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Study Reveals Ancestry-Related Differences in Postmortem Brain Gene Activity

Brain DNA

NEW YORK – A team from the Lieber Institute for Brain Development (LIBD), Johns Hopkins University, and Neumora Therapeutics has characterized gene expression and methylation patterns in postmortem brain samples from neurotypical individuals with admixed Black American ancestry, revealing ancestry-related shifts in genes from immune and vascular pathways.

"We have provided a detailed characterization of how genetic ancestry influences gene expression and DNA methylation in the human brain," first and co-corresponding author Kynon Benjamin, a researcher affiliated with the LIBD and Johns Hopkins University, and his colleagues wrote in Nature Neuroscience on Monday, noting that the results "consistently highlight enrichment for immune response pathways and absence of neuronal functions."

The work was done through a collaboration known as the African Ancestry Neuroscience Research Initiative that includes representatives from the Lieber Institute, Morgan State University, Duke University, and African American community leaders from Baltimore.

The researchers relied on RNA sequencing, array-based SNP genotyping, and whole-genome bisulfite sequencing data generated by the LIBD to assess gene expression, germline variation, and DNA methylation, respectively, in postmortem brain samples from 151 Black American neurotypical individuals with a range of admixed African and European ancestry from the BrainSeq Consortium.

"We leveraged genetic diversity within an admixed population to limit environmental confounders, resulting in converging evidence of the immune response in genetic ancestry-associated transcriptional changes in the brain," the authors explained.

Collectively, they considered data for some 425 postmortem brain samples spanning the hippocampus, the dorsolateral prefrontal cortex (DLPFC), the caudate nucleus, and the dentate gyrus.

With these data, the team narrowed in on 2,570 genes that appeared to show distinct expression depending on ancestry, particularly genes known to be active in non-neuronal cells and genes with roles in immune or vascular activity. On the other hand, there were lower-than-usual rates of differentially expressed genes in neuronal cell types.

Altogether, the results suggest that ancestry-associated differentially expressed genes in the human brain are "strongly associated with a brain-specific immune response," the authors reported, "with the direction of effects varying according to brain region."

In addition, differentially expressed genes with ties to ancestry appeared to explain a significant subset of the heritability behind conditions such as Alzheimer's disease, Parkinson's disease, or ischemic stroke, the researchers reported. In contrast, they saw a dip in the heritability for behavioral measures or conditions such as schizophrenia or depression when they incorporated ancestry-associated expression insights.

From these and other findings, the investigators suggested that ancestry-related expression patterns in the brain might also impact a range of conditions previously linked to immune system activity, hinting that treatments focused on immune response may help to curb some of the genetic contribution to related health disparities.

"This landmark work enriches our understanding of the role of genetic ancestry in the brain, opens new avenues for the development of ancestry-aware therapeutics, and paves the way for more equitable personalized medicine," co-senior and co-corresponding author Daniel Weinberger, Lieber Institute director and CEO, said in a statement.

With the help of methylation profiles for the brain regions considered, the researchers also explored the extent to which epigenetic features and environmental factors affected gene expression in the brain. Based on the variable methylated regions detected, they estimated that environmental factors account for roughly 15 percent of the expression variability found.

The authors cautioned that "we cannot confirm that methylation variation is solely attributed to environmental factors, nor can we ensure that methylation captures all environmental factors," and noted that additional measurements focused on social determinants of health "could have directly measured specific environmental exposures instead of using DNA methylation as a proxy."