Person-level contributions of bipolar polygenic risk score to the prediction of new-onset bipolar disorder in at-risk offspring.

BACKGROUND: Previous work indicates that polygenic risk scores (PRS) for bipolar disorder (BD) are elevated in adults and youth with BD, but whether BD-PRS can inform person-level diagnostic prediction is unknown. Here, we test whether BD-PRS improves performance of a previously published risk calculator (RC) for BD. METHODS: 156 parents with BD-I/II and their offspring ages 6-18 were recruited and evaluated with standardized diagnostic assessments every two years for >12 years. DNA was extracted from saliva samples, genotyping performed, and BD-PRS calculated based on a 2021 meta-analysis. Using a bootstrapped and cross-validated penalized Cox regression, we assessed whether BD-PRS (alone and interacting with clinical variables) improved RC performance. RESULTS: Of 227 offspring, 38 developed BD during follow-up. The penalized regression selected BD-PRS and interactions between BD-PRS and parental age at mood disorder onset (AAO), depression, and anxiety. The resulting RC discriminated offspring who developed BD (vs. those that did not) with good accuracy (AUC = 0.81); removing BD-PRS and its interaction terms was associated with a significant decrement to the AUC (decrement = 0.07, p = 0.039). Further exploration of selected interaction terms indicated that all were significant (p-values<0.02), indicating that BD-PRS has a larger effect on the outcome in offspring with depression and anxiety, whose affected parent had a younger AAO. CONCLUSIONS: The addition of BD-PRS to clinical/demographic predictors in the RC significantly improved its accuracy. BD-PRS predicted BD on the person-level, particularly in offspring of parents with earlier AAO who already had symptoms of anxiety and depression at intake.

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents.

OBJECTIVE: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. METHODS: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. RESULTS: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets. CONCLUSIONS: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.

Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth.

Importance: Establishing genetic contributions to the transmission of bipolar disorder (BD) from parents to offspring may inform the risk of developing this disorder and further serve to validate BD in youth. Objective: To evaluate the specific association of BD polygenic risk scores (PRSs) on the familial transmission and validity of pediatric BD. Design, Setting, and Participants: This community-based case-control longitudinal study (Pittsburgh Biological Offspring Study) included parents with BD I/II and their offspring and parents without BD (healthy or non-BD psychopathology) and their offspring. Participants were recruited between March 2001 and May 2007, and analysis took place from December 2020 to September 2021. Exposures: PRSs for BD, major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder. Main Outcomes and Measures: Participants were prospectively evaluated using standardized interviews blind to parental diagnosis. DNA was extracted from saliva and genotyped. PRSs were constructed based on independent large-scale genome-wide association studies. Results: A total of 156 parents with BD I/II and 180 parents without BD (mean [SD] age, 39.6 [7.9] years; 241 female [72%]) as well as 251 offspring of parents with BD and 158 offspring of parents without BD (mean [SD] age, 10.4 [4.7] years; 213 female [52%]) of European ancestry were analyzed. Participants were assessed a mean of 6.7 times during a mean (SD) of 13 (3.4) years of follow-up (84% retention). More offspring of parents with BD developed BD (58 [23.1%] vs 8 [5.1%]; P < .001) and depression (126 [50.2%] vs 52 [32.9%]; P < .001) compared with offspring of parents without BD. BD PRS was higher in both parents and offspring with BD than parents and offspring without BD (parents: odds ratio, 1.50; 95% CI, 1.19-1.89; P < .001; explained 4.8% of the phenotypic variance vs offspring: hazard ratio, 1.34; 95% CI, 1.03-1.7; P = .02; explained 5.0% of the phenotypic variance). BD PRS did not differ across BD subtypes. In a model combining parental and offspring BD PRS, the parental BD PRS association with offspring BD was fully mediated by offspring BD PRS (hazard ratio, 1.40; 95% CI, 1.05-1.86; P = .02). Parental BD had a stronger direct association than parental or offspring BD PRS with offspring BD risk (hazard ratio, 5.21; 95% CI, 1.86-14.62; P = .002), explaining 30% of the variance. Parental and offspring BD PRS explained 6% of the BD onset variance beyond parental diagnosis. There were no significant between-group differences in PRSs for major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder in parents or offspring and they were not significantly associated with BD onset. Conclusions and Relevance: The findings of this study add to the extant clinical validation of BD in youth. Parental BD and offspring BD PRS independently associated with the risk of BD in offspring. Although this is promising, the association of BD PRS was relatively small and cannot be used alone to determine BD risk until further developments occur.

