Amy Shakeshaft

Neurodevelopmental and psychiatric conditions often originate in youth and can lead to adverse social and functional outcomes. It is unclear whether these associations are driven by genetic liability to these conditions, with possible developmental differences. We examined multivariable associations between polygenic scores (PGS) for attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder, depression, anxiety and three outcomes: peer problems, educational attainment/employment and suicidality, in childhood, adolescence and young-adulthood. Data were analysed from the Avon Longitudinal Study of Parents and Children; outcomes at ages 10–13, 16 and 24–25 years. ADHD PGS was associated with peer problems (OR = 1.13, p = 0.020; OR = 1.21, p < 0.0001; OR = 1.14, p = 0.010) and lower educational attainment/employment in childhood, adolescence and young-adulthood(OR = 1.40, p < 0.0001; OR = 1.62, p < 0.0001; OR = 1.29, p = 0.005 respectively) and suicidality in childhood (OR = 1.13, p = 0.030). ASD PGS was associated with peer problems and suicidality in childhood (OR = 1.24, p < 0.0001; OR = 1.24, p = p = 0.004; OR = 0.77, p = 0.007). Depression PGS was associated with peer problems in childhood and young-adulthood (OR = 1.18, p = 0.003; OR = 1.21, p < 0.0001), and poorer educational attainment/employment and suicidality in adolescence (OR = 1.39, p = 0.004; OR = 1.28, p < 0.0001) and young-adulthood (OR = 1.26, p = 0.017; OR = 1.42, p < 0.0001). We did not find strong evidence of associations for schizophrenia, bipolar disorder or anxiety PGS. These findings suggest that genetic liability to neurodevelopmental and psychiatric conditions are associated with a range of social/functional outcomes, although the strength and direction of association vary by PGS, outcome and development stage. This highlights the importance of examining genetic liability to multiple conditions simultaneously and of a developmental perspective.

Background: Anxiety and depression often co-occur and typically arise early in the life course. Despite the high prevalence of these conditions in low- and middle-income countries, evidence of early-life factors associated with their developmental patterns remains limited in these settings. Understanding these factors could shape prevention efforts. Methods: Using the Brazil-based Pelotas 2004 Birth Cohort (n=3,815), we examined associations between socioeconomic, maternal, and child factors and previously-derived co-developmental trajectories of anxiety and depression across childhood and adolescence. The likelihood of anxiety and depression diagnoses was assessed using the Development and Wellbeing Assessment bands at ages 6, 11 and 15. Early-life factors were measured from birth to age 6. Results: Previous analyses identified four anxiety and depression co-development trajectories across childhood and adolescence, characterised by stable-low (53.9%), increasing (28.1%), decreasing (15.1%) and persistent-high (2.9%) likelihood of diagnoses. Using the stable-low class as the reference, maternal depression (child aged 1) and childhood emotional/behavioural problems (age 4) were associated with all three other classes (odds ratio (OR) range for maternal depression: 2.52-5.49; for emotional/behavioural problems: 1.06-1.10). Childhood trauma was associated with decreasing (OR: 3.62, 95% CI: 2.44, 5.37) and persistent-high (OR: 3.21, 95% CI: 1.51, 6.85) classes. Low maternal education (OR: 2.90, 95% CI: 1.28, 6.54) and low support from the child’s father during pregnancy (OR: 2.77, 95% CI: 1.20, 6.42) were associated with the persistent-high class. Maternal cohabitation with a partner at birth was associated with lower odds of children being in the increasing class (OR: 0.65, 95% CI: 0.44, 0.96). Conclusion: The co-development of anxiety and depression showed associations with a range of early-life factors. Some factors were associated with anxiety and depression regardless of age at onset (e.g., maternal depression), whilst others were more strongly associated with adolescent-onset (e.g., maternal cohabitation) or persistence across both developmental periods (e.g., maternal education). What’s known?: Mental disorders have been recognized as a major contributor to global disease burden, exhibiting high prevalence among younger populations. Anxiety and depression often co-occur. However, little is known about the early-life factors associated with co-occurrence across childhood and adolescence, particularly in low- and middle-income countries (LMICs). What’s new?: Using a Brazilian longitudinal birth cohort, we identified socioeconomic, maternal and child factors associated with anxiety and depression co-developmental trajectories. Some factors showed associations across both childhood and adolescence (e.g., maternal depression) whilst others were more specific to childhood-onset (e.g., trauma) or adolescent-onset (e.g., maternal cohabiting). What’s relevant?: Our findings identify early-life risk factors associated with co-development of anxiety and depression in an LMIC setting, highlighting potential targets for interventions to prevent adverse trajectories.

