with widespread alterations in childhood and more focal changes in adulthood. Children also showed the most prominent effects highlighting the involvement of orbitofrontal cortex and putamen, alongside additional regions such as frontal and paralimbic areas. Genetic pleiotropy analyses identified overlap between TS/CTD-associated genetic effects on brain structure and neuroanatomical differences. Cross-disorder comparisons revealed correlations with ADHD and OCD and age-related patterns. These findings demonstrate altered neurodevelopmental trajectories in TS/CTD and implicate systems underlying inhibitory control and urge regulation.

Eating disorder (ED) and obsessive-compulsive disorder (OCD) exhibit clinical and genetic overlap, yet whether they converge at the molecular level in the human brain is unknown. We perform large-scale transcriptomic profiling of the dorsolateral prefrontal cortex (DLPFC) and caudate in postmortem tissue from 86 controls, 57 individuals with ED, and 27 with OCD. ED shows robust, region-specific transcriptional dysregulation (102 differentially expressed genes [DEGs] in DLPFC and 222 in caudate at FDR <1%) that replicates in an independent cohort. OCD shows no single-cohort DEGs, but meta-analysis across three datasets identifies 57 caudate-associated genes. Despite these differences, transcriptome-wide effects strongly correlate between ED and OCD (DLPFC r = 0.67; caudate r = 0.75), indicating shared molecular pathology. Joint ED + OCD analysis identifies 233 DEGs in DLPFC and 815 in caudate, implicating GABAergic signaling, neuroendocrine regulation, mitochondrial metabolism, and CHD8-associated networks. Genetically regulated expression analyses identifies five genes (WDR6, NCKIPSD, P4HTM, DALRD3, and SHISA5) with convergent risk associations across disorders and brain regions, all mapping to a gene-dense region on chromosome 3. These findings define a shared cortico-striatal transcriptional architecture and identify candidate genes for transdiagnostic intervention.

Objective:Obsessive-compulsive disorder (OCD) frequently co-occurs with bipolar disorder (BD) or schizophrenia (SCZ), and, importantly, can often precede their onset. However, the genetic architecture and directionality underlying these relationships remain unclear. We leveraged large-scale genome-wide association study (GWAS) data to examine shared genetic architecture and directional relationships among OCD, BD and SCZ, and used major depressive disorder (MDD) as a comparator. Methods:Using linkage disequilibrium score regression (LDSC), MiXeR, and Generalized Summary-data-based Mendelian Randomization (GSMR) as well as complementary Mendelian randomization approaches, we characterized genetic correlations, polygenic overlap (Dice coefficient), and effect direction concordance (ρβ) across disorders. Results:We observed substantial genetic correlations between OCD and BD (rg=0.37), BD type 2 (BD2) (rg=0.54), and SCZ (rg=0.39), with a large proportion of shared causal variants between OCD and both BD (Dice=0.85) and SCZ (Dice=0.84). MiXeR analyses indicated that OCD and BD2 share a smaller proportion of causal variants (Dice=0.57) but there is a high concordance of effect directions amongst these causal variants (ρβ=0.96), whereas OCD and MDD showed minimal overlap but strong concordance among shared variants (Dice=0.09, ρβ=1). Directional GSMR and complementary TwoSampleMR analyses supported a causal effect of genetic risk to OCD on liability to BD (b=0.20, p=1.5×10), SCZ (b=0.52, p=9.5×10 21), and MDD (b=0.24, p=1.06×10), with little evidence for reverse causal effects. Conclusions:Together, these findings indicate that genetic liability to OCD can represent an early component of transdiagnostic psychiatric risk, with implications for understanding and potentially predicting the emergence of broader psychopathology across the life course.

Psychiatric disorders are highly heritable and polygenic, influenced by environmental factors and often comorbid. Large-scale genome-wide association studies (GWASs) through consortium efforts have identified genetic risk loci and revealed the underlying biology of psychiatric disorders and traits. However, over 85% of psychiatric GWAS participants are of European ancestry, limiting the applicability of these findings to non-European populations. Latin America and the Caribbean, regions marked by diverse genetic admixture, distinct environments and healthcare disparities, remain critically understudied in psychiatric genomics. This threatens access to precision psychiatry, where diversity is crucial for innovation and equity. This Review evaluates the current state and advancements in psychiatric genomics within Latin America and the Caribbean, discusses the prevalence and burden of psychiatric disorders, explores contributions to psychiatric GWASs from these regions and highlights methods that account for genetic diversity. We also identify existing gaps and challenges and propose recommendations to promote equity in psychiatric genomics.

