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.

Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and rare genetic variation remain poorly understood. Leveraging data from Swedish national registers and genomic data from the All of Us Research Program, we estimated family-based heritability at 55% and whole-genome sequencing-based heritability at 46%. Rare coding variant analysis identified HMGCR as a gene in which rare damaging variants confer risk for postpartum psychosis (FDR < 0.05). Analyses of 240,009 participants from the All of Us Research Program and 58,990 participants from the Mount Sinai BioMe Biobank identified significant associations linking deleterious rare variants in HMGCR to vascular dementia and mental disorder, not otherwise specified, supporting the gene's broader psychiatric relevance. Additionally, among the top 200 genes ranked by association statistics, 17% of bipolar disorder, 21% of schizophrenia, and 16-25% of multiple autoimmune disorders exhibit a possible association with postpartum psychosis. These findings reveal unique genetic contributions and shared pathways, providing a foundation for understanding pathophysiology and advancing therapeutic strategies.

Autism Spectrum Disorder (ASD) arises from complex genetic and environmental factors, with inherited genetic variation playing a substantial role. This study introduces a novel approach to uncover moderate effect size (MES) genes in ASD, which individually do not meet the ASD liability threshold but collectively contribute when paired with specific other MES genes. Analyzing 10,795 families from the SPARK dataset, we identified 97 MES genes forming 50 significant gene pairs, demonstrating a substantial association with ASD when considered in tandem, but not individually. Our method leverages familial inheritance patterns and statistical analyses, refined by comparisons against control cohorts, to elucidate these gene pairs' contribution to ASD liability. Furthermore, expression profile analyses of these genes in brain tissues underscore their relevance to ASD pathology. This study underscores the complexity of ASD's genetic landscape, suggesting that gene combinations, beyond high impact single-gene mutations, significantly contribute to the disorder's etiology and heterogeneity. Our findings pave the way for new avenues in understanding ASD's genetic underpinnings and developing targeted therapeutic strategies.

Rare deleterious variants in SHANK3 are established causes of autism spectrum disorder (ASD), but the extent to which they define a phenotypically and genetically coherent ASD subgroup remains unclear. Using the SPARK cohort, we identified 132 SHANK3 variant carriers; 108 had phenotype data and were compared with 47,555 non-carrier ASD cases. SHANK3 damaging variant carriers showed lower cognitive ability, poorer motor coordination, and delayed developmental milestones. Protein-truncating variant and deletion carriers showed similarly severe phenotypic profiles, whereas duplication carriers did not differ from non-carriers. A combined threshold of intelligence quotient (IQ) < 70 and impaired motor coordination (DCDQ total score) < 35 defined a discriminative cognitive-motor phenotype among cases meeting this cognitive-motor phenotype. Beyond SHANK3 , SLC6A1 was the only additional gene reaching false discovery rate significance, while pathway analyses implicated synaptic and chromatin-related processes. Phenotype-meeting cases did not show elevated ASD polygenic risk, supporting a rare-variant-enriched cognitive-motor subgroup within ASD.

Objective: Autistic individuals may face elevated risk for PTSD, yet the degree to which this risk differs by sex remains unknown. We examined the association between autism and incident PTSD, characterized sex differences in risk, identified high-risk subgroups, and described post-diagnosis clinical trajectories. Method: We conducted a population-based matched cohort study using Swedish national registers. Individuals born 1990 through 2010 were followed from age 6 years through December 31, 2017. Autistic individuals (N=42,862) were matched 1:10 to controls (N=412,251) on sex and birth year. Cox proportional hazards regression estimated hazard ratios (HRs) for incident PTSD. Among those who developed PTSD, we compared care utilization, hospitalization rates, and persistence of care contacts. Results: During mean follow-up of 5.1 years, 401 autistic individuals (0.9%) and 903 controls (0.2%) developed PTSD (incidence rates: 18.3 vs 4.2 per 10,000 person-years). Autism was associated with 4.4-fold increased PTSD risk (HR=4.37; 95% CI, 3.93-4.86). Risk was higher among females (HR=4.79) than males (HR=3.39; P interaction=.006). Among autistic individuals, comorbid ADHD conferred additional risk (HR=1.38; 95% CI, 1.14-1.68). Ten-year cumulative incidence reached 6.0% among autistic females with ADHD. Autistic individuals with PTSD had higher care utilization (mean visits: 5.0 vs 3.9; P<.001), more psychiatric hospitalizations (27.9% vs 19.8%; P=.002), and more persistent courses (24.8% vs 12.3% with contacts in all 3 post-diagnosis years; P=.001). Conclusion: Autism is associated with substantially elevated PTSD risk, particularly among females with comorbid ADHD. When PTSD occurs, autistic individuals experience more severe and persistent clinical courses, supporting targeted screening and sustained follow-up.   ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by a grant from the Beatrice and Samuel A. Seaver Foundation (BM, SS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Regional Ethical Review Board in Stockholm approved this study (Dnr 2013/862-31/5). Swedish law permits register-based research without individual consent when data are anonymized. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data may be obtained from a third party and are not publicly available. Data cannot be shared publicly owing to restrictions by law. Data are available from the National Medical Registries in Sweden after approval by the Swedish Ethical Review Authority.