Importance Anxiety and depression frequently co occur and show developmentally patterned co-development from childhood to adolescence. Adult psychiatric outcomes vary according to the timing, sequencing, and persistence of early symptoms, yet it remains unclear whether patterns of co development are comparable across high income and low and middle income country contexts. Objective Examine joint developmental trajectories of anxiety and depression from childhood to adolescence and their associations with anxiety and depression diagnoses in young adulthood. Design, Setting and Participants Population based prospective cohort studies in the UK (Avon Longitudinal Study of Parents and Children [ALSPAC], N=9,586) and Brazil (Pelotas 2004 Birth Cohort, N=3,815). Main Outcomes and Measures Trajectories were derived using parallel process latent growth models and latent class growth analyses of anxiety and depression using the Development and Well Being Assessment at early childhood (6-7 years), middle childhood (10-11 years), and adolescence (13-15 years). Diagnoses of anxiety and depression at 18 years were assessed via the Clinical Interview Schedule (ALSPAC) and the Mini International Neuropsychiatric Interview (Pelotas). Results Prevalence of anxiety and depression from early childhood to adolescence was similar across cohorts. Co‑development was stronger in ALSPAC, with modest increases in both conditions, whereas in Pelotas, anxiety increased rapidly while depression showed little average change. In both cohorts, four trajectory classes were identified: stable‑low (ALSPAC, 41%; Pelotas, 54%), increasing (31%; 28%), decreasing (23%; 15%), and persistent‑high anxiety/increasing depression (5%; 3%). Compared with the stable‑low class, youth in the increasing and persistent‑high classes had elevated odds of depression (ALSPAC: OR=2.0 [95% CI, 1.4-2.8] and 4.2 [2.6-6.7]; Pelotas: 2.2 [1.5-3.3] and 2.9 [1.4-6.0]) and anxiety in young adulthood (ALSPAC: 1.6 [1.2-2.2] and 4.8 [3.2-7.0]; Pelotas: 1.7 [1.2-2.6] and 2.9 [1.5-5.8]). No increased risk was observed in the decreasing class. Conclusions and Relevance Patterns of anxiety and depression co development were comparable across the UK and Brazil, suggesting shared developmental pathways. However, more rapid increases in anxiety among Brazilian youth may reflect context specific risk factors. Persistence or emergence beyond early childhood was critical for identifying later diagnostic risk in both settings, highlighting the importance of early monitoring and intervention.

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: Depression is a highly heterogeneous condition. Depression with an onset in childhood and early adolescence has a worse clinical course, is more heritable, and shows a lower genetic correlation with other depression subtypes, than does later‐onset depression. It is also more strongly associated with neurodevelopmental (ND) comorbidities and genetic liability to attention‐deficit hyperactivity disorder. Thus, we hypothesised that early‐onset depression represents a distinctive ‘neurodevelopmental’ depression subtype associated with an increased burden of rare copy number variants (CNVs) that are enriched in ND conditions. We tested this hypothesis using four population cohorts across the UK, Norway, and Sweden. Methods: Participants were ascertained from four population cohorts across the UK, Norway, and Sweden. Early‐onset depression was defined as a score >11 on the self‐reported Short Mood and Feelings Questionnaire between ages 10 and 14 years (cases n = 5994 vs. controls n = 26,388) and, for secondary analyses, using ICD‐10 criteria for major depressive disorder (MDD) with onset 14 years (cases n = 856 vs. controls n = 96,769). Carriers of large, rare (>500 kb, p = 0.12) or ND CNVs (OR = 1.06 [0.85–1.31], p = 0.60). No robust associations were observed between early‐onset depression, defined using ICD‐10 MDD criteria, and large rare CNVs (OR = 1.08 [0.86–1.36], p = 0.49) or ND CNVs (OR = 0.69 [0.34–1.39], p = 0.30). Conclusion: Our findings did not support the hypothesis that individuals with early‐onset depression show enrichment for large, rare or known ND CNVs.

Background: Irritability is a common reason for referral to child and adolescent mental health services. However, debate exists as to whether irritability is best conceptualised and treated as a feature of mood disorder, oppositional defiant disorder or a core symptom of ADHD. Methods: We use network analyses to examine the relationships between adolescent irritability, headstrong/hurtful ODD items, depression and ADHD phenotypes, and polygenic scores (PGS) for depression and ADHD using the Avon Longitudinal Study of Parents and Children (ALSPAC). In primary analysis, irritability, depression, headstrong/hurtful ODD items and ADHD were defined using the Development and Well‐Being Assessment (DAWBA) at age 15. In secondary analysis, phenotypes were defined using the Short Mood and Feelings Questionnaire (SMFQ) and the Strengths and Difficulties Questionnaire (SDQ) ADHD and behavioural subscales at age 13. Finally, we tested for network replicability using confirmatory network analysis in the Millennium Cohort Study (MCS). Results: Results of network analyses using the DAWBA in ALSPAC indicated irritability was most strongly associated with headstrong/hurtful ODD items, followed by ADHD and depression. When including PGS, we observed an edge between irritability and depression PGS but not between irritability and ADHD PGS. Irritability appeared to be the primary pathway between ADHD and depression as well as between headstrong/hurtful ODD items and depression. Results were similar using SMFQ/SDQ in ALSPAC and confirmatory network analysis indicated excellent model fit in MCS. Conclusions: Although irritability appears to be transdiagnostic, phenotypically, it was most strongly associated with headstrong/hurtful ODD items and broader behavioural problems, which favours the ICD‐11 approach of including irritability as a specifier of ODD. However, irritability appeared to be a key connector between both ADHD and behavioural problems to depression; thus, is important to monitor and treat in affected youth with ADHD or behavioural problems.

