New Genetic Variants Associated with Pain Intensity in Multiple Ancestry Groups

By Fred Schwaller | June 27, 2024 | Posted in

A genome-wide association study looks to the Million Veteran Program to learn more about the genetics of pain. The findings could lead to better therapies, including for migraine.

About 25% to 50% of the susceptibility to developing chronic pain is explained by inherited genetic factors, but exactly which genes and genetic variants play a role, and exactly how they contribute to disease risk, remains an ongoing effort. A new study now makes use of a diverse dataset to enhance genetic knowledge of pain, with treatment implications for multiple pain conditions, including migraine.

The research, led by Henry Kranzler, University of Pennsylvania Perelman School of Medicine and the Crescenz Veterans Affairs Medical Center, Philadelphia, US, examined genetic contributions to pain intensity in nearly 600,000 veterans from multiple ancestry groups, including African Americans, European Americans, and Hispanic Americans – a more diverse dataset than is typical of similar genetic studies.

The study found many common genetic variants that were associated with pain intensity, including a number of variants that were specific to the different ancestry groups. The study also found that some of the variants were in or near genes that encode molecules targeted by currently licensed drugs, as well as by drugs now in clinical trials. That raises the possibility that those drugs could potentially be repurposed to treat chronic pain and migraine.

“This study identified some new genes involved in pain and, importantly, in groups of people from different ancestries. Studies like this help us to understand the biological mechanisms of pain, and therefore give clues to developing new drugs or repurposing existing drugs for treatment,” said Blair Smith, University of Dundee, UK. Smith, a physician and a professor of population health science with expertise in pain genetics, was not involved with the research.

The study appeared in the April 2024 issue of Nature Medicine.

A large, diverse dataset with information about pain intensity
The new work is a genome-wide association study (GWAS), a type of investigation that has become a mainstay of human genetics research. For GWAS, researchers scan the entire genome to identify single nucleotide polymorphisms (SNPs) that are associated with a particular trait or disease of interest. (A SNP is a variant at a single base position in DNA.)

However, most GWAS of pain traits to date have been performed in people of European ancestry, which leaves out other groups who may have different variants that the more limited datasets will miss. Studying the genomes of more diverse populations could help uncover new pain mechanisms and expand the reach of pain medicine to people who have not been included in research. That made the current research necessary – and unique.

“Our study is the first time anyone has looked at cross-ancestry data in the pain field,” said Sylvanus Toikumo, first author of the study and also from the University of Pennsylvania Perelman School of Medicine and the affiliated VA Medical Center.

The team had access to data from the Million Veteran Program, a health research program run by the US Department of Veterans Affairs that is focused on improving the health and wellness of the one million veterans who are taking part in it. This program has data on a diverse group of veterans, including pain ratings from routine pain screening, making it possible to look for genetic associations with pain intensity.

The new study included data from close to 600,000 veterans in total, including more than 100,000 African Americans, over 400,000 European Americans, and almost 50,000 Hispanic Americans.

The researchers considered which measure of pain to use to examine potential genetic associations. In the end, Kranzler said they chose pain intensity.

“We decided to go with a structured measure of pain, which is pain intensity. It’s not chronic pain per se, but it’s a quantitative measure of pain across years as a proxy for chronic pain. We used all pain types together on a continuous outcome from zero to 10 [rather than looking at individual pain conditions],” said Kranzler.

The genetics of pain is largely in the brain
The researchers were able to identify 125 independent genetic variants linked with pain intensity in their Million Veteran Program sample. Sixty-six of these variants were new ones that had not been reported in previous studies.

The team found some important differences in genetic variants among the different groups. For instance, there were 86 independent SNPs in the European American group, 74 in the Hispanic American group, and 57 in the African American group.

The researchers were also able to uncover which tissues, and which cell types, contained a higher fraction of the genetic variants associated with pain intensity. In GWAS, this is known as enrichment.

Here, the team found enrichment of SNPs especially in the brain, and particularly in a type of neuron that contains the inhibitory neurotransmitter GABA.

“We have new SNPs that point us to certain mechanisms previously not reported in pain genetics studies. Most notable is the idea that SNPs associated with pain intensity are highly enriched in neuronal cells in the brain,” said Toikumo.

What else was associated with pain intensity?
The researchers were also interested to learn what other factors were genetically correlated with pain intensity. Here, they found the strongest genetic correlations of pain intensity with other pain conditions such as multisite chronic pain, back pain, and neck/shoulder pain.

They also discovered strong positive correlations with psychiatric traits like depression, as well as with insomnia, smoking, obesity, substance use, and substance use disorders, among others.

“Some of these links we’ve known for a long time, but this confirms a biological basis for these connections. From a clinical standpoint, it therefore tells us that if we treat pain without treating other co-morbid conditions, we’re not likely to achieve a successful outcome,” said Smith.

The researchers also performed a transcriptome-wide association study – similar to a GWAS except the focus is on RNA rather than DNA – and a proteome-wide association study, which looks at all the proteins translated from RNA. The goal was to uncover associations of pain intensity with variation in RNA or proteins.

The authors found 145 transcriptomic targets and 32 