Genetic factors play a central role in the risk for developing obsessive-compulsive disorder (OCD), a finding established through twin, family, and large-scale cohort studies. Current genetic research aims to identify the specific genetic and genomic variants contributing to OCD risk.1 This involves investigating both common genetic variation-studied through genome-wide association studies (GWAS)-and rare genetic and genomic variation-studied through genome/exome sequencing or chromosomal microarray.

OBJECTIVE:The authors provide recommendations on incorporating recent advances in psychiatric genetics into clinical practice for mental health clinicians. METHOD:The International Society for Psychiatric Genetics Education Committee met monthly to come to a consensus on priority topics in psychiatric genetics. Topics were then assigned to small teams of subspecialty experts to summarize the current knowledge base and create an illustrative clinical case. Topics included, familial aggregation, common and rare genetic variants, epigenetics, gene-environment interactions, pharmacogenomics, genetic counseling, and ethical and social implications. Each section was reviewed and revised by all committee members and then finalized by the Committee Chair. RESULTS:Key findings highlight the importance of understanding the genetic architecture of psychiatric disorders, the potential applications of genetic information in risk assessment, diagnosis, treatment selection, and patient education, as well as the ethical and social considerations surrounding the use of genetic data. The committee emphasizes the need for a nuanced approach that integrates genetic factors with environmental and experiential factors in a holistic model of care. CONCLUSION:As psychiatric genetics continues to evolve rapidly, mental health clinicians must stay informed about the latest findings and their clinical implications. Ongoing education, collaboration with genetics professionals, and effective communication strategies are crucial to harness the power of genetics while avoiding potential pitfalls such as genetic determinism and stigma. The committee recommends a balanced perspective that recognizes the complex interplay of genetic and non-genetic factors in shaping mental health outcomes.

Importance:Obsessive-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. Objective:To identify rare coding genetic variants contributing to OCD risk and examine genetic overlap with chronic tic disorders (CTD) and other psychiatric conditions. Design:Family-based and case-control whole-exome sequencing (WES) study. Settings:WES data were aggregated from 11 independent cohorts across Sweden, the United States, and the United Kingdom. Participants:A total of 47,194 individuals were available, and 44,089 passed quality control for analysis. The final sample included 6,071 individuals with OCD, comprising 1,202 probands from family-based trios and 4,869 cases, and 38,018 controls. Exposures:Rare damaging coding variants identified by WES. Main Outcomes and Measures:Identification of OCD risk genes through rare variant analyses, meta-analysis with CTD data, gene-set enrichment analyses, and evaluation of cross-disorder genetic overlap using curated gene sets. Results:The analysis provided an estimate of approximately 470 autosomal genes contributing to OCD risk through rare genetic variation. CHD8 reached genome-wide significance (q < 0.05). Meta-analysis with CTD data revealed additional risk genes, including CELSR3 (q < 0.05), QRICH1, and WWC1 (q < 0.1). We observed significant genetic overlap between OCD, autism spectrum disorder (ASD), and developmental delay: 33% of ASD genes with FDR < 0.1 showed association with OCD (p < 0.001), and 36% showed possible associations in the shared OCD-CTD genetic architecture (p < 0.001), but minimal rare-variant overlap with bipolar disorder and schizophrenia risk genes. We also found that CHD8-regulated genes were enriched for both rare and common variant associations with OCD. Conclusions and Relevance:In this largest study to date of rare coding variation in OCD, we confirm CHD8 as the first genome-wide significant rare-variant risk gene, show that genes that are targets of CHD8 can carry rare and common variant risk for OCD, and identify multiple additional genes and pathways contributing to risk. Taken together, the findings show that OCD shares substantially greater genetic overlap with neurodevelopmental conditions than with adult-onset psychiatric disorders, refining the developmental framework of OCD and informing future mechanistic and clinical research.