Neurodevelopmental and psychiatric conditions often originate in youth and can lead to adverse social and functional outcomes. However, it is unclear whether these associations are driven by genetic liability to these conditions, with possible developmental differences. We examined multivariable associations between polygenic scores (PGS) for attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder, depression, anxiety and three outcomes: peer problems, educational attainment/NEET (not in education, employment or training) and suicidality, in childhood, adolescence and young-adulthood. Data were analysed from the Avon Longitudinal Study of Parents and Children, with outcomes at ages 10–13, 16 and 24–25 years. ADHD PGS was associated with peer problems in childhood, adolescence and young-adulthood, as well as with lower educational attainment in childhood/adolescence and NEET status in young-adulthood. ASD PGS was associated with greater educational attainment in childhood and adolescence, and increased likelihood of suicidality in childhood. Depression PGS was associated with peer problems in childhood and young-adulthood, and poorer educational attainment/NEET and suicidality in adolescence and young-adulthood. We did not find strong evidence of associations for schizophrenia, bipolar disorder or anxiety PGS. These findings suggest that genetic liability to neurodevelopmental and psychiatric conditions are associated with a range of social/functional outcomes, although the strength and direction of association varies by PGS, outcome and development stage. This highlights the importance of examining genetic liability to multiple neurodevelopmental and psychiatric conditions simultaneously and of a developmental perspective.

Background: The prevalence of youth anxiety and depression has increased globally, with limited causal explanations. Long-term physical health conditions (LTCs) affect 20–40% of youth, with rates also rising. LTCs are associated with higher rates of youth depression and anxiety; however, it is uncertain whether observed associations are causal or explained by unmeasured confounding or reverse causation. Methods: Using data from the Norwegian Mother, Father, and Child Cohort Study (MoBa) and Norwegian National Patient Registry, we investigated phenotypic associations between childhood LTCs, and depression and anxiety diagnoses in youth (−4) and anxiety disorder risk (OR = 1.44 [1.20, 1.73], p = 7.9×10⁻⁵). Observational and MR analyses in MoBa were consistent with a causal relationship between migraine and depression (IVW OR = 1.38 [1.19, 1.60], p_FDR = 1.8x10⁻⁴). MR analyses using iPSYCH2015 did not support a causal link between LTC genetic liabilities and youth-onset depression or in the reverse direction. Conclusions: Childhood LTCs are associated with depression and anxiety in youth, however, little evidence of causation between LTCs genetic liability and youth depression/anxiety was identified from MR analyses, except for migraine.

Anxiety and depression (emotional disorders) are familial and heritable, especially when onset is early. However, other cross-generational studies suggest transmission of youth emotional problems is explained by mainly environmental risks. We set out to test the contribution of parental non-transmitted genetic liability, as indexed by psychiatric/neurodevelopmental common polygenic liability, to youth emotional problems using a UK population-based cohort: the Millennium Cohort Study. European (N = 6328) and South Asian (N = 814) ancestries were included, as well as a subset with genomic data from both parents (European: N = 2809; South Asian: N = 254). We examined the association of transmitted (PGS_T) and non-transmitted polygenic scores (PGS_NT) for anxiety, depression, bipolar disorder and neurodevelopmental disorders (attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD], schizophrenia) with youth emotional disorder and symptom scores, measured using the parent- and self-reported Strengths and Difficulties Questionnaire emotional subscale at 6 timepoints between ages 3–17 years. In the European sample, PGS_T for anxiety and depression, but not bipolar disorder, were associated with emotional disorder and symptom scores across all ages, except age 3, with strongest association in adolescence. ADHD and ASD PGS_T also showed association across ages 11–17 years. In the South Asian sample, evidence for associations between all PGS_T and outcome measures were weaker. There was weak evidence of association between PGS_NT for anxiety and depression and age 17 symptom scores in the South Asian sample, but not in the European sample for any outcome. Overall, PGS_T for depression, anxiety, ADHD and ASD contributed to youth emotional problems, with stronger associations in adolescence. There was limited support for non-transmitted genetic effects: these findings do not support the hypothesis that parental polygenic psychiatric/neurodevelopmental liability confer risk to offspring emotional problems through non-transmitted rearing/nurture effects.