OBJECTIVE:Mothers' mental health and life satisfaction may have been negatively affected due to challenges during the COVID-19 pandemic. Given the risk of future crises, knowledge of possible mitigating factors in this population is essential. This study aims to examine whether the pandemic affected the level of protective factors such as social support, physical activity and employment situation, and how these factors are associated with mental distress and life satisfaction. DESIGN:Longitudinal cohort study. OUTCOME MEASURES:Primary outcomes were mental distress (measured by the eight-item version of the Hopkins Symptom Checklist) and life satisfaction (measured by the Satisfaction With Life Scale). As the first step, we investigated changes in the levels of social support (defined by the number and frequency of social contact), physical activity (average hours of physical activity during a week), employment situation (actively working vs sick leave or unemployed), alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption) and relationship satisfaction (measured by the five-item version of the Relationship Satisfaction Scale). METHODS:We analysed data from two waves of the Norwegian Mother, Father and Child Cohort Study (n=~18 000 mothers); one pre-pandemic wave and one wave where half of the sample responded after the onset of the pandemic, with pandemic exposure being defined by questionnaire response timing rather than cohort recruitment. To assess changes in protective factors over time and pandemic exposure, we used difference-in-differences analyses and regression discontinuity design. Associations between protective factors with mental distress and life satisfaction, and possible moderation by pandemic exposure, were investigated using multiple regression models with interaction terms adjusted for potential confounders. RESULTS:Apart from physical activity, which declined less across time in the pandemic group (B=0.09, 99% CI 0.05 to 0.12), protective factors did not change during the pandemic. Social support, employment situation and relationship satisfaction were associated with mental distress and life satisfaction, whereas physical activity showed a unique relationship with mental distress. Most associations were similar across pandemic exposure groups, except employment situation which appeared to have a stronger protective effect in the pandemic group (β=-0.12, 99% CI -0.24 to -0.00). CONCLUSIONS:Changes over time in self-reported levels of protective factors were generally consistent among mothers independent of the pandemic. These factors appear to play an equally important role for mental distress and life satisfaction both under ordinary circumstances and during public health crises. Our findings enhance the understanding of how potential protective factors among mothers are associated with mental distress and life satisfaction in the context of a global stressor. Future studies should investigate additional mitigating factors that may be particularly relevant during global crises and explore the causal relationship between protective factors, mental health and life satisfaction.

Background:Post-COVID syndrome (PCS) remains a substantial public health concern, yet its genetic determinants are poorly understood. Psychiatric disorders and related traits influence infection risk and acute COVID-19 outcomes, raising the possibility that shared genetic liability may also shape long-term symptom persistence. We examined whether polygenic scores (PGS) for schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and neuroticism are associated with PCS, and explored potential pathways underlying these associations. Methods:We analysed three population-based cohorts from Denmark, Norway and Iceland (total n = 80,726; PCS cases = 6103) between March 2020 and June 2022. PCS was defined as COVID-19-related symptoms lasting ≥3 months. Logistic regression models estimated associations between standardised PGS and PCS among COVID-19 positive individuals, adjusting for ancestry principal components. Additional analyses assessed associations with COVID-19 infection. In a subset with available personality data, models were additionally adjusted for measured Neuroticism (NEO-FFI). Supplementary analyses examined associations between PGS and COVID-19 infection risk, and we conducted LD score regression (LDSC) and proteomic analyses as contextual genetic and biological characterisations of the PGS traits. Findings:Higher PGS for neuroticism, MDD and ADHD were consistently associated with increased odds of PCS across all cohorts (ORs per SD: ∼1.07-1.16). Quintile analyses showed a graded pattern, with the highest PGS quintile displaying 30-45% higher odds of PCS than the lowest. PGS for SCZ and BPD showed no evidence of association with PCS. PGS associations with COVID-19 infection were weaker and inconsistent. In the subset with available personality data, these associations remained essentially unchanged after adjusting for measured Neuroticism, indicating that they are not solely attributable to observed personality differences. LDSC and proteomic analyses did not alter the primary interpretation of the PGS-PCS associations. Interpretation:Polygenic liability for neuroticism, MDD, and ADHD is associated with increased risk of PCS across three national cohorts. This pattern is consistent with shared symptom-related liability contributing to these associations, although the data do not allow differentiation between post-viral sequelae and pre-existing symptom liability. While PGS explain only a modest proportion of PCS variance, they provide useful insight into underlying psychiatric and personality-related factors associated with persistent symptom reporting following COVID-19 infection. Funding:The study was funded by EU Horizon REACT study (101057129), environMENTAL study (101057429), Nordforsk (project numbers 105668 and 138929), and the Independent Research Fund Denmark (0214-00127B).

