An international team has used genetic atlases of the human brain to identify hundreds of new genomic loci that help explain brain structure.
Studying the human brain
The development of large-scale MRI and genetic datasets has helped discover the common genetic variants that contribute to the morphology of the human cerebral cortex. In addition, studies in model organisms have revealed the genetic mechanisms underlying cortical area and thickness patterning. However, it has been difficult to define aspects of cortical development that are human-specific or shared across mammals.
In addition, previous genome-wide association studies (GWAS) have mostly been conducted in older adults. As a result, it is important to investigate neurodevelopmental programming at earlier ages.
Impact of genetic variants on the brain
In a recent study, published in Science, researchers used genetically informed brain atlases in GWAS to determine the impact of genetic variants on the brain. These GWAS were specifically of regional cortical surface area and thickness including 39,898 adults and 9,136 children.
From their analysis, the team uncovered 440 genome-wide significant loci in the discovery UK Biobank cohort and 800 from a post-hoc combined meta-analysis. Most loci in adulthood were captured in childhood showing signatures of negative selection. Many of the genes that these loci mapped to were associated with neurodevelopmental disorders, such as autism, epilepsy and intellectual disability as well as dementia.
This study demonstrates the benefits of using genetically informed atlases. As these atlases conform to genetic cortical patterning, they can increase discoverability and heritability, while also lowering polygenicity. These findings have also illuminated how genes impact the brain and have identified a hierarchy of brain development.
Chi-Hua Chen, who led the work, commented:
“To some extent, the molecular machinery for normal brain development and disorders overlaps, which could reflect a continuous spectrum of genetic effects on normal brain structural variation to aberrant neurodevelopment. One possible mechanism is that certain genetic compositions cause abnormal brain development, which leads to neurodevelopmental disorders. The loci we discovered can be used by researchers for further mechanistic studies of how genes impact the brain and diseases.”
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