Keynote series Dr. Paul M. Thompson - Inside ENIGMA: How Global Science Is Decoding the Human Brain

By Felipe Rivera

From more than 200,000 brain scans across 47 countries, with the efforts of 2,000 scientists over 16 years, one question has driven them all: What defines the health and the vulnerabilities of the human brain?

The ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Consortium is a global initiative that began in 2009 and has made significant contributions to the field of neuroscience, with its impact only growing stronger. This international collaboration focuses on large-scale research, combining brain imaging and genetic data. 

By analyzing different modalities like magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), resting state functional MRI (rsfMRI), electroencephalogram (EEG), and magnetoencephalography (MEG), they sought to answer how major disorders affect the brain. By screening millions of variants in our genetic code (GWAS, eWAS, CNVs), researchers aim to understand how genetic variation influences the brain during development, aging, and in the context of disease. So far, ENIGMA has produced the largest MRI studies of many neuropsychiatric conditions such as Parkinson’s disease (PD), epilepsy, stroke, schizophrenia, bipolar disorder (BD), depression, post-traumatic stress disorder (PTSD), addiction, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). 

Adapted from Thompson, P. M. et al. (2020)

The birth of a global collaboration

ENIGMA, like many great human inventions, was born out of need. Neuroscientists observed quite frequently that the results of many neuroimaging and genetic studies were failing to be replicated. This represented a big issue, given that in science the robustness of results is what paves the way for the next step. Researchers realized that in order to detect real genetic effects on the brain, huge sample sizes would be needed. That is why ENIGMA set out to acquire big data sets of brain scans combined with genetic data to uncover how our DNA influences brain structure and functions, hoping to identify biomarkers in diverse neuropsychiatric conditions. A key aspect of this process included using consistent data analysis protocols across studies to enhance accuracy. However, while collaborating is always best for scientific improvement, it doesn’t necessarily mean it’s easy, especially when dealing with health-related data sets. 

A unique approach of the initiative was to run a “distributed consortium” where each group across the globe ran standardized protocols and analyses locally, instead of centralizing all the data. This made it easier for international sites to participate while maintaining control of their data. Over the years, different groups made it possible to share anonymized individual-level data for more detailed analyses and enhanced harmonization of genetic and brain imaging data across sites. Processing the data with consensus-based methods allowed a new level of consistency which was only enriched by rigorous quality control protocols. ENIGMA’s meta-analyses were useful to understand the effect sizes of pooled data from multiple cohorts. Then, many groups started running mega-analyses where aggregating individual-level data is possible, opening the door for more sophisticated analyses such as machine learning, interaction modeling, and polygenic risk score. It is important to mention that ENIGMA does not maintain an open-access database. Each data request must be approved by the original researchers, assuring safe management of potentially clinically sensitive patient information.

Not long after the ENIGMA Consortium was founded, its statistical power became evident when genetic loci associated with variation in subcortical volumes were identified. Researchers were right, genetic data needs huge sample sizes in order to find meaningful results. Over 200 genetic loci that affect brain size and shape were discovered, each having a small effect of 0.1%-1% but together they can explain up to 20% of the variation. Through a collaboration with CHARGE Consortium and UK Biobank, a genetic atlas of the cerebral cortex of how common genetic variants shape different brain regions was made a reality. In 2020, when ENIGMA was celebrating its 10th anniversary, a great article was published by Thompson and collaborators in Translational Psychiatry summarizing the history and the findings thus far of the Consortium. In this review, readers are able to catch up on the main findings of all the disorder-based neuroimaging studies in schizophrenia, BD, depression, PTSD, addiction, OCD, ADHD, ASD, 22q11.2 deletion syndrome, epilepsy, brain injury, PD, stroke, and HIV’s impact on the brain.  

Nowadays, ENIGMA’s impact has gone beyond specific brain-disorder discoveries. For starters, the Consortium has proven that the replication crisis in neuroscience can be tackled by using very large sample sizes and standardized analysis methods. Sometimes, large data sets can be built on data that has been accumulated in individual laboratories over the years that otherwise would remain unused. Obtaining funding for data collection is an enormous challenge, and this is an opportunity to make the most out of the hard work that is being done across the world. ENIGMA has also set a standard for how large-scale brain/genetic studies can be successfully conducted by building standardized pipelines. Finally, what makes ENIGMA especially powerful is its ability to reveal faint signals and patterns that typically remain hidden in limited-sample research, thanks to a spectacular global teamwork effort. 

In the mentioned review article, the authors quote Aristotle when referring to ENIGMA’s mission statement: “Individually, we contribute little to the quest for truth, but working together, the whole vast world of science is within our reach.” After all of these years and exciting discoveries, it is clear that this international driving force has taken a life of its own and will continue to expand to previously unapproachable scientific oceans. Let’s keep on working together.  

Source

Thompson, P. M., Jahanshad, N., Ching, C. R. K., Salminen, L. E., Thomopoulos, S. I., Bright, J., Baune, B. T., Bertolín, S., Bralten, J., Bruin, W. B., Bülow, R., Chen, J., Chye, Y., Dannlowski, U., De Kovel, C. G. F., Donohoe, G., Eyler, L. T., Faraone, S. V., Favre, P., . . . Zelman, V. (2020). ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries. Translational Psychiatry, 10(1). https://doi.org/10.1038/s41398-020-0705-1

Talairach Lecture by Paul M. Thompson at OHBM Annual Meeting 2025: Talairach Lecture 2025: Worldwide Collaboration & AI in the Global Quest to Map Human Brain Diseases