White Matter Structure and Genetics May Reveal Links to Brain-Related Disorders

A new study has used brain images from over 30,000 people to map genetic associations with structural differences in the white matter of the brain, with possible links to several heritable brain-related disorders. The research is published in Science Advances.

Brain structure and genetics

Two different types of tissue make up our brains – gray matter and white matter. Gray matter is common in functionally significant areas of the brain such as the cerebellum and cerebral cortex, meaning the importance of white matter is sometimes overlooked.

The white matter – named for the color of the fatty myelin sheaths that surround the axons of nerve cells in the brain – conducts neural signals along connections that link different regions of the brain, forming large networks as part of the structural “connectome”.

Previous studies have suggested that variations in the structure of white matter may be linked to genetic predisposition to several psychiatric and neurological conditions like major depressive disorder and schizophrenia. However, various brain imaging methods have been unsuccessful in linking structural changes in white matter to specific genes or positions in the genome (loci).

Research to investigate how DNA variants, genes and pathways may alter white matter structure is sorely needed to understand how this may influence predisposition to brain disorders.

In the current study, the researchers aimed to determine how genes or genetic variants can impact the white matter connectome, and the potential links to brain disorders and behavioral traits.

It’s written in the white matter

The researchers analyzed the brain images and genotyping data from 30,810 adult participants taken from the UK Biobank. They examined brain images obtained using diffusion tensor imaging (DTI) – a type of MRI scan – and applied a technique called tractography which visualizes white matter fibers (tracts) in 3D to identify common structural variations.

Next, they performed genome-wide association analysis using the participants’ genotyping data, finding 325 genetic loci that were associated with the identified structural changes.

“Nerve fibers in the brain are arranged in bundles that connect different parts of the brain together to form larger networks. Looking across the > 30,000 participants, we found hundreds of variants in the genome that were associated with inter-individual variation in white matter connections,” explained Professor Clyde Francks, senior investigator at the Max Planck Institute for Psycholinguistics and senior author of the study.

Additionally, using previously published genetic data gathered over the human lifespan, Francks and colleagues found these genetic variants tended to be most active during embryonic and fetal brain development. Their roles included the generation of new nerve cells and their “wiring” to the correct location in the brain, suggesting some structural variations may be established early on in life.

The findings also shed light on possible links between these structural changes and brain-related disorders. “People with higher genetic dispositions to psychiatric disorders tended to have slightly reduced amounts of white matter connections in their brains, quite broadly throughout their brains, but somewhat differently for different disorders,” Francks explained. For example, genetic predisposition to autism was associated with white matter connectivity in regions of the brain related to attention and working memory, while predisposition to bipolar disorder was associated with brain regions involved in mood.

“These findings suggest that a reduced network of white matter connections is a risk factor for psychiatric disorders, and that the specific connections that are affected can influence the precise type of psychiatric trait that a person is disposed to,” Francks added.

The connectome and other brain functions

Addressing some of the limitations of the study, Francks highlighted that the methodology used was limited by the need to analyze over 30,000 brain images in a matter of a few months. “There are other computational approaches that have advantages in terms of allowing for more fine-grained features of white matter networks, but which would have made our run-time last for several years,” he explained. “Our approach performed sufficiently well to identify many new genetic effects on the brain’s white matter, but there is surely more to discover.”

Francks also explained that the study of the brain’s language centers, a specialist topic of his department, is now being targeted for further research. “In our future work on the genetics of dyslexia and other language-related traits and disorders, we will pay special attention to the genes that we have implicated in wiring the brain’s language network.”

Reference: Sha Z, Schijven D, Fisher S, Francks C. Genetic architecture of the white matter connectome of the human brain. 2023. Sci. Adv. doi: 10.1126/sciadv.add2870

Prof. Clyde Francks was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.