Lower urinary tract symptoms (LUTS) in children and young adults are common and can significantly impact quality of life. While prior studies suggest a genetic component, the extent of familial aggregation and heritability remains unclear. To estimate the familial aggregation and heritability of LUTS in a nationwide cohort of children and young adults. This population-based cohort study used data from Swedish national registers to identify all live-born singleton children in Sweden between January 1, 1995, and December 31, 2005, with follow-up through December 31, 2018. Familial relationships were determined using the Swedish Multi-Generation Register, and LUTS cases were identified using ICD-10 diagnoses and prescription data from the Swedish National Patient Register and Swedish Prescribed Drug Register. Family history of LUTS, defined by sibling and cousin relationships. Familial aggregation of LUTS was assessed by estimating relative recurrence risks (RRs) with 95% CIs among siblings and cousins of affected individuals. Heritability was estimated using Falconer’s Liability Threshold Model. Among 982,903 individuals, LUTS cases were identified using ICD-10, narrow ICD-medication, and broad ICD-medication definitions. Familial aggregation was strongest among siblings, with relative risks of 7.41 (95% CI, 5.72–9.60; P < .001) for storage LUTS and 6.53 (95% CI, 2.09–20.38; P = .001) for voiding LUTS using the narrow ICD-medication definition. Cousin recurrence risks were lower, supporting a genetic contribution to LUTS. Sex-specific analyses showed higher familial aggregation in same-sex sibling pairs, particularly for voiding LUTS in female-female pairs (RR, 14.22; 95% CI, 1.97–102.82; P = .009). Heritability estimates further supported a genetic basis for LUTS. Storage LUTS heritability was 55% (95% CI, 45.5%–64.7%) using the narrow ICD-medication definition and 48% (95% CI, 46.8%–48.6%) using the broad definition. Voiding LUTS heritability was lower, at 40% (95% CI, 37.6%–43.2%) and 26% (95% CI, 14.8%–37.7%) for the narrow and broad definitions, respectively. These findings provide strong evidence for a genetic contribution to LUTS in children and young adults, with higher familial aggregation among closely related individuals and same-sex sibling pairs. The moderate to high heritability estimates suggest that genetic factors play a key role in LUTS susceptibility, with potential sex-specific influences. These findings may inform risk stratification, early intervention strategies, and future genetic research. To what extent do genetic factors contribute to lower urinary tract symptoms (LUTS) in children and young adults? In this population-based cohort study of 982,903 individuals, LUTS exhibited strong familial aggregation, with siblings of affected individuals having up to a 7.41-fold increased risk. Heritability estimates ranged from 26% to 55%, suggesting a substantial genetic contribution. These findings support a strong genetic basis for LUTS, with potential sex-specific genetic influences, highlighting the need for risk prediction and genetic research in LUTS.

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. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

OBJECTIVE:Previous studies have shown that parental factors are associated with an increased risk for attention deficit hyperactivity disorder (ADHD). However, the pathways by which parental factors are associated with risk of ADHD in offspring are not well understood. These associations can arise directly from parental genotypes inherited by offspring, and/or via environmental effects, some of which may themselves be influenced by the parental genotype (i.e., parental genetic nurture). This study specifically examined the impact of the maternal phenotype on offspring ADHD risk, above and beyond the direct genetic effect of maternally inherited genes. METHODS:The study population consisted of 982,544 individuals from the Swedish Medical Birth Register. The authors partitioned the liability of ADHD into direct additive genetic effect, maternal genetic nurture effect, and maternal common environment effect. RESULTS:A total of 66,707 (7%) individuals with an ADHD diagnosis were identified in the birth cohort. Maternal half-siblings were associated with a higher ADHD risk compared to paternal half-siblings, suggesting maternal effect. Estimates indicated 66.1% direct additive genetic effect (95% credible interval=0.647, 0.676) and 14.3% maternal genetic nurture effect (95% credible interval=0.136, 0.151). Additionally, evidence for substantial assortative mating among individuals with ADHD was observed. CONCLUSIONS:The findings indicate that maternal genotypes influence offspring's risk of ADHD through environmental pathways beyond the effects of direct genetic transmission. Exploring the impact of the genetics of the mother beyond the maternally inherited genes can lead to new insights into ADHD risk. Future studies should also investigate paternal effects to provide a more comprehensive understanding of the ADHD risk architecture.

Abstract Child psychiatry is a specialized discipline. The child psychiatry patient must be considered within the context of their current psychiatric signs and symptoms, psychosocial history, developmental stage, family structure, and any medical or neurological factors. The clinician should conduct a comprehensive assessment, including collateral sources, in order to consolidate a sound working diagnosis and treatment plan. Compared to adult psychiatry, the depth and breadth of research regarding medication and psychosocial treatments in youth are limited; however, evidence-based treatments, both pharmacological and psychotherapeutic, continue to emerge for many childhood-onset psychiatric disorders. Psychopharmacology is considered the first-line approach for attention-deficit/hyperactivity disorder, bipolar disorder, and psychotic illnesses, and it is also indicated for moderate to severe presentations of depressive and anxiety disorders, obsessive–compulsive disorder (OCD), and Tourette disorder. Specialized psychotherapies are first-line treatments for autism and mild to moderate depressive and anxiety disorders, OCD, and Tourette disorder.