BACKGROUND:The extensive genetic overlap between anxiety disorders (ANX) and major depression (MD) may partly reflect the inclusion of comorbid cases in genome-wide association studies (GWASs). We investigated this genetic relationship between ANX and MD, with and without mutual comorbidity. METHODS:Using the UK Biobank, we performed disorder-specific GWASs for ANX-only (cases/controls = 9980/179,442) and MD-only (cases/controls = 15,301/179,038) and derived polygenic risk scores (PRSs). In the Norwegian Mother, Father, and Child Cohort Study (MoBa), we tested associations between PRS and MD-only (n = 7486), ANX-only (n = 1992), and comorbid ANX and MD (ANX-MD) (n = 3468) cases and controls (n = 85,851). PRS associations with anxiety and depression symptoms were tested in MoBa (n = 54,862). GWASs including comorbid cases (MD-comorbid [MD with comorbid ANX] or ANX-comorbid [ANX with comorbid MD]) were used for comparison. Genetic correlations were compared by comorbidity status, and Mendelian randomization was employed to assess causal relationships. RESULTS:MD-comorbid and ANX-comorbid PRSs showed a stronger association with ANX-MD cases than with their primary disorders, MD-only (z = -2.82, padjusted = .01) and ANX-only (z = -2.36, padjusted = .03), respectively. MD-only PRS was more strongly associated with MD-only than with ANX-only cases (z = 3.63, padjusted = 6.9 × 10-4). The genetic correlation (rg) was lower between ANX-only and MD-only (rg = 0.53, SE = 0.11) than between ANX-comorbid and MD-comorbid (rg = 0.91, SE = 0.01). Bidirectional causal effects observed in comorbidity-inclusive analyses were attenuated to null when comorbid states were excluded. Gene sets of MD-comorbid, ANX-comorbid, and MD-only, but not of ANX-only, were enriched for the immune regulation pathway-interleukin 21 production. CONCLUSIONS:The genetic distinction between ANX and MD becomes more pronounced when comorbid cases are excluded. The findings underscore the importance of disorder-specific genetic studies for advancing precision medicine.

We conducted genome-wide meta-analyses (N = 141,505; Estonian Biobank and Norwegian Mother, Father and Child Cohort Study) with polygenic score-based validation (N = 19,857; Dutch Lifelines cohort) of self-reported attention-deficit/hyperactivity disorder (ADHD) symptoms in adults from the general population. We identified eight genetic loci associated with either total symptoms, inattention or hyperactivity-impulsivity domains. Distinct genetic architectures underlying the two symptom domains were demonstrated by their moderate genetic correlation (r g =0.35, 95% CI 0.26 to 0.43) and by contrasting genetic association patterns across other phenotypes and medical conditions. Hyperactivity-impulsivity showed stronger genetic links with ADHD diagnosis, negative r g -s (-0.28 to -0.19) with educational traits, and more associations with diagnoses in electronic health records. Whereas inattention was weakly genetically associated with ADHD diagnosis, showed positive r g -s (0.24 to 0.29) with educational phenotypes, and fewer links with clinical outcomes. This is the first genome-wide study to detect significant signals associated with adult ADHD symptoms and symptom dimensions.

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.