Youth Experience Tracker Instrument: A self-report measure of developmental antecedents to severe mental illness.

AIM: We sought to examine the structure, internal consistency, convergent and criterion validity of the Youth Experience Tracker Instrument (YETI), a new brief self-report measure designed to facilitate early identification of risk for severe forms of mental illness, including major depressive disorder, bipolar disorder, and schizophrenia. METHODS: We collected 716 YETIs from 315 individuals aged 8 to 27 with and without familial risk of severe mental illness. The YETI measures six developmental antecedents that precede and predict serious forms of mental illness: affective lability, anxiety, basic symptoms, depressive symptoms, psychotic-like experiences, and sleep. A battery of concurrent questionnaires and interviews measured the same constructs. RESULTS: The best-fitting bifactor model supported the validity of both total score and antecedent-specific subscales. Internal consistency was high for the total score (ω = 0.94) and subscales (ω = 0.80-0.92; ρ = 0.72). The total score captured the majority of information from the 26 YETI items (hierarchical omega ωh = 0.74). Correlations of YETI subscales with established measures of the same constructs (r = 0.45-0.80) suggested adequate convergent validity. We propose cut-offs with high negative predictive values to facilitate efficient risk screening. CONCLUSION: The YETI, a brief self-report measure of antecedents, provides an alternative to using multiple longer instruments. Future research may examine the predictive validity of the YETI for the onset of major mood and psychotic disorders.

Genetic counselling for the prevention of mental health consequences of cannabis use: A randomized controlled trial-within-cohort.

BACKGROUND: Cannabis use is a risk factor for severe mental illness. However, cannabis does not affect everyone equally. Genetic information may help identify individuals who are more vulnerable to the harmful effects of cannabis on mental health. A common genetic variant within the AKT1 gene selectively increases risk of psychosis, only among those who use cannabis. Therapeutically oriented genetic counselling may enable us to reduce cannabis exposure among genetically sensitive individuals. METHODS: Using a trial-within-cohort design, we aim to test if genetic counselling, including the option to receive AKT1 rs2494732 genotype, reduces cannabis use. To this end, we have designed a genetic counselling intervention: Interdisciplinary approach to Maximize Adolescent potential: Genetic counselling Intervention to reduce Negative Environmental effects (IMAGINE). RESULTS: IMAGINE will be implemented in a cohort of children and youth enriched for familial risk for major mood and psychotic disorders. Approximately 110 eligible individuals aged 12-21 years will be randomized in a 1:1 ratio to be offered a single genetic counselling session with a board-certified genetic counsellor, or not. Allocated youth will also be invited to attend a follow-up session approximately 1 month following the intervention. The primary outcome will be cannabis use (measured by self-report or urine screen) at subsequent annual assessments as part of the larger cohort study. Secondary outcomes include intervention acceptability and psychopathology. CONCLUSION: This study represents the first translational application of a gene-environment interaction to improve mental health and test an intervention with potential public health benefits. This study is registered with clinicaltrials.gov (NCT03601026).

Cognitive-behavioural interventions for prevention and treatment of anxiety in young children: A systematic review and meta-analysis.

