African ancestry genes may be linked to risk of certain brain disorders in Black Americans

Black Americans are known to be at higher risk for certain neurological disorders, and the reasons for this disparity remain unclear. Now, after examining the postmortem brains of 151 people, Baltimore researchers have identified genes that could help explain why.

In these people, who all identified as black or African-American, the scientists analyzed the influence of two different ancestry: African and European.

They found that genes associated with African ancestry appear to affect certain brain cells in ways that could increase the risk of Alzheimer’s disease and stroke.

But genes associated with European ancestry appear to influence other brain cells in ways that could increase the risk of Parkinson’s disease, a disorder less common among Black Americans.

The study also investigated whether genetic ancestry influences neurons, which are essential for 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 in their white counterparts.

Yet the researchers found no evidence that genetic ancestry influenced the neurons. This could mean that societal factors, such as economic and psychological stress, exposure to traumatic events, and racial bias in diagnosis, explain the disparity — although the study did not include any direct measure of this possibility.

The results, published in the journal Natural neuroscience, are a first step toward “mitigating some of the increased risk associated with different ancestries,” says Dr. Kafui Dzirasa, a researcher and professor of psychiatry at Duke University who was an advisor to the study, but not a author.

A community effort

Black Americans have been underrepresented in most genomic studies of neurological disorders.

As a result, scientists know relatively little about whether African ancestry affects a person’s risk of developing 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 leaders from the African American community, the Lieber Institute for Brain Development, Duke University, and Morgan University State.

One of the initiative’s early challenges was gaining the trust of Baltimore’s black residents. This meant involving prominent African American educators, businessmen and church leaders, including Rev. Alvin Hathaway, Sr., who served as pastor of Union Baptist Church until 2021.

“It was necessary to build relationships with families and communities so that when their loved ones died, they were willing to donate their brains to medical research,” says Dzirasa, who advises the initiative.

The Baltimore team’s study is the first to result from this effort.

Since much brain research has focused on people who identify as white, the team decided to look only at the brains of people who identify as black or African American. Each brain was donated for research purposes 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 mixing – 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 U.S. history to identify how European ancestry versus African ancestry affects gene expression in the brain,” says Kynon Jade Benjamin, a researcher at the Lieber Institute and the 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. This process can be influenced by a person’s genes, experiences, and environment.

The study was designed to minimize differences that could be attributed to two of these factors: experience and environment. As a result, they accounted for about 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 the cells that form the walls of blood vessels, Benjamin says.

The discovery of blood vessels could be one reason why strokes caused by a blocked artery are 50% more common among African Americans than among their white counterparts.

And differences in immune cells between the two lineages could help explain why African Americans are more likely to live with Alzheimer’s dementia, but less likely to get Parkinson’s disease.

Both of these disorders have been associated with an overreaction of the brain’s immune cells, leading to inflammation. And these immune responses are more likely when certain genes are activated or “upregulated,” Benjamin says.

“For Parkinson’s disease, we saw an increase in European ancestry,” he says. “When we studied stroke and Alzheimer’s disease, we saw upregulation of genes associated with African ancestry.”

African Americans age 70 and older are about twice as likely as their white counterparts to live with Alzheimer’s disease. But they are half as likely to be diagnosed with Parkinson’s disease.

“We’re seeing these health disparities, which we know are partly environment-related,” Benjamin says, “but there’s also a huge genetic component.”

Neurons and psychiatric disorders

The study didn’t provide much insight into why Black Americans are about 20 percent more likely than white Americans to suffer from 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 gray matter of the brain. But the study found that ancestry had no effect on gene expression in these cells.

This 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 might be a different explanation.

In the adult brain, immune cells respond to injury or infection, he explains. But earlier in life, “these same types of brain cells can give rise to psychiatric disorders.”

For example, immune cells called microglia “can prevent too many brain cells from being connected to each other by cutting off (the connections),” Dzirasa says. “They are almost like a gardener pruning bonsai trees to get them into the right shape.”

Disruptions in this process, called synaptic pruning, have been linked to schizophrenia and autism spectrum disorders, Dzirasa says.

A path to precision medicine

Although 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, Benjamin says.

An examination of the overall European ancestry of each person in the study revealed a range from zero to more than 60 percent.

This means doctors must look beyond race when assessing a black person’s risk for a disease like cystic fibrosis, which is most common in people of Northern European ancestry, explains Benjamin.

“If a patient has a particular type of symptoms, don’t rule them out just because they’re African American,” he says. “With this particular gene, they could be European.”

The study also shows “clearly and scientifically” why genetic research needs to be more diverse, Dzirasa says.

Discovering genes that protect a person with a particular ancestry against a disease like Parkinson’s could help scientists understand how to protect everyone.

Race is a social construct, not a biological one, Dzirasa says. Despite this, he still notes race when he glances at a patient’s chart, because it says something about their life experience and disease risk.

But he’s looking forward to an emerging approach, known as precision medicine, that doesn’t take race into account.

“The most optimal future is one in which we understand each person’s individual genomic architecture and then prescribe medications based on that,” says Dzirasa.