Autism spectrum disorder (ASD) is estimated to be up to four times as common in males as in females, yet the causes of this prevalence difference are not well established. One possible driver is genetic variation on the X chromosome, as it contains genes capable of contributing to ASD (e.g., PTCHD1, MECP2) and is known to play a role in genetic disorders with differential sex prevalence (e.g., color blindness). However, a lack of power compared to the autosomes combined with the complexities of modeling its biology have led to the X being largely overlooked in sequencing studies. Here, we develop quantitative X-linked TADA, a new model designed specifically for application to this chromosome, and use it to analyze rare variation from 50,663 individuals with ASD (and 136,670 individuals total). We find 9 genes on the X associated with ASD at a false discovery rate (FDR) < 0.05 and an additional 9 genes at FDR < 0.2, with many of these previously identified as involved in specific neurodevelopmental disorders. Point estimates of the liability conferred by de novo variants on the X are similar in females and males, with both sexes' estimates elevated >20% above the corresponding autosomal values. We also develop a general theory of how X-linked variation of any additive or non-additive effect influences liability and describe its implications for prevalence. Using this theory and our empirical results, we show how genetic variation on the X could contribute to the sex-differential prevalence of ASD.

Objective: Parental prenatal mood and anxiety disorders (PMAD) are linked to child neurodevelopmental disorders (NDDs), but evaluations of the magnitude and mechanisms of this association are limited. This study estimates the strength of the association and whether it is impacted by genetic and environmental factors. Method: A systematic search of PubMed, CENTRAL, PsycINFO, OVID, and Google Scholar was performed for articles published from January 1988 to January 2024. Of 2,170 articles screened, 64 met the inclusion criteria. Meta-analyses were conducted on 20 studies, and 44 were included in the narrative synthesis. We conducted random-effects meta-analyses, along with tests for heterogeneity (I^2) and publication bias (Egger's test). The review followed PRISMA and MOOSE guidelines. Results: Maternal PMADs were associated with a significantly increased risk of ADHD (OR 1.91, 95% CI 1.45-2.52) and ASD (OR 1.57, 95% CI 1.37-1.81) in children. Paternal PMADs were also associated with the risk of NDDs, with combined odds for ASD and ADHD (OR 1.24, 95% CI 1.15-1.34). Several studies suggested that the link between parental PMADs and offspring NDDs might be impacted by both genetic and environmental factors, including the impact of ongoing parental depression on child behavior. Conclusions and Relevance: Parental PMADs are significantly associated with an increased risk of NDDs in children. These associations may be influenced by both genetic predispositions and environmental factors. Understanding these pathways is important for informing interventions aimed at mitigating mental health risks in families and supporting child development.

