Worldwide study cracks brain’s genetic code

2 April 2020

A massive genetic study of the human cerebral cortex, the deeply wrinkled sheet of neurons covering the brain, identifies hundreds of genes that give rise to its physical characteristics, which are as unique to each person as a fingerprint. The findings could someday provide clues about the origins of certain brain disorders and behavioral traits.

The landmark research, conducted by a global consortium co-led by researchers at USC, QIMR Berghofer Medical Research Institute in Australia and UNC – Chapel Hill, recently appeared in Science. Scientists from 184 different institutions and universities, among which the Donders Institute, contributed to the paper.
The cerebral cortex – often referred to as the brain’s “grey matter” – plays a crucial role in thinking, information processing, memory and attention. Its folds are a way of packing in more neurons, or brain cells. The human brain in particular many folds, while a mouse brain, by comparison, is smooth.

Genetic differences

MRI scans allow researchers to measure specific characteristics about the cortex that are unique in each individual. The extent of the folds and the thickness of the cortex have previously been linked to cognitive abilities and various neurological and psychiatric disorders, including Alzheimer’s disease, schizophrenia, depression, and autism.

“Our goal was to look at how genetics might alter the brain as we see it on MRI, a tool which is used every day and around the world to understand brain health and monitor disease progression,” said Neda Jahanshad, assistant professor at the Mark and Mary Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC.

Katrina Grasby, a postdoctoral researcher in the psychiatric genetics research group at QIMR Berghofer, said, “We focus on genetic differences, or genetic variants, that are common and regularly encountered, rather than rare genetic mutations, in order to shed light on how our genetics contribute to the differences among all of us.”

50 thousand people

In order to achieve this goal, said QIMR Berghofer associate professor Lucia Colodro-Conde, researchers studied MRI scans and DNA from more than 50 thousand people across 20 countries.

The project was powered by ENIGMA, a collaborative worldwide consortium launched over 10 years ago by Paul Thompson, a professor at USC’s Stevens Neuroimaging and Informatics Institute. Thompson said scientists from 45 countries actively contribute to ENIGMA daily. He called the new genetic roadmap of the brain a “Rosetta stone” that will help translate how disease-risk genes impact physical brain structure, which in turn have neurological consequences.

Pre-natal development

Over 300 genetic regions in our DNA were found to influence the structure of the cortex. The degree of the cortical folding, which is measured as surface area, and the thickness of the cortex are largely driven by different genetic factors, researchers found.

The genetics that influence cortical surface area seem to exert their effects during early pre-natal development. “This implies that genetic effects prior to birth can influence how the brain is folded as an adult,” said Jason Stein, assistant professor of genetics and neuroscience at the University of North Carolina at Chapel Hill. On the other hand, genetic variants influencing thickness appear to be driven by genes active in the adult cortex.

Genetic factors that have been associated with increased risk for depression, ADHD, or insomnia were related to the genetics found to reduce surface area, while genetic factors that increase risk for Parkinson’s disease were conversely found to correlate with those genetic factors that contribute to greater surface area.

The researchers have made their full set of results downloadable. Authors, including Janita Bralten, a tenure track researcher from Radboud University in the Netherlands, cite that only through collaborative science can we begin to understand the complex relationships between genes, brain structure, and ultimately how our brains function in health and disease.

Broadly supported

More than 360 scientists from 296 departments across 184 different institutions and universities contributed to the paper. In addition to Thompson and Stein, Sarah Medland (QIMR Berghofer Medical Research Institute, Australia) is a senior co-author.
The study was funded by national and international public and private funding agencies. These include the National Institute of Biomedical Imaging and Bioengineering, the National Institute of Aging, and the National Institute for Mental Health, all at the US National Institutes of Health, the Australian National Health and Medical Research Council, and foundational support including the Michael J. Fox Foundation and the Kavli Foundation.