Importance:A narrow range of food consumption and/or restricted eating is a core feature of avoidant/restrictive food intake (ARFI) disorder. However, there is limited knowledge of developmental characteristics of children with ARFI and its etiological influences, which constrains research, prevention, and intervention efforts. Objective:To estimate the prevalence of ARFI phenotypes in a population-based sample, examine developmental characteristics across childhood, and investigate the genetic architecture of ARFI using genome-wide association analyses. Design, Setting, and Participants:This preregistered study used data from children born from 1999 to 2009 in the population-based Norwegian Mother, Father, and Child Cohort Study (MoBa), with mother-reported data on ARFI symptoms at 3 and 8 years and linkage with diagnostic data from population health registries. Data were analyzed from March 2024 to May 2025. Exposures:Multiple items were used to identify children with broad ARFI. These children were subclassified into 3 groups based on symptom persistence: ARFI-broad transient (only at age 3 years), emergent (only at age 8 years), and persistent (ages 3 and 8 years). Children in these groups with 1 or more indicators of clinical significance (eg, nutritional deficiency) were further classified into ARFI-clinical subgroups. Main Outcomes and Measures:ARFI groups were compared across developmental characteristics from 6 months to 14 years. Genome-wide methods were used to examine single-nucleotide variant (SNV) heritability (SNV-h2), conduct genetic association analyses, and quantify genetic correlations with other phenotypes. Results:Of 35 751 children with available ARFI assessments at 3 and 8 years (18 236 male [51%]), the prevalence of ARFI-broad persistent, transient, and emergent was 2129 (6.0%), 6338 (17.7%), and 3001 (8.4%), respectively. The prevalence of ARFI-clinical persistent, transient, and emergent was 624 (1.8%), 1157 (3.2%), and 484 (1.4%), respectively (2265 [6.3%] overall). Children with ARFI-broad persistent exhibited more developmental difficulties compared with children with no ARFI. SNV-h2 ranged from 8% to 16%. Two independent genome-wide significant loci were identified. For ARFI-clinical, a significant association was identified with ADCY3 (z = 5.42; P = 3.03 × 10-8). Small to moderate genetic correlations were observed for ARFI-broad, ARFI-clinical and mental health, cognitive/educational, anthropometric, food-associated, and gastrointestinal disorder phenotypes. Conclusions and Relevance:This cohort study found that the prevalence of ARFI in the general pediatric population was substantial, and affected children had an associated elevated risk of developmental difficulties across multiple domains. Findings suggest a need for broad support interventions and advance understanding of the genetic underpinnings of ARFI.

Early temperament, such as socio-emotional development and activity level, varies widely, yet its underlying biological associations are not understood. We identified genetic variation associated with infant and toddler temperament using genome-wide association meta-analyses. We studied parent-rated emotionality, activity, shyness and sociability (n = 43,963-72,663) in the second and third postnatal years and a cross-age average. Cross-age single nucleotide polymorphism heritabilities for emotionality, activity, shyness and sociability were 6.79% (95% confidence interval (CI), (4.71%, 8.87%)), 9.55% (95% CI, (7.04%, 12.06%)), 15.26% (95% CI, (12.24%, 18.28%)) and 3.42% (95% CI, (1.30%, 5.54%)), respectively. Ten genome-wide significant loci were discovered. Two loci colocalized with expression quantitative trait loci in the adult cortex: RHEBL1 (posterior probability, 0.93; associated with activity) and MR1 (posterior probability, 0.99; with emotionality). Genetic correlations were observed between early temperament and later outcomes, such as emotionality and adult neuroticism, activity and attention deficit/hyperactivity disorder (ADHD), sociability and autism, and shyness and adult extraversion. Multi-ancestry (n = 56,083-78,894) and European-ancestry analyses gave similar results. Infant and toddler temperament is associated with genetic variation and shows genetic continuity with later outcomes.

Most studies assessing the association between infection accumulation and mental disorders focus on hospitalization-based severe infections. However, most infections are more common, and community acquired. This study aimed to evaluate the effects of community-based infection accumulation on risk to develop a mental disorder, and risk factors modulating this association. A nationwide population-based matched cohort study was conducted, utilizing the registries of Clalit Health Services, the largest healthcare organization in Israel. Individuals born between the years 1995–2005 with history of specific infections (n = 35 020) were propensity score matched to an unexposed group with no such history (n = 35 020). These individuals were followed up until 2024 for a mental disorder onset. Serology, nasal and saliva-based tests for cytomegalovirus, herpesviruses, hepatitis, influenza, or toxoplasma gondii starting from birth were identified, and patients were followed for onset of anxiety, depression schizophrenia and bipolar disorders. Individuals with history of infection accumulation demonstrated higher risk to develop a mental disorder, with risk gradually increasing after one (HR, 1.08, 95%CI, 1.01–1.17, p = 0.036), two (HR, 1.19, 95%CI, 1.09–1.30, p < 0.001) and three or more infections (HR, 1.81, 95%CI, 1.32–2.48, p < 0.001) up to first five years post-infection. These associations were stronger in females, individuals of older age and individuals with larger families. The findings suggest that community-based immune challenges might shape vulnerability for mental disorders, and stress the need to consider infection history in future efforts to develop patient-tailored prevention and intervention strategies.