The discovery of genetic risk factors has transformed human genetics, yet the pace of new gene identification has slowed despite the exponential expansion of sequencing and biobank resources. Current approaches are optimized for the extremes of the allele frequency spectrum: rare, high-penetrance variants identified through burden testing, and common, low-effect variants mapped by genome-wide association studies. Between these extremes lies variants of intermediate frequency and effect size where statistical power is limited, pathogenicity is often misclassified, and gene discovery lags behind empirical evidence of heritable contribution. This 'missing middle' represents a critical blind spot across disease areas, from neurodevelopmental and psychiatric disorders to cancer and aging. In this review, we organize strategies for risk gene identification by variant frequency class, highlighting methodological strengths and constraints at each scale. We draw on lessons across fields to illustrate how innovations in variant annotation, joint modeling, phenotype refinement, and network-based inference can extend discovery into the intermediate range. By framing the frequency spectrum as a unifying axis, we provide a conceptual map of current capabilities, their limitations, and emerging directions toward more comprehensive risk gene discovery.

Clinical biobanks linking electronic health records (EHRs) with genotype data enable the study of genomic risk factors in real-world populations. However, recall-by-genotype (RbG) of psychiatric risk variants in diverse healthcare-system biobanks remains scarce. Leveraging BioMe, a multi-ancestry biobank within the Mount Sinai Health System, we recalled carriers of rare copy number variants (CNVs) that confer increased risk for neurodevelopmental disorders (NDDs) to establish empirical benchmarks for RbG implementation. We recontacted 892 participants: 335 NDD CNV carriers, 217 individuals with schizophrenia without NDD CNVs, and 340 neurotypical controls without NDD CNVs. Participants completed clinical and cognitive assessments. Overall, 18% of recontacted participants responded to recruitment, and 8% completed the study: 30 NDD CNV carriers, 20 individuals with schizophrenia, and 23 controls. The mean age was 48.8 years, 66% were female, and self-reported ancestry was 37% African, 34% Hispanic, and 26% European. Seventy percent of NDD CNV carriers had at least one neuropsychiatric or developmental condition, including mood or anxiety disorders (40%). Among 22 NDD CNV carriers at loci implicated in impaired cognition, performance was lower than controls on Digit Span Backward (β = -1.76, FDR = 0.04) and Digit Span Sequencing (β = -2.01, FDR = 0.04). NDD CNV carriers also outperformed the schizophrenia group on verbal learning (β = 4.5, FDR = 0.05). Recall of individuals-including those with psychiatric illness-yielded phenotypes not captured in EHRs and provides empirical benchmarks relevant to RbG implementation and precision psychiatry in diverse healthcare systems.

Importance Antipsychotics are increasingly used in the perinatal period. However, evidence of their effectiveness in the perinatal population is limited. Objectives To examine the risk of severe psychiatric relapse during the perinatal period associated with discontinuation of antipsychotic treatment before or during pregnancy in women with primary psychotic disorders or bipolar disorder. Design, Setting, and Participants This cohort study used linked Danish and Swedish national birth registers to identify pregnancies leading to singleton live births from 1998 to 2022 in Denmark and from 2007 to 2017 in Sweden. Women diagnosed with psychotic disorders or bipolar disorder, with a gestational age between 154 and 315 days, and 2 or more antipsychotic prescriptions filled within 1 year before pregnancy were included. Data were analyzed from August 2024 to October 2025. Exposure The exposure of interest was antipsychotic discontinuation. Discontinuation was defined as no prescription refill within the expected prescription duration plus a 60-day grace period. Women were classified into groups: prepregnancy discontinuation, pregnancy discontinuation, and continuation. The prepregnancy discontinuation group was matched 1:1 to the continuation group, and the pregnancy discontinuation group was separately matched 1:1 to the same continuation group. Main Outcomes and Measures The outcome of interest was severe psychiatric relapse in the perinatal period. Hazard ratios (HRs) were estimated for psychiatric relapse, defined as inpatient treatment for psychiatric disorders during pregnancy and up to 3 months post partum, using a stratified Cox proportional hazards regression model. Results A total of 2000 women with primary psychotic disorders (1265 from Denmark and 735 from Sweden) and 1292 women with bipolar disorder (341 from Denmark and 951 from Sweden) were included. The mean (SD) age was 30.8 (6.0) years for women with psychotic disorders and 29.1 (7.7) years for women with bipolar disorder. For women with psychotic disorders discontinuing antipsychotics before pregnancy, the adjusted HR (AHR) of psychiatric relapse was 1.24 (95% CI, 0.82-1.90) compared with continuation. Pregnancy discontinuation had a higher point estimate for relapse risk (328 pairs; AHR, 1.60 [95% CI, 1.01-2.54]) compared with continuation of antipsychotics. Among women with bipolar disorder, prepregnancy discontinuation (102 pairs; AHR, 0.50 [95% CI, 0.22-1.11]) and pregnancy discontinuation (92 pairs; AHR, 1.00 [95% CI, 0.48-2.10]) point estimates did not show an increased risk of severe relapse, but statistical power was limited. Conclusions and Relevance In this cohort study, women with psychotic disorders who discontinued antipsychotic treatment during pregnancy were at a higher risk of severe relapse and the results for those who discontinued prepregnancy suggest a possible increase in risk, compared with those who continued, which aligns with findings observed beyond the perinatal period; results in women with bipolar disorder were inconclusive. There is an urgent need to investigate the effectiveness of antipsychotics on both severe and nonsevere relapses in the perinatal period in prospective clinical cohort studies.

