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Large-Scale Study Reveals Genetics of White Matter Connections in the Human Brain

NEW YORK – A team of researchers in the Netherlands has discovered genetic factors contributing to connections between areas of white matter in the human brain, including ties between genetic risk of brain disorders and white matter structure.

Drawing on brain imaging and genotyping data from nearly 31,000 participants in the UK Biobank, the researchers, led by Clyde Francks at the Max Planck Institute for Psycholinguistics in Nijmegen, discovered 325 genetic loci associated with white matter structural connectivity, 80 percent of which had not been previously implicated in this process.

Some of the loci were linked to genes strongly expressed in glial cells, suggesting an important role for this cell type in establishing brain structure.

"I think our findings add to a growing literature that glial cells, and not only neurons, are important for forming and maintaining connections in the brain," Francks said in an email.

"Ultimately this might provide a route to targeted therapy for various different brain disorders, for example by stimulating or repressing specific functions of glial cells, while taking into account the particular genetic liability of the individual person," he added.

For their study, published in Science Advances on Friday, Francks and his team analyzed brain imaging data from the UK Biobank using a computational technique called tractography, which maps nerve fiber connections, to create maps of participants’ white matter connections. With the help of genome-wide genotyping data, they then uncovered associations between inter-individual differences in white matter connections and 325 genetic loci.

Next, using previously published human brain gene expression data, they found that the genes implicated by these loci tended to be most active in prenatal brain development, suggesting that white matter connections are established very early in life, and that those genes were upregulated in stem cells, astrocytes, microglia, and neurons. Previous studies focusing on white matter microstructure had also pointed to the importance of glial cells in white matter architecture.

The researchers also studied associations between white matter connectivity and polygenic risk scores for various brain disorders — including schizophrenia, autism, and Alzheimer's disease — and found that people with higher genetic disposition to one of these tended to have slightly reduced amounts of white matter connections in their brains that affected specific regions. For example, higher genetic risk of autism was associated with reduced connectivity of brain regions involved in attention and working memory, while higher genetic risk scores for schizophrenia were associated with less connectivity of brain regions involved in language and working memory, Francks said.

In another part of the study, he and his colleagues identified 31 genetic variants associated with white matter connections between brain regions in the left hemisphere that are involved in language, an area of specific interest for Francks' 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," he noted.