Background: Early adolescence is a common period of onset for depressive symptoms. In part, this may reflect a developmental manifestation of individual's genetic propensities as they undergo physiological and hormonal changes and interact with new environments. Many commonly proposed mechanisms assume direct effects of an individual's own genes on emerging variation in their depressive symptomatology. However, estimates of genetic influence based on analyses in unrelated individuals capture not only direct genetic effects but also genetic effects from parents and other biologically related family members. Aim: In data from the Norwegian Mother, Father and Child Cohort (MoBa), we used linear mixed models to distinguish developmentally-stable and adolescence-specific direct and parental indirect genetic effects. We examined effects of polygenic scores for major depressive disorder (MDD), ADHD, anxiety disorders, and educational attainment (EA) on depressive symptoms, which were assessed by maternal reports at ages 8 and 14. Results: Children's own MDD polygenic scores showed adolescence-specific effects on depressive symptoms ( b_PGS*wave=0.041, [95% CI: 0.017, 0.065]). Developmentally-stable direct effects from children's polygenic scores for MDD (b=0.016, [0.006, 0.039]), ADHD (b=0.024, [0.008, 0.041]) and EA (b=-0.02, [ -0.038, -0.002]) were also evident. The only evidence of indirect genetic effects was a stable effect of maternal EA polygenic scores (b=0.04, [0.024, 0.054]). Conclusion: Direct genetic effects linked to genetic liability to MDD accounted for emerging variation in depressive symptoms in adolescence. These results imply that specific etiological mechanisms related to MDD may become particularly relevant for depressive symptoms during early adolescence compared to at earlier ages. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This work was partly funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (project No. 101057529). M.M.B., L.J.H., A.D.A., L.H, REW and A.H. was supported by the South-Eastern Norway Regional Health Authority (#2020022, #2022083, #2019097; #2020023; #2020024). A.H., L.H. and B.G. were supported by the Research Council of Norway (#274611, #336085). A.H. and A.D.A. were supported by grants from European Union's Horizon Europe Research and Innovation programme (FAMILY; #101057529, HOMME #101142786; and Marie Skłodowska-Curie grant ESSGN #101073237). HA was funded by NordForsk (#156298 and #230738) and RCN (#324620). NMD, JBP and AH acknowledge funding from the MRC (UKRI1510). NMD is supported by The Research Council of Norway (#295989) and NIMH (MH130448). JBP acknowledge funding from IRISK: European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (I-RISK, grant agreement No. 863981) and FAMILY: by the European Union's Horizon Europe Research and Innovation Programme (FAMILY, grant No. 101057529) under the UK government's Horizon Europe funding guarantee [UK Research and Innovation (UKRI) grant No. 575067]. ### 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 consent obtained from the Norwegian mother, father and child cohort (MoBa) participants does not allow for the sharing of individual level data with analyses. Data from MoBa, Medical birth registry of Norway (MBRN) and (Statistics Norway)SSB used in this study can be made available to researchers, provided approval from the Norwegian regional committees for medical and health research ethics (REK)(2016/1702), compliance with the EU General Data Protection Regulation (GDPR) and approval from the data owners. 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 All data produced in the present study are available upon request to Norwegian Institute of Public Health.

