The genetic structure of anxiety disorders and major depressive disorder: examining the distress and fear model using twin and genomic methods

Anxiety and major depressive disorders are the most common mental health problems. They are highly comorbid, as individuals with an anxiety disorder are more likely to be diagnosed with major depressive disorder, and vice versa. A two-dimensional model of distress and fear may constitute the most optimal hierarchical model to explain this comorbidity. The distress and fear model suggests that generalised anxiety disorder and major depressive disorder fall under a distress dimension while the other anxiety disorders, including social anxiety, specific phobia, panic disorder, and agoraphobia, cluster under a fear dimension. Twin and preliminary genomic findings provide partial genetic support for this model. However, there is mixed evidence regarding the genetic factors underpinning the fear disorders, and genetically sensitive studies including all fear disorders are rare. The present study will address this gap by examining the distress and fear structure using two complementary genetic approaches: twin and genome-wide structural equation modelling (GW-SEM). Data from approximately 8,000 participants from the Twins Early Development Study at 26 years old (TEDS26) and 58,000 participants from studies in the National Institute for Health and Care Research (NIHR) Mental Health BioResource, including the Genetic Links to Anxiety and Depression (GLAD) Study and the COVID-19 Psychiatric and Neurological Genetics (COPING) study will be used. Participants completed online questionnaires to evaluate anxiety and major depressive disorders. For each disorder, two measures were collected: a detailed symptom-based and a brief single-item measure. The detailed measures were adapted versions of the Composite International Diagnostic Interview, Short Form (CIDI-SF). Brief single-item diagnoses were evaluated using a measure of past diagnosis by a professional via the Mental Health Diagnosis Questionnaire (MHD). We will test and compare two types of structural models using both twin and genomic modelling: a unidimensional and a two-dimensional genetic model. Common pathway models will be tested using twin data in OpenMx, and genomic structural equation analyses will be conducted using individual-level genomic data from the GLAD Study and COPING in GW-SEM. Analyses will be run from July to September 2023. We anticipate that the two-dimensional common pathway model will show a better fit than the unidimensional model, thereby providing support for the distress and fear classification. Findings will contribute to a better understanding of the genetic structure of the distress and fear model, and as such, will better inform disorder classification and treatment.