BACKGROUND: Anxiety disorders are common and impairing throughout the life course. Propensity to anxiety disorders manifests as distress and avoidance of novel stimuli (called behavioural inhibition) as early as in infancy. Already in preschool children, anxiety disorders impact emotional development and school readiness. Anxiety disorders and behavioural inhibition are prospectively associated with increased risk of mood disorders, substance use, and suicide. Therefore, early targeted prevention and treatment need to be considered. Cognitive-behavioural interventions are effective for anxiety in older age group but their efficacy for preschool children remains to be established. METHODS: We searched PsycINFO, PubMed, and Embase until September 19th, 2019 using terms describing anxiety, behavioural inhibition, intervention, and young children. We included studies with young children participating in a cognitive-behavioural intervention for anxiety disorders, anxiety symptoms, or behavioural inhibition. We completed random-effects robust meta-analyses to (1) compare anxiety measures before and after intervention and to (2) compare intervention and control groups. RESULTS: We identified 43 samples including 2656 participants with a mean age of 5.45 (SD = 1.00) years. Anxiety decreased after cognitive-behavioural intervention (standardized mean difference [SMD] = -1.34, 95%CI -1.59 to -1.09, p < 0.0001). Anxiety decreased more in children who received intervention than in children in control conditions (SMD = -0.81, 95%CI -1.00 to -0.63, p < 0.0001). The difference remained significant after correcting for potential publication bias and outliers (SMD = -0.89, 95% CI -1.13 to -0.66, p < 0.0001). The improvement was maintained over follow-up. CONCLUSIONS: Cognitive-behavioural interventions are effective for prevention and treatment of anxiety in young children.

Cognition in offspring of parents with psychotic and non-psychotic severe mental illness.

BACKGROUND: Cognitive impairment is a feature of severe mental illness (SMI; schizophrenia, bipolar disorder, major depressive disorder). Psychotic forms of SMI may be associated with greater cognitive impairment, but it is unclear if this differential impairment pre-dates illness onset or whether it reflects a consequence of the disorder. To establish if there is a developmental impairment related to familial risk of psychotic SMI, we investigated cognition in offspring of parents with psychotic and non-psychotic SMI. METHOD: Participants included 360 children and youth (mean age 11.10, SD 4.03, range 6-24), including 68 offspring of parents with psychotic SMI, 193 offspring of parents with non-psychotic SMI, and 99 offspring of control parents. The cognitive battery assessed a range of functions using standardized tests and executive function tasks from the Cambridge Automated Neuropsychological Test Battery. RESULTS: Compared to controls, offspring of parents with psychotic SMI performed worse on overall cognition (ß = -0.32; p < 0.001) and 6 of 15 cognitive domains, including verbal intelligence, verbal working memory, processing speed, verbal learning and memory, verbal fluency, and sustained attention. Offspring of parents with non-psychotic SMI performed worse than controls on 3 of the 15 domain specific cognitive tests, including verbal intelligence, visual memory and decision-making. CONCLUSIONS: Widespread mild-to-moderate cognitive impairments are present in young offspring at familial risk for transdiagnostic psychotic SMI. Offspring at familial risk for non-psychotic SMI showed fewer and more specific impairments in the domains of verbal intelligence, visual memory and decision-making.

Visual memory and psychotic symptoms in youth.

BACKGROUND: Psychotic symptoms are common during childhood and adolescence and may indicate transdiagnostic risk of future psychiatric disorders. Lower visual memory ability has been suggested as a potential indicator of future risk of mental illness. The relationship between visual memory and clinician-confirmed definite psychotic symptoms in youth has not yet been explored. METHODS: We examined visual memory and psychotic symptoms among 205 participants aged 7-27 years in a cohort enriched for parental mood and psychotic disorders. We assessed visual memory using the Rey Complex Figure Test (RCFT) and psychotic symptoms using validated semi-structured interview measures. We tested the relationship between visual memory and psychotic symptoms using mixed-effects logistic regression. RESULTS: After accounting for age, sex, and family clustering, we found that psychotic symptoms were significantly associated with lower visual memory (OR = 1.80, 95% CI 1.06-3.06, p = 0.030). This result was unchanged after accounting for general cognitive ability. CONCLUSION: Lower visual memory performance is associated with psychotic symptoms among youth, regardless of general cognitive ability. This finding may inform future targeted early interventions.