PURPOSE:The COVID-19 pandemic affected both substance use patterns and impacted healthcare systems. Substance-induced psychosis (SIP) is a severe mental disorder characterized by severe psychosis triggered by substance use. The number of treated SIP episodes may be sensitive to both changes in substance availability and treatment access. We study investigated whether the monthly prevalence of SIP episodes and mortality among SIP patients changed during the pandemic in Norway, comparing observed cases during 2020-2021 to predictions based on pre-pandemic trends. METHODS:We analyzed data from the Norwegian Patient Registry (2012-2021), we identified 7,150 individuals diagnosed with SIP (ICD-10 F1x.5). Monthly prevalence rates for overall SIP episodes and substance-specific SIP diagnoses (i.e., due to alcohol, cannabis, amphetamines, or multiple substances) and yearly mortality rates were predicted using ensemble time-series models. Deviations during the pandemic were assessed against 95% prediction intervals derived from pre-pandemic data. RESULTS:The observed monthly prevalence of episodes of any SIP during 2020-2021 largely matched predictions, with some deviations. Alcohol-induced psychosis showed lower than expected rates in 2020 but higher in 2021. Cannabis-induced psychosis rates were below expectations. Amphetamine-induced psychosis and psychosis due to multiple substances showed higher-than-expected rates during lockdowns, with lower rates between lockdowns. Mortality rates among SIP patients for all-cause mortality, suicide, and accidental poisoning during the pandemic were similar to those in the pre-pandemic period. CONCLUSIONS:The pandemic did not seem to alter the overall number of SIP episodes. There were, however, some drug-specific changes. This may reflect drug availability, changes in substance use, or changes in healthcare access. A high mortality burden was observed among patients with SIP. However, mortality rates due to all causes, suicide, and accidental poisoning in this group were similar in the pandemic and pre-pandemic periods.

Lockdowns and social restrictions imposed in response to the Covid-19 pandemic intensified the proximity and reciprocal exposure among members of nuclear families. It is unclear how variation in mental distress during this period is attributed to potential influences of family members. This study used genetic data from adolescents (n = 4 388), mothers (n = 27 852) and fathers (n = 25 953), to disentangle the contributions of parent-driven, child-driven, and partner-driven components to mental distress during the first two months of the Covid-19 lockdown. Separate models also included adolescents’ non-pandemic mental distress as outcomes (n = 13 484). Trio genome-wide complex trait analyses separated two types of genetic components; direct–how an individual’s genotype is associated with their own mental distress, and indirect–how an individual’s genotype is associated with the mental distress of family members. A trio polygenic score (PGS) design was used to investigate associations of specific genetic liability factors with mental distress, and whether these changed over time (PGS×time). Results suggest that family-level genetic factors contribute to mental distress; variance components capturing indirect genetic effects accounted for 10% of adolescent mental distress (mother-driven), 2–3% of maternal (partner-driven), and 5% of paternal mental distress (child-driven). Mothers’ depression and ADHD PGS were positively associated with fathers’ mental distress. No PGS×time interactions were found. Direct genetic effects accounted for 9–10% variance in mental distress across family members, partly explained by genetic variants associated with anxiety, depression, ADHD and neuroticism. These findings highlight the importance of family dynamics and emphasize the potential value of including family members in mental health interventions.

Background The timing of delivery requires shared decision-making between pregnant women and obstetricians, balancing perinatal and long-term outcomes. Although prematurity and fetal growth restriction are recognized risk factors for adverse neurodevelopment, it remains unclear whether gestational age within the term period or fetal size at birth has the more enduring association with long-term neurodevelopment among term-born children. Objective To compare the persistence of associations of gestational age (37-41 weeks) and fetal size (defined as birth weight for gestational age) with early childhood neurodevelopment and adolescent academic performance. Study Design Term-born children without congenital malformation from the Norwegian Mother, Father and Child Cohort Study (MoBa) were included in the study. Primary outcomes were parent-reported language and motor development at 6 months, 18 months, 3 years, and 5 years, and national test scores (Math, Reading, and English) at fifth grade (age 10-11 years), eighth grade (age 13-14 years), and ninth grade (age 14-15 years). Exposures were gestational age at term (37-41 weeks) and fetal size categories at birth: small-for-gestational-age (SGA, <10th percentile), appropriate-for-gestational-age (AGA, 10-90th percentile), large-for-gestational-age (LGA, >90th percentile). Results Among 92,551 term-born children, gestational age and fetal size showed distinct patterns of association with neurodevelopmental outcomes from infancy to adolescence. Earlier birth within the term range was associated with less favorable language and motor development in early childhood, but these associations diminished rapidly by 18 months and were minimal by age 5. In contrast, smaller fetal size (i.e., SGA) was associated with poorer academic performance that persisted throughout adolescence, including lower math scores at ages 10-11 years (β = -2.32, 95% CI: -3.15, -1.49), 13-14 years (β = -1.79, 95% CI: -2.52, -1.06), and 14-15 years (β = -1.85, 95% CI: -2.69, -1.02). The associations of gestational age and fetal size were statistically independent of each other. Conclusions Among term-born children, fetal size showed more enduring associations with long-term neurodevelopment than differences in gestational age within the term period. These findings suggest that gestational age and fetal size represent distinct, non-interchangeable sources of information when counseling families about long-term neurodevelopment after term births.

