Genetic variants influencing longitudinal brain changes

29 April 2022

Rachel Brouwer (assistant professor CNCR – CTG) recently published her work in Nature Neuroscience. The study is a large-scale collaboration of research groups worldwide and identifies genetic variants that are associated with the speed of structural brain changes over time.

The human brain is continuously changing throughout life, but not every individual shows the same pattern. Individual differences in how much the brain changes over time have been shown to be associated with cognitive functioning in health, and a range of psychiatric and neurological diseases. As already established through twin studies, the amount of this change is heritable, but the underlying genetic mechanisms were largely unknown. The current study set out to identify genetic variants that are associated with brain development and ageing by including data from > 15,000 individuals that had structural brain imaging two times. The results showed that each brain structure follows a specific trajectory over the lifespan, often with increases in younger participants, and decreases in older age. Genome-wide association studies were performed to associate the rate of change in the brain to genetic variation. “The exiting thing for me is that we did not only investigate the effects of genetic variants on change, but also allowed these effects to vary with age”, Rachel Brouwer says. “This is in line with the observation that genes are not always expressed at the same level throughout the lifespan.”

The study implicated three genes that seem involved in the rates of change in several brain regions. One of these, the APOE gene is well-known for carrying risk variants for Alzheimer’s disease, but this study suggests a potential role of this gene in hippocampus and amygdala development early in life. Future genetic studies including in larger sample sizes and individuals from non-European ancestry will help better understand the biology of structural brain development and ageing, and ultimately should aim to provide targets for treatment or prevention of diseases that are characterized by a deviant pattern of brain structural changes.

This study was performed by the ENIGMA plasticity working group led by Dr Rachel Brouwer (Complex Trait Genetics, VU Amsterdam and Department of Psychiatry, Department of Psychiatry, UMC Utrecht) and Prof Hulshoff Pol (UU University, Department of Psychiatry, UMC Utrecht) which includes 40 cohorts / 200+ researchers from throughout the world. The ENIGMA plasticity working group is part of the ENIGMA consortium, led by Prof Paul Thompson.