RCN: Identifying Causal Risk Factors and Treatments for Depression, Anxiety, and ADHD in Young People

Context: Depression, anxiety, and attention deficit hyperactivity disorder (ADHD) are common mental health conditions that occur from childhood to adolescence and have major impacts on young people’s well-being, development, and educational and economic outcomes. The Challenge Discovering effective interventions to mitigate the adverse consequences of these conditions requires reliable causal evidence. However, limitations of existing evidence include: Limited evidence from RCTs: There are relatively few randomised trials of young people and those that do have small sample sizes, limited follow-up, and do not record critical outcomes of interest to patients and the public. Observational studies can be unreliable because controlling all pre-existing differences between individuals (confounding), reverse causation, and differentiating familial factors is challenging. Conventional Mendelian randomization using population-based summary data can be unreliable because it does not differentiate societal and familial factors from causation. This project aims to leverage large-scale genetic data to better understand the causes of these conditions and inform the development of effective interventions to improve young people's mental health. It will use a novel Mendelian randomization phenome-wide association study (MR-PheWAS) within family Mendelian randomization and drug-target Mendelian randomization analyses. Aims and approaches Aim: To provide reliable causal evidence of mechanisms that affect young people’s mental health. This project will develop reliable evidence of causal mechanisms and potential intervention targets and strategies to improve outcomes for young people with 1) depression and anxiety and 2) ADHD using three approaches: Approach 1: Discover when the earliest symptoms of depression, anxiety and ADHD emerge and evaluate the direction of causation for risk factors. Approach 2: Investigate how familial factors affect young people’s mental health. Approach 3: Evaluate existing drugs and discover new targets for improving young people’s mental health. Secondary objectives Apply, adapt and validate existing pipelines and methods for depression, anxiety and ADHD. Disseminate our research findings. Develop and deliver advanced methods workshops and short courses. Impacts Advance scientific knowledge by providing new evidence about modifiable environmental risk factors and potential effective interventions. Apply rigorous methods by developing and applying three novel molecular genetic techniques, including MR-PheWAS, within family and drug-target Mendelian randomization. Provide new evidence from some of the largest family-based studies in the world, such as the Norwegian Mother, Father and Child Cohort Study (MoBa), Millennium Cohort Study (MCS), and Born in Bradford (BiB). Include diverse populations by analysing ethnically diverse samples from BiB and MCS, improving the diversity of genetic epidemiological studies. Direct and indirect benefits Build collaborations via interdisciplinary collaborations with researchers with expertise in clinical psychiatry (Argyris), psychology (Pingault), quantitative sociology (Bann), population genetics (Badini), genetic epidemiology (Hemani), social epidemiology (Howe), econometrics (Sanderson), and internationally, clinical psychology (Havdahl). Training and capacity building, particularly for early career researchers and graduate students, via short courses and tutorial papers. Dissemination of findings and best practices via pre-registration, code review, reproducible code publication, and guidelines for genetic epidemiological analyses. How will this project improve human health and clinical practice? This project will improve our understanding of the causes of depression, anxiety, and ADHD in young people using longitudinal and genetic data. The findings will inform the development of future interventions, ultimately improving outcomes for young people, their families, and society.