Background:Escalating mental health service demands have created a need to better identify young people most likely to require continued support from mental health services at the transition between childhood and adulthood. Anxiety is the most common adolescent mental health condition, yet its clinical significance and prognosis are not well understood. We aimed to examine the risk of young adult-onset psychiatric disorders in individuals with an adolescent anxiety disorder, and identify stratifiers of risk of subsequent psychiatric disorders in this group. Methods:Individuals from the Norwegian Mother, Father, and Child Cohort Study (MoBa) with linked health records and aged 18 or over as of the 31 st December 2023 were included. Those diagnosed with any ICD-10 anxiety disorder when aged 10-17 years were defined as having an adolescent anxiety disorder (n=2107, controls n=47,582). Polygenic scores (PGS) for psychiatric and neurodevelopmental conditions were calculated using LDpred2. Anxiety, comorbidities, and parental psychiatric history were defined through linked ICD-10 diagnoses. Sex was defined through linked records. Individuals were defined as having a young adult-onset psychiatric disorder if they first received any new psychiatric diagnosis aged 18-24. Results:Adolescent anxiety diagnosis was associated with increased risk of all adult-onset psychiatric disorders (HR= 2.33-8.65). Post-traumatic stress disorder PGS, parental history of severe mental illness, and female sex were associated with increased risk of transition to a young adult-onset psychiatric disorder in people with an adolescent anxiety disorder. Conclusions:Adolescent anxiety greatly increases the risk of a psychiatric disorder during the transition to adult life. Clinicians should consider female sex and parental psychiatric history when prioritising young people with anxiety for adult mental health service support. Future research needs to further consider whether polygenic scores would aid risk stratification in clinical practice.

