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GWAS Reveals New Loci Linked to Brain White Matter Microstructure

NEW YORK – A team led by researchers at the University of North Carolina at Chapel Hill has tracked down more than 150 parts of the genome that seem to influence the microstructure of white matter in the human brain, including loci that overlap with sites previously linked to brain diseases and other traits or conditions.

For a study published in Science on Thursday, the researchers performed a genome-wide association study that included more than 43,800 individuals who had diffusion magnetic resonance imaging, or dMRI, of their brain done, focusing in on variants at 151 new or known loci that were significantly linked to white matter microstructure.

Along with loci previously implicated in glioma or other brain conditions, they saw ties between white matter microstructure and dozens of other traits or diseases and found genes linked to white matter structure that are targeted by existing drugs.

"The targets of many drugs commonly used for disabling cognitive disorders have genetic associations with white matter, which suggests that the neuropharmacology of many disorders can potentially be improved by studying how these medications work in the brain white matter," senior author Hongtu Zhu, a researcher at UNC Chapel Hill, and his colleagues wrote.

The team's various analyses clarified some of the implications of these genetic contributors. For example, the associations highlighted the importance of glial cells, such as oligodendrocytes, in white matter architecture, as common variants influencing the regulation of these brain cells tended to be overrepresented among white matter-related variants detected in the study.

In a related perspectives article in Science, University of Colorado researcher Christopher Filley, who was not involved in the study, emphasized that a "complete portrait of the structural basis of cognition and emotion cannot neglect the white matter because it interacts so intimately with its gray matter counterpart."

For the discovery stage of the GWAS, Zhu and colleagues considered dMRI and genotyping data for more than 34,000 UK Biobank participants, focusing on five diffusion tensor imaging-based microstructure metrics that offer a look at 21 specific white matter tracts in the cerebral cortex.

From these data, the researchers narrowed in on 42 loci linked to white matter tract structure in the past, along with 109 new loci associated with the diffusion tensor imaging metrics. They noted that 30 of those novel loci structures were found through analyses centered on specific white matter tracts.

"Our results illuminate the broad genetic control of white matter microstructural differences and the contribution of tract-specific [fractional anisotropy principal components] in identifying genetic variants associated with white matter tracts," the authors reported, adding that the genetic effects detected "are spread across a large number of genomic regions, consistent with the observed polygenic genetic architecture of many brain-related traits."

After validating suspicious variants in another 17,700 individuals from nine prior studies, the team performed meta-analyses that included discovery and validation cohort participants from European and non-European ancestry groups, along with gene-centered and drug target analyses that pointed to more than a dozen white matter-related genes that are targeted by existing antipsychotic, antidepressant, antidementia, and other neuropsychiatric drugs.

The team cautioned that the current findings largely stemmed from genetic data for individuals with European ancestry, and centered on diffusion tensor imaging parameters, leaving untapped genetic insights for other white matter metrics and populations.

"The emerging recognition of white matter and its contribution to human behavior will advance medicine as well as neuroscience," Filley wrote in his perspectives article. "Considering both environmental and genetic factors clarifies the structure and function of normal and abnormal tracts, and this knowledge promises in turn to improve the diagnosis and treatment of people in whom white matter dysfunction may be disturbing neurobehavioral capacity."