Affective lability in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia.

Affective lability, defined as the propensity to experience excessive and unpredictable changes in mood, has been proposed as a potential transdiagnostic predictor of major mood and psychotic disorders. A parental diagnosis of bipolar disorder has been associated with increased affective lability in offspring. However, the association between affective lability and family history of other mood and psychotic disorders has not been examined. We measured affective lability using the self- and parent-reported Children's Affective Lability Scale in a cohort of 320 youth aged 6-17 years, including 137 offspring of a parent with major depressive disorder, 68 offspring of a parent with bipolar disorder, 24 offspring of a parent with schizophrenia, and 91 offspring of control parents. We tested differences in affective lability between groups using mixed-effects linear regression. Offspring of a parent with major depressive disorder (ß = 0.46, 95% CI 0.17-0.76, p = 0.002) or bipolar disorder (ß = 0.47, 95% CI 0.12-0.81, p = 0.008) had significantly higher affective lability scores than control offspring. Affective lability did not differ significantly between offspring of a parent with schizophrenia and offspring of control parents. Our results suggest that elevated affective lability during childhood is a marker of familial risk for mood disorders.

Neurodevelopmental and genetic determinants of exposure to adversity among youth at risk for mental illness.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and lower cognitive ability have been linked with increased likelihood of exposure to adversity. We hypothesized that these associations may be partly due to genetic factors. METHODS: We calculated polygenic scores for ADHD and intelligence and assessed psychopathology and general cognitive ability in a sample of 297 youth aged 5-27 years enriched for offspring of parents with mood and psychotic disorders. We calculated an adversity score as a mean of 10 indicators, including socio-economic disadvantage, childhood maltreatment and bullying. We tested the effects of polygenic scores, externalizing symptoms and IQ on adversity scores using mixed-effects linear regression. RESULTS: Externalizing symptoms and general cognitive ability showed expected positive and negative relationships with adversity, respectively. Polygenic scores for intelligence were unrelated to adversity, but polygenic scores for ADHD were associated with adversity (ß = 0.23, 95% CI 0.13 to 0.34, p < .0001). ADHD polygenic scores uniquely explained 4.0% of variance in adversity score. The relationship between polygenic scores for ADHD and adversity was independently significant among individuals with (ß = 0.49, 95% CI 0.25 to 0.75, p < .0001) and without (ß = 0.14, 95% CI 0.02 to 0.26, p = .022) ADHD. CONCLUSIONS: A genetic score indexing liability to ADHD was associated with exposure to adversity in early life. Previously observed associations between externalizing symptoms, lower cognitive ability and adversity may be partially attributed to genetic liability to ADHD.

Psychotic symptoms are associated with lower cortical folding in youth at risk for mental illness

Background: Cortical folding is essential for healthy brain development. Previous studies have found regional reductions in cortical folding in adult patients with psychotic illness. It is unknown whether these neuroanatomical markers are present in youth with subclinical psychotic symptoms. Methods: We collected MRIs and examined the local gyrification index in a sample of 110 youth (mean age ± standard deviation 14.0 ± 3.7 yr; range 9­25 yr) with a family history of severe mental illness: 48 with psychotic symptoms and 62 without. Images were processed using the Human Connectome Pipeline and FreeSurfer. We tested for group differences in local gyrification index using mixed-effects generalized linear models controlling for age, sex and familial clustering. Sensitivity analysis further controlled for intracranial volume, IQ, and stimulant and cannabis use. Results: Youth with psychotic symptoms displayed an overall trend toward lower cortical folding across all brain regions. After adjusting for multiple comparisons and confounders, regional reductions were localized to the frontal and occipital lobes. Specifically, the medial (B = ­0.42, pFDR = 0.04) and lateral (B = ­0.39, pFDR = 0.04) orbitofrontal cortices as well as the cuneus (B = ­0.47, pFDR = 0.03) and the pericalcarine (B = ­0.45, pFDR = 0.03) and lingual (B = ­0.38, pFDR = 0.04) gyri. Limitations: Inference about developmental trajectories was limited by the cross-sectional data. Conclusion: Psychotic symptoms in youth are associated with cortical folding deficits, even in the absence of psychotic illness. The current study helps clarify the neurodevelopmental basis of psychosis at an early stage, before medication, drug use and other confounds have had a persistent effect on the brain.