Background Parental genetics matters for children’s behavioural difficulties, but the extent to which this is due to direct genetic transmission versus environmentally mediated indirect genetic effects remains unclear. Methods We studied eight European birth cohorts with over 33,000 family-based trio samples. We analysed polygenic scores (PGSs) for 13 mental health and neurodevelopmental conditions and their composite indices (PC1 and mean) representing general neuropsychiatric liabilities, as well as educational attainment (EA) and alcohol and cigarette use, from children (PGSc), mothers (PGSm), and fathers. Child internalising, externalising, and total difficulties reported by mothers and/or fathers were examined at preschool and school ages. We then conducted multivariate meta-analyses to combine cohort-level results. Findings We observed several direct genetic effects on externalising difficulties, while indirect genetic influences were mainly identified for internalising difficulties. Specifically, child PGSs for attention-deficit/hyperactivity disorder (ADHD) and EA predicted higher and lower levels, respectively, of child externalising and total difficulties (all p FDR<0·001; for school-aged externalising difficulties, PGSc-ADHD: β=0·121 [95% CI 0·091 to 0·151], p FDR<0·0001; PGSc-EA: β=−0·095 [95% CI −0·127 to −0·063], p FDR<0·0001), whereas maternal PGSs for major depressive disorder (MDD) and general neuropsychiatric liabilities were associated with internalising and total difficulties across parental raters and child ages (all p FDR<0·05; for school-aged internalising difficulties, PGSm-MDD: β=0·049 [95% CI 0·017 to 0·081], p FDR=0·016; PGSm-PC1: β=0·056 [95% CI 0·022 to 0·091], p FDR=0·011). No statistically significant effects from paternal PGSs were identified. Interpretation In this multi-cohort study, findings across multiple traits, raters, and ages supported several direct genetic effects of ADHD and EA on child externalising difficulties and indirect genetic effects on internalising difficulties, especially maternal depression and general neuropsychiatric liabilities. These suggest that child internalising difficulties are not solely driven by direct genetic transmission. More comprehensive research is needed to better understand the mechanisms involved, and ultimately how to ameliorate child behavioural difficulties. Funding EU, ERC, RCN, RCF, UKRI, SERI, DFG Evidence before this study Indirect genetic effects (IGEs) refer to the influence of parental genotypes on offspring outcomes beyond direct genetic effects (DGEs), for example via environmental pathways. While IGEs on offspring cognitive traits are well-established for educational attainment, evidence for IGEs of parental liabilities to mental health and neurodevelopmental conditions remains limited. To assess the current state of evidence, we conducted a systematic search of published studies applying trio-based polygenic score (PGS) designs to child and adolescent mental health outcomes. We identified 141 primary studies in MEDLINE, Embase, PsycInfo, and Web of Science, by 6 March 2025, after removing duplicates; following screening, 12 studies met inclusion criteria (see supplement for a full description including results). Ten out of the 12 studies focused on externalising outcomes, with little or inconsistent support for IGEs. When observed, IGEs were mainly driven by maternal liabilities to autism, educational attainment, and cognitive performance on child outcomes. The current evidence was too limited and heterogeneous to synthesize findings quantitatively, therefore a qualitative synthesis was conducted. Many studies were statistically underpowered, and the observed IGEs were in all cases sample-specific. There were no published multi-cohort studies. Added value of this study We integrated information across over 33,000 mother-father-child trios from eight European cohorts, investigating 18 PGSs from parents and children, using maternal and paternal ratings of offspring’s internalising, externalising, and total difficulties as outcomes at both preschool and school age. We mainly observed DGEs on externalising difficulties, consistent with previous studies. Some evidence of IGEs was found for internalising and total difficulties. IGEs were often found to be maternally driven, with the most robust evidence across ages and raters emerging for maternal depression and general neuropsychiatric liabilities. Implications of all the available evidence The current evidence suggests that children’s behavioural difficulties, especially internalising difficulties, may be partly driven by the environment shaped by maternal neuropsychiatric liabilities. Ours and previous findings highlight a pressing need for more comprehensive studies across different cohorts, raters, outcomes, and time points to understand the true extent of IGEs in the intergenerational transmission of mental health. ### Competing Interest Statement O.A.A. is a consultant to CorTechs.ai and Precision Health, and has received speaker's honoraria from BMS, Lundbeck, Lilly, Janssen, Sunovion, and Otsuka, with no conflict of interest relevant to this work. The other authors declare no biomedical financial interests or potentially competing interests. ### Funding Statement This study was funded by the European Union's Horizon Europe Research and Innovation Programme, European Research Council, ERAnet Neuron, Academy of Finland (Council of Finland), Research Council of Norway, South-Eastern Norway Regional Health Authority, Horizon Europe, UK Research and Innovation, Swiss State Secretariat for Education, Research and Innovation, and German Research Foundation ### 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 PREDO study protocol was approved by the Ethics Committee of Obstetrics and Gynaecology and Women, Children and Psychiatry of the Helsinki and Uusimaa Hospital District and by the participating hospitals. All studies were approved by their institutional ethics review committees and all participants provided written informed consent (see supplement). 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 Correspondence and requests for materials should be addressed to: jari.lahti{at}helsinki.fi

