The reasons for black Americans having a higher risk of some neurological disorders have always been unclear, but after examining the post-mortem brains of 151 people, researchers in Baltimore believe they have identified genes that may help explain why.
In those people, who all identified as black or African American, the scientists analysed the influence of two different ancestries – African and European – and discovered that genes associated with African ancestry appear to affect certain brain cells in ways that could increase the risk of Alzheimer’s and stroke.
But genes associated with European ancestry seem to influence other brain cells in ways that could increase the risk of Parkinson’s disease, which is less common in black Americans.
NPR reports that the study also probed whether genetic ancestry influenced neurons, which are critical to memory, movement, and thinking.
Neurons appear to play an important role in certain psychiatric disorders, including schizophrenia, which are diagnosed more frequently in black Americans than their white counterparts, yet the researchers found no evidence that genetic ancestry influenced neurons.
This could mean that societal factors, like economic and psychological stress, exposure to traumatic events, and racial bias in diagnosis, account for the disparity – although the study did not include any direct measure of this possibility.
The results, published in Nature Neuroscience, are a first step towards mitigating some of the increased risk accompanying different ancestries, according to Dr Kafui Dzirasa, an investigator and professor of psychiatry at Duke University who was an advisor to the study, but not an author.
A community effort
Black Americans have been under-represented in most genomic studies of neurological disorders. As a result, scientists know relatively little about whether African ancestry affects a person’s risk for these disorders, or their response to a particular treatment.
This dearth of research led to the creation, in 2019, of the African Ancestry Neuroscience Research Initiative, a collaboration involving African American community leaders, the Lieber Institute for Brain Development, Duke University and Morgan State University.
One of the early challenges for the initiative was to earn the trust of Baltimore’s black residents.
“You had to build relationships with families and communities such that when their loved ones died, they were willing to donate their brains to medical research,” said Dzirasa, who advises the initiative.
The Baltimore team’s study is the first to come out of the effort.
Because so much brain research has focused on white people, the team decided to look only at brains from black or African American people. Each brain was donated for research by a person’s next-of-kin.
But a person’s self-identified race allowed for a wide range of genetic ancestry. As a result of centuries of intermixing – including the rape of enslaved women and girls before 1865 – the genomes of most black individuals contain a combination of European and African ancestry.
“We leveraged the history of the US to pinpoint how European ancestry versus African ancestry affects gene expression in the brain,” said Kynon Jade Benjamin, a researcher at the Lieber Institute and at Johns Hopkins University who led the work.
Genes vs. environment
Gene expression describes how certain genes are turned on or off in a particular cell. That process can be influenced by a person’s genes, experiences, and environment.
The study was designed to minimise the differences that could be attributed to two of those factors: experience and environment. As a result, they accounted for an estimated 15% of the differences in gene expression, while genetic ancestry accounted for more than 60%.
A person’s ancestry was most likely to influence gene expression in immune cells and cells that form the walls of blood vessels, Benjamin said.
The blood vessel finding could be one reason that strokes caused by a blocked artery are 50% more common in African Americans than in their white counterparts.
And the two lineages’ immune cell differences could help explain why African Americans are more likely to have Alzheimer’s dementia, but less likely to get Parkinson’s.
Both disorders have been linked to an over-reaction by the brain’s immune cells, resulting in inflammation. And those immune responses are more likely when certain genes are switched on, or “upregulated”, Benjamin said.
“For Parkinson’s, we saw an upregulation in European ancestry. When we looked at stroke and Alzheimer’s, we saw an upregulation in the genes associated with African ancestry.”
African Americans 70 and older are about twice as likely as their white counterparts to have Alzheimer’s, but just half as likely to be diagnosed with Parkinson’s.
“We see these health disparities, which we know are partly to do with environment,” Benjamin said, “but there’s also a huge genetic component.”
Neurons and psychiatric disorders
The study did not offer much insight into why black Americans are about 20% more likely than white Americans to experience serious mental health problems, including schizophrenia and depression.
These disorders are thought to involve neurons, the cells that generate electrical impulses and are known as the brain’s grey matter. But the study found that ancestry had no effect on gene expression in these cells.
That could mean that a person’s environment and experience, rather than their genes, play a key role when it comes to mental illness.
But Dzirasa, who has spent his career studying genes and mental illness, thinks there may be a different explanation.
In adult brains, immune cells respond to injury or infection, he says. But earlier in life, “those same brain cell types may be giving rise to psychiatric disorders”.
“For example, immune cells called microglia can prevent too many brain cells from being connected with each other by sort of trimming [the connections] away,” he said. “They’re almost like a gardener trimming down bonsai trees to the right shape.”
Disturbances in that process, called synaptic pruning, have been linked to schizophrenia and autism spectrum disorder, he said.
A path to precision medicine
Even though the study used self-identified race as a starting point, it also shows why racial categories are a poor indicator of a person’s genetic background, said Benjamin.
A look at the overall European ancestry of each person in the study found a range from zero to more than 60%.
That means doctors need to look beyond race when assessing a black person’s risk for a disease like cystic fibrosis – most common in people of Northern European ancestry, Benjamin added.
“If a patient comes in with some particular symptom, don’t rule it out just because he or she is African American. At that particular gene, they could be European.”
The study also shows “clearly and scientifically” why genetic research needs to be more diverse.
Finding genes that protect someone with a particular ancestry from a disease like Parkinson’s could help scientists figure out how to protect all people.
Race is a social construct, not a biological one, Dzirasa said. Even so, he still notes race when glancing at a patient’s chart because it does indicate something about their life experience and disease risk.
But he looks forward to an emerging approach, known as precision medicine, that doesn’t look at race.
“The more optimal future is one in which we understand each person’s individual genomic architecture, and then prescribe medicines based on this.”
Study details
Analysis of gene expression in the postmortem brain of neurotypical Black Americans reveals contributions of genetic ancestry
Kynon Benjamin, Qiang Chen, Daniel Weinberger et al.
Published in Nature Neuroscience on 20 May 2024
Abstract
Ancestral differences in genomic variation affect the regulation of gene expression; however, most gene expression studies have been limited to European ancestry samples or adjusted to identify ancestry-independent associations. Here, we instead examined the impact of genetic ancestry on gene expression and DNA methylation in the postmortem brain tissue of admixed Black American neurotypical individuals to identify ancestry-dependent and ancestry-independent contributions. Ancestry-associated differentially expressed genes (DEGs), transcripts and gene networks, while notably not implicating neurons, are enriched for genes related to the immune response and vascular tissue and explain up to 26% of heritability for ischemic stroke, 27% of heritability for Parkinson disease and 30% of heritability for Alzheimer’s disease. Ancestry-associated DEGs also show general enrichment for the heritability of diverse immune-related traits but depletion for psychiatric-related traits. We also compared Black and non-Hispanic white Americans, confirming most ancestry-associated DEGs. Our results delineate the extent to which genetic ancestry affects differences in gene expression in the human brain and the implications for brain illness risk.
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