MEGA-OCD: A Global Data-Driven Initiative to Discover Biosignatures of OCD - ABSTRACT We launch the MEGA-OCD Initiative - the largest, most highly powered neuroimaging investigation of obsessive compulsive disorder (OCD), drawing on diverse worldwide data to rigorously address pressing questions in OCD with unprecedented statistical power. OCD is a leading cause of global disability, and a severe and debilitating mental disorder. Symptoms start in childhood for about 50% of cases, and less than half of patients respond to first line interventions, so most OCD patients have a chronic course. Multimodal neuroimaging can elucidate circuitry and mechanisms underlying disease and treatment response, but studies have failed to address 3 major barriers to discovery: 1) inadequate sample sizes with low statistical power, coupled with variation in unimodal imaging methods, yielding a reproducibility crisis; 2) clinical heterogeneity (where brain correlates depend on developmental and disease stage); and 3) poor representation of diverse populations. To address this and NIH’s Call for Diversity, we create a highly-powered international study of unprecedented scale - the first with the global inclusion and data harmonization expertise to identify factors robustly influencing disease course, and genetic drivers of brain alterations. Drawing on 10 years’ experience coordinating international OCD studies, we combine data from two worldwide OCD consortia: ENIGMA-OCD Consortium - where 43 sites in 18 countries actively participate with data from 3,583 OCD cases (668 children/2,915 adults) and 3,505 controls (654 children/2,851 adults), and the Global-OCD Consortium - evaluating 268 deeply-phenotyped unmedicated adults with OCD, 256 healthy controls, and 80 unaffected siblings across 5 continents (North and South America, Africa, Asia, and Europe). Leveraging both samples and the expertise of these consortia, our Aims are: 1) establish biosignatures of OCD by combining structural, diffusion, and resting state functional MRI, and relate these ‘multi-layer’ signatures to age, developmental and disease stage, medication, and comorbidities. We launch worldwide analyses of task-based fMRI (focusing on emotion, inhibitory control, executive function) to yield novel functional insights into OCD; 2) use multimodal machine learning to fuse clinical and imaging metrics to: discriminate OCD from health, identify OCD biotypes corresponding to clinical subtypes, and predict treatment response; and 3) determine how OCD brain signatures relate to gene expression. A global resource for OCD researchers, our novel MEGA-OCD Initiative will identify reproducible multi-modal biosignatures of disease that incorporate diversity in developmental stage, clinical profiles (subtypes, comorbidity, cognition) and culture. Robust brain-based signatures of OCD profiles and biotypes and understanding neurogenetic risk for OCD will advance neurocircuit models of OCD, contribute to new treatment targets, and provide a foundation for precision psychiatry. Leveraging diverse samples (ENIGMA-OCD: 43 sites/18 countries; Global-OCD: 5 sites/5 continents), our findings will have both local and global impact and be relevant to populations around the globe.