BACKGROUND:Internalizing disorders are among the most common psychiatric conditions in adolescence, often associated with long-term adverse outcomes. Early identification of at-risk youth is important for effective intervention, though it remains challenging due to the multifactorial nature of risk. Machine learning (ML) offers opportunities to integrate multiple data sources and improve risk prediction for internalizing disorders. METHODS:We used data from 13,743 adolescents (mean age 14.45 years; 52.7% female) participating in the Norwegian Mother, Father and Child Cohort Study (MoBa), linked to national health registries. Logistic regression with elastic net regularization was applied to predict the risk of an internalizing disorder (mood, anxiety or stress-related) occurring within one to five years after assessment. Nested models of increasing complexity incorporated sociodemographic, clinical, lifestyle, mental health, psychosocial, and genetic predictors. Model performance was evaluated in a hold-out test set. Simplified models combining three questionnaire scales were also evaluated. RESULTS:Test-set performance increased with model complexity, reaching area under the receiver operating characteristic curve (AUC) of 0.731 for the full model. Mental health self-reported symptoms and psychosocial predictors contributed most to the discrimination. Simplified models using three questionnaire scales, alongside age and sex, achieved AUCs up to 0.718 and effectively stratified adolescents into high- and low-risk groups (OR80/20 ranged 6.11-9.35). CONCLUSION:Multimodal ML models integrating registry information, mental health symptoms, psychosocial factors, and genetic data demonstrated moderate predictive performance. Simplified models with three questionnaire items reached comparable performance, highlighting their potential utility in the early identification of adolescents at elevated internalizing disorder risk.

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.

Abstract Background/Objectives Childhood appetitive traits are heritable behavioural phenotypes hypothesized to link genetic susceptibility to obesity risk. Yet their genetic architecture and role in mediating polygenic adiposity risk remain poorly understood. Methods We conducted the largest survey of childhood eating behaviour to date, allowing us to perform genome-wide association studies of six appetitive domains derived from 18 items of the parent-reported Children’s Eating Behaviour Questionnaire in up to 31,018 eight-year-old children from the Norwegian Mother, Father and Child Cohort Study (MoBa). A trio-based design enabled decomposition of direct and indirect genetic effects on appetite and BMI. Results We identified ten independent genome-wide significant loci for childhood eating behaviour, primarily across Food Responsiveness , Satiety Responsiveness , and Food Fussiness , eight of which lie at established childhood or adult BMI loci. Food Responsiveness and Satiety Responsiveness showed both phenotypic and genetic correlations with BMI trajectories from early childhood through adolescence. Statistical mediation analyses indicated that 22.1% and 10.4% of the aggregated genetic association with BMI at age 8 could be decomposed through these traits, respectively. Locus-specific patterns further suggested mechanistic pathways, with the FTO locus acting predominantly via Food Responsiveness , and the ADCY3 locus via Satiety Responsiveness . Trio analyses demonstrated that both BMI and eating behaviour associations were predominantly explained by children’s inherited alleles, with minimal contribution from indirect effect from parental adiposity, although parental genetic liability influenced reporting of Satiety Responsiveness . Conclusions Childhood appetitive traits capture a substantial proportion of genetic susceptibility to adiposity through distinct eating behaviour pathways (under standard mediation assumptions). These effects are primarily driven by the child’s own genotype rather than indirect parental influences, positioning appetite as a plausible, biologically grounded target for early obesity prevention.

Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. Here we performed a genome-wide association meta-analysis of generalized anxiety symptom severity in 693,869 individuals of European ancestry from 14 cohorts. We identified 80 independent genome-wide significant variants within 74 loci, 39 of which were newly associated with anxiety. SNP-based heritability was 5.9% (posterior s.d. = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African and South Asian ancestry samples (R2 = 1.2-2.9%). Significant genetic correlations (rg) were estimated with mental and physical health traits, including case-control anxiety, neuroticism and depression (rg = 0.71-0.85), irritable bowel syndrome (rg = 0.57), coronary artery disease, endometriosis and migraine (rg = 0.20-0.27). Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain. These findings highlight the discovery power gained from analysing a quantitative trait rather than a case-control phenotype in anxiety genetics.

Pre-existing psychiatric disorders have been associated with the severity of acute respiratory infections, including COVID-19, particularly in hospitalized populations. However, the underlying mechanisms, especially in community-based populations, remain unknown, limiting preparedness for future pandemics. We investigated the role of genetic liability for psychiatric disorders and related traits in COVID-19 and other respiratory infection severity among individuals reporting SARS-CoV-2 testing and available respiratory symptom data. We included population-based cohort data from Denmark, Estonia, Iceland, Norway, and the United Kingdom (N = 78,507; 62