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.

The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high likelihood for autism spectrum disorder (ASD), intellectual disability and other associated developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic liability across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries (GALA) Consortium was formed, presenting here the largest sequencing study of autism in Latin American individuals (n > 15,000, including 4,717 participants with an ASD diagnosis). We identified 35 genome-wide significant (false discovery rate < 0.05) autism-associated genes, with substantial overlap with findings from European cohorts, and highly constrained genes showing consistent signal across populations. The results provide support for emerging (for example, MARK2, YWHAG, PACS1, RERE, SPEN, GSE1, GLS, TNPO3 and ANKRD17) and established autism genes and for the utility of genetic testing approaches for deleterious variants in individuals from diverse backgrounds; the results also demonstrate the ongoing need for more inclusive genetic research and testing. We conclude that the biology of autism is consistent across populations, with no detectable influence of ancestry.

Tourette Syndrome (TS) and Persistent Tic Disorder (PTD) are childhood-onset neuropsychiatric conditions with high heritability. Due to current sample size limitations, identifying TS/PTD risk genes has been challenging. This study addressed this issue by conducting a meta-analysis of microarray copy number variant (CNV) studies from three TS/PTD genomics consortia, supplemented with new data from 3,291 cases. This approach more than doubled the sample size of previous TS/PTD CNV studies, with CNV calls generated from 5,725 TS/PTD cases and 10,982 matched controls. The results confirmed that TS/PTD cases 1) have a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes (OR = 1.68, P = 9.3×10^-5) and 2) are more likely to carry established neurodevelopmental CNVs (OR = 1.42, P = 3.9×10^-2) compared to controls. Additionally, a novel, genome-wide significant CNV locus for TS/PTD was discovered, involving duplications at 17q12 (hg19 chr17:34.8 - 36.2 Mb). This locus is associated with a known duplication syndrome associated with variable neuropsychiatric traits, but has not been previously linked to tic disorders. Eight cases and one control carried the canonical ~1.4 Mb duplication at chr17:34.8 - 36.2 Mb, while one additional case had a smaller 110 kb duplication within this known CNV that included only one gene, ACACA (acetyl-CoA carboxylase, OR = 26.7, P = 5.69×10^-7). Overall, this study provides further evidence that rare, genic CNVs play a substantial role in the genetic architecture of TS/PTD and identifies a new genome-wide significant association with this neurodevelopmental disorder.

