Mega-Analysis Methods in ENIGMA: The Experience of the Generalized Anxiety Disorder Working Group (2025)

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group

Translational Psychiatry

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random int...

Heritability estimates on resting state fMRI data using ENIGMA analysis pipeline

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing, 2018

Big data initiatives such as the Enhancing NeuroImaging Genetics through Meta-Analysis consortium (ENIGMA), combine data collected by independent studies worldwide to achieve more generalizable estimates of effect sizes and more reliable and reproducible outcomes. Such efforts require harmonized image analyses protocols to extract phenotypes consistently. This harmonization is particularly challenging for resting state fMRI due to the wide variability of acquisition protocols and scanner platforms; this leads to site-to-site variance in quality, resolution and temporal signal-to-noise ratio (tSNR). An effective harmonization should provide optimal measures for data of different qualities. We developed a multi-site rsfMRI analysis pipeline to allow research groups around the world to process rsfMRI scans in a harmonized way, to extract consistent and quantitative measurements of connectivity and to perform coordinated statistical tests. We used the single-modality ENIGMA rsfMRI prepr...

ENIGMA and Global Neuroscience: A Decade of Large-Scale Studies of the Brain in Health and Disease across more than 40 Countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics throughMeta Analysis) Consortium, a global alliance of over 1,400 scientists across 43 countries, studying the humanbrain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicatedgenetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), poolingworldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, andgenetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normalvariation due to sex and gender differences, or development and aging; still other WGs develop methodologicalpipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodalMRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studiesto date in schizop...

Distinct neurostructural signatures of anxiety-, fear-related and depressive disorders: a comparative voxel-based meta-analysis

2021

Internalizing disorders encompass anxiety, fear and depressive disorders. While the DSM-5 nosology conceptualizes anxiety and fear-related disorders as an entity, dimensional psychopathology models suggest that generalized anxiety disorders (GAD) and major depression originate from an overarching “anxious-misery” factor whereas fear-related disorders originate from the “fear” factor. Given that a neurobiological evaluation is lacking, we conducted a comparative neuroimaging meta-analysis of gray matter volume alterations to determine common and disorder-specific brain structural signatures in these disorders. The PubMed, Web of Knowledge, and Scopus databases were searched for case-control voxel-based morphometric studies through December, 2020 in GAD, fear-related anxiety disorders (FAD, i.e., social anxiety disorders, SAD; specific phobias, SP; panic disorders, PD; and agoraphobia, AG) and major depressive disorder (MDD). Neurostructural abnormalities were assessed within each dis...

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Brain imaging and behavior, 2014

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Pilot multimodal twin imaging study of generalized anxiety disorder

2012

Background: Generalized anxiety disorder (GAD) is a common chronic condition that is relatively understudied compared to other psychiatric syndromes. Neuroimaging studies have begun to implicate particular neural structures and circuitry in its pathophysiology; however, no genetically informative research has examined the potential sources of reported brain differences.