BACKGROUND:SHANK2 disorder is a rare neurodevelopmental disorder caused by a deletion or pathogenic sequence variant of the SHANK2 gene and is associated with autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay. To date, research in SHANK2 has focused on laboratory-based in vivo and in vitro studies with few prospective clinical studies in humans. METHODS:A remote assessment battery was comprised of caregiver interviews with a psychiatrist, psychologists, and a genetic counselor, caregiver-reports, and review of records. Results from this cohort were reported using descriptive statistics. An age-matched sample of participants with SHANK3 haploinsufficiency (Phelan-McDermid syndrome, PMS) was used to compare adaptive behavior between the two groups. RESULTS:All ten participants demonstrated delays in adaptive behavior, with most motor skills preserved and a weakness in communication. According to parent report, 90% of participants carried a formal diagnosis of ASD, 50% of participants carried a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and mild-to-moderate developmental delays were noted. Sensory hyperreactivity and seeking behaviors were more pronounced than sensory hyporeactivity. Medical features included hypotonia, recurrent ear infections, and gastrointestinal abnormalities. No similar facial dysmorphic features were observed. Compared to PMS participants, individuals with SHANK2 disorder had significantly higher adaptive functioning. CONCLUSIONS:Consistent with previous studies of SHANK2 disorder, these results indicate mild to moderate developmental impairment. Overall, SHANK2 disorder is associated with developmental and adaptive functioning delays, high rates of autism, including sensory symptoms and repetitive behaviors, and ADHD. This study was limited by its remote nature, diverse age range, and the homogeneous racial and ethnic sample. Future studies should examine larger, diverse cohorts, add cognitive testing, capture longitudinal data, and include in-person assessments.

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.

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.

DDX3X syndrome is a surprisingly common newly discovered genetic neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, language delays, attention-deficit/hyperactivity disorder, and medical comorbidities. Two hundred individuals with DDX3X syndrome have been described in the literature to date, with varied levels of detail. Individuals with DDX3X syndrome often have complex presentations including symptoms in the neurological, psychiatric/psychological, ophthalmologic, and gastrointestinal domains. Owing to this complex presentation, an overview of symptom prevalence, medical recommendations, and suggested medical surveillance is vital for the care and health of individuals with DDX3X syndrome. In this article, we summarize the present clinical knowledge of DDX3X syndrome and provide recommendations for clinical assessments and care based on a comprehensive review of the existing literature and of new, not yet published DDX3X syndrome cohorts. As more is learned about DDX3X syndrome, we anticipate that these recommendations will evolve.

BACKGROUND:Risk for Tourette disorder, and chronic motor or vocal tic disorders (referenced here inclusively as CTD), arise from a combination of genetic and environmental factors. While multiple studies have demonstrated the importance of direct additive genetic variation for CTD risk, little is known about the role of cross-generational transmission of genetic risk, such as maternal effect, which is not transmitted via the inherited parental genomes. Here, we partition sources of variation on CTD risk into direct additive genetic effect (narrow-sense heritability) and maternal effect. METHODS:The study population consists of 2 522 677 individuals from the Swedish Medical Birth Register, who were born in Sweden between 1 January 1973 and 31 December 2000, and followed for a diagnosis of CTD through 31 December, 2013. We used generalised linear mixed models to partition the liability of CTD into: direct additive genetic effect, genetic maternal effect and environmental maternal effect. RESULTS:We identified 6227 (0.2%) individuals in the birth cohort with a CTD diagnosis. A study of half-siblings showed that maternal half-siblings had twice higher risk of developing a CTD compared with paternal ones. We estimated 60.7% direct additive genetic effect (95% credible interval, 58.5% to 62.4%), 4.8% genetic maternal effect (95% credible interval, 4.4% to 5.1%) and 0.5% environmental maternal effect (95% credible interval, 0.2% to 7%). CONCLUSIONS:Our results demonstrate genetic maternal effect contributes to the risk of CTD. Failure to account for maternal effect results in an incomplete understanding of the genetic risk architecture of CTD, as the risk for CTD is impacted by maternal effect which is above and beyond the risk from transmitted genetic effect.