Clinical biobanks with electronic health records (EHRs) linked to genotype data continue to expand yielding an opportunity to further characterize disease-relevant genomic risk factors, yet few recall-by-genotype studies from biobanks have been published to date. For example, copy number variants (CNVs) that significantly increase risk for multiple neurodevelopmental disorders (NDDs) and negatively affect neurocognition, may present in up to 2% of population cohorts, with public health implications for ascertaining NDD CNV carriers. From BioMe, a multi-ancestry biobank derived from the Mount Sinai healthcare system (New York, NY), 892 adult participants were recontacted for deep phenotyping, including 335 NDD CNV carriers as well as comparators, 217 individuals with schizophrenia and 340 controls. Clinical and cognitive assessments were administered to each participant. There was no disclosure of genetic information. Eight percent of recontacted biobank participants completed the study (30 NDD CNV carriers across 15 unique loci, 20 schizophrenia and 23 controls). The study sample had a mean age of 48.8 (10.2) years, was 66% female and of diverse ancestry, 36% African, 34% Hispanic, and 26% European. Overall, 70% of 30 NDD-CNV carriers harbored at least one neuropsychiatric or developmental phenotype, including 40% with mood or anxiety disorders. Further, 22 NDD CNV carriers were significantly impaired compared to controls on digit span backwards (Beta=-1.76, FDR=0.04) and digit span sequencing (Beta=-2.01, FDR=0.04), but higher performing than schizophrenia on verbal learning (Beta=4.5, FDR=0.05). Thirty NDD CNV carriers were successfully recruited from a multi-ancestry biobank, as well as healthy controls and low-functioning individuals with schizophrenia. Deep phenotyping corroborated past reports, while also identifying discordance with EHRs. Future recall-by-genotype studies may further benchmark the study design and elucidate feasibility.

OBJECTIVE:Postpartum psychosis is one of the most severe psychiatric conditions, with high risks of suicide and infanticide if untreated. Although genetic factors contribute to the risk of postpartum psychosis, the extent of familial risk remains to be determined. The authors compared relative recurrence risk across different family relationship types, hypothesizing that relative recurrence risk for postpartum psychosis varies by degree of genetic relatedness and is higher in female full siblings than in cousins. METHODS:This cohort study consisted of 1,648,759 women from the Swedish nationwide registers, of whom 2,514 (0.15%) experienced postpartum psychosis within 3 months of their first-ever childbirth. The authors estimated the relative recurrence risk of postpartum psychosis for female full siblings and cousins as a measure of familial risk. RESULTS:The relative recurrence risk of postpartum psychosis in full siblings was 10.69 (95% CI=6.60, 16.26) when adjusted for year of and age at childbirth. Although cousins showed an elevated relative recurrence risk, these results did not reach statistical significance (1.78, 95% CI=0.70, 3.62). Despite the higher familial risk of postpartum psychosis among full siblings, the absolute risk for women with an affected sibling was relatively low, estimated at 1.60% within the entire population. CONCLUSIONS:The observed increased risk of postpartum psychosis in full siblings suggests both genetic and shared environmental influences. However, the lack of significant results in cousins hampers a more accurate distinction between these factors. Furthermore, despite increased relative recurrence risk in siblings, their overall likelihood of developing postpartum psychosis remains low. This study underscores the need for further research to better understand the intricate interplay of genetics and shared environment in the development of postpartum psychosis.

Background: Autism spectrum disorder (ASD) shows significant clinical variability, likely due to a combination of genetic and environmental factors. Preterm birth is a known risk factor for ASD, occurring in approximately 13% of diagnosed individuals. While genetic factors contribute to preterm birth in the general population, the relationship between genetic variation, preterm birth, and ASD heterogeneity remains unclear. Methods: We investigated the genetic factors associated with preterm birth in 31,947 autistic individuals using data from the SPARK (Simons Foundation Powering Autism Research for Knowledge) sample. We conducted 3 ancestry-specific genome-wide association studies for African/African American, admixed American, and non-Finnish European ancestries, followed by a meta-analysis of 3308 preterm cases and 28,639 controls using METAL. Functional mapping and gene-based analyses were performed using FUMA, and genetic correlations were estimated using LDSC and Popcorn. Polygenic risk scores (PRSs) were computed with BridgePRS, using PRS of preterm birth in the general population. Results: Our study identified ancestry-specific genetic loci associated with preterm birth in ASD cases. Although the meta-analysis results were not statistically significant, the estimated single nucleotide polymorphism heritability was 14%, indicating a meaningful contribution of common genetic variants. Across ancestry groups, preterm birth status was not significantly associated with PRSs for any psychiatric or medical conditions analyzed. However, polygenic liability to preterm birth in the general population was linked to several congenital anomalies after multiple testing adjustments. Conclusions: These findings highlight the importance of diverse ancestries and early-life exposures in understanding ASD heterogeneity. Future research should replicate these findings in larger samples and explore rare variants associated with preterm birth to better understand the relationship between gestational duration and clinical and genetic differences in ASD.