Active behaviors and screen time in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia.

Activities may be modifiable factors that moderate the risk and resilience in the development of mental health and illness. Youth who spend more time using screens are more likely to have poor mental health. Conversely, time spent engaged in active behaviors (i.e., physical activity, socializing and reading) is associated with better mental health. The choice of activities may be important in offspring of parents with mental illness, who are at increased risk for developing mental disorders. Among 357 youth of the FORBOW (Families Overcoming Risks and Building Opportunities for Well-being) cohort aged 6-21, we examined whether parental diagnosis of mental illness (i.e., major depressive disorder, schizophrenia and bipolar disorder) and current levels of depression influenced the amount of time their offspring spent using screens and engaging in active behaviors. Parental history of mental illness and higher levels of current depression in mothers were associated with less time spent engaged in active behaviors and more time spent using screens. Creating opportunities and incentives for active behaviors may redress the balance between youth with and without a familial history of mental illness.

Basic symptoms in offspring of parents with mood and psychotic disorders.

BACKGROUND: Basic symptoms, defined as subjectively perceived disturbances in thought, perception and other essential mental processes, have been established as a predictor of psychotic disorders. However, the relationship between basic symptoms and family history of a transdiagnostic range of severe mental illness, including major depressive disorder, bipolar disorder and schizophrenia, has not been examined. AIMS: We sought to test whether non-severe mood disorders and severe mood and psychotic disorders in parents is associated with increased basic symptoms in their biological offspring. METHOD: We measured basic symptoms using the Schizophrenia Proneness Instrument - Child and Youth Version in 332 youth aged 8-26 years, including 93 offspring of control parents, 92 offspring of a parent with non-severe mood disorders, and 147 offspring of a parent with severe mood and psychotic disorders. We tested the relationships between parent mental illness and offspring basic symptoms in mixed-effects linear regression models. RESULTS: Offspring of a parent with severe mood and psychotic disorders (B = 0.69, 95% CI 0.22-1.16, P = 0.004) or illness with psychotic features (B = 0.68, 95% CI 0.09-1.27, P = 0.023) had significantly higher basic symptom scores than control offspring. Offspring of a parent with non-severe mood disorders reported intermediate levels of basic symptoms, that did not significantly differ from control offspring. CONCLUSIONS: Basic symptoms during childhood are a marker of familial risk of psychopathology that is related to severity and is not specific to psychotic illness. DECLARATION OF INTEREST: None.

Sleep in Offspring of Parents With Mood Disorders.

Background: Sleep problems in childhood are an early predictor of mood disorders among individuals at high familial risk. However, the majority of the research has focused on sleep disturbances in already diagnosed individuals and has largely neglected investigating potential differences between weeknight and weekend sleep in high-risk offspring. This study examined sleep parameters in offspring of parents with major depressive disorder or bipolar disorder during both weeknights and weekends. Methods: We used actigraphy, sleep diaries, and questionnaires to measure several sleep characteristics in 73 offspring aged 4-19 years: 23 offspring of a parent with major depressive disorder, 22 offspring of a parent with bipolar disorder, and 28 control offspring. Results: Offspring of parents with major depressive disorder slept, on average, 26 min more than control offspring on weeknights (95% confidence interval, 3 to 49 min, p = 0.027). Offspring of parents with bipolar disorder slept, on average, 27 min more on weekends than on weeknights compared to controls, resulting in a significant family history × weekend interaction (95% confidence interval, 7 to 47 min, p = 0.008). Conclusions: Sleep patterns in children and adolescents were related to the psychiatric diagnosis of their parent(s). Future follow-up of these results may clarify the relations between early sleep differences and the risk of developing mood disorders in individuals at high familial risk.

Genetic disposition to inflammation and response to antidepressants in major depressive disorder.

BACKGROUND: Inflammation may play an important role in depression and its treatment. A previous study found that increased C-reactive protein (CRP), a marker of systemic inflammation, is associated with worse response to the serotonergic antidepressant escitalopram and better response to the noradrenergic antidepressant nortriptyline. It is unclear whether this reflects genetic disposition to inflammation. METHODS: We analyzed genotype data and weekly Montgomery-Åsberg Depression Rating Scale scores (MADRS) from 755 unrelated individuals obtained over a 12-week period in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. We calculated a polygenic risk score for CRP level based on genome-wide meta-analysis results from the CHARGE Consortium. RESULTS: A higher polygenic risk score for CRP was associated with slightly better response to escitalopram and slightly worse response to nortriptyline, reflected in a statistically significant interaction between polygenic risk score and drug (beta = 1.07, 95% CI = 0.26-1.87, p = 0.0093). DISCUSSION: A differential association between CRP-PRS and antidepressant drug that is in a direction opposite to that found with serum CRP measurement suggests that previously observed effect of inflammation on antidepressant efficacy may be driven by state factors distinct from genetic influences on systemic inflammation.

Gene-environment interplay in the etiology of psychosis.

Schizophrenia and other types of psychosis incur suffering, high health care costs and loss of human potential, due to the combination of early onset and poor response to treatment. Our ability to prevent or cure psychosis depends on knowledge of causal mechanisms. Molecular genetic studies show that thousands of common and rare variants contribute to the genetic risk for psychosis. Epidemiological studies have identified many environmental factors associated with increased risk of psychosis. However, no single genetic or environmental factor is sufficient to cause psychosis on its own. The risk of developing psychosis increases with the accumulation of many genetic risk variants and exposures to multiple adverse environmental factors. Additionally, the impact of environmental exposures likely depends on genetic factors, through gene-environment interactions. Only a few specific gene-environment combinations that lead to increased risk of psychosis have been identified to date. An example of replicable gene-environment interaction is a common polymorphism in the AKT1 gene that makes its carriers sensitive to developing psychosis with regular cannabis use. A synthesis of results from twin studies, molecular genetics, and epidemiological research outlines the many genetic and environmental factors contributing to psychosis. The interplay between these factors needs to be considered to draw a complete picture of etiology. To reach a more complete explanation of psychosis that can inform preventive strategies, future research should focus on longitudinal assessments of multiple environmental exposures within large, genotyped cohorts beginning early in life.

Etiology in psychiatry: embracing the reality of poly-gene-environmental causation of mental illness.

Intriguing findings on genetic and environmental causation suggest a need to reframe the etiology of mental disorders. Molecular genetics shows that thousands of common and rare genetic variants contribute to mental illness. Epidemiological studies have identified dozens of environmental exposures that are associated with psychopathology. The effect of environment is likely conditional on genetic factors, resulting in gene-environment interactions. The impact of environmental factors also depends on previous exposures, resulting in environment-environment interactions. Most known genetic and environmental factors are shared across multiple mental disorders. Schizophrenia, bipolar disorder and major depressive disorder, in particular, are closely causally linked. Synthesis of findings from twin studies, molecular genetics and epidemiological research suggests that joint consideration of multiple genetic and environmental factors has much greater explanatory power than separate studies of genetic or environmental causation. Multi-factorial gene-environment interactions are likely to be a generic mechanism involved in the majority of cases of mental illness, which is only partially tapped by existing gene-environment studies. Future research may cut across psychiatric disorders and address poly-causation by considering multiple genetic and environmental measures across the life course with a specific focus on the first two decades of life. Integrative analyses of poly-causation including gene-environment and environment-environment interactions can realize the potential for discovering causal types and mechanisms that are likely to generate new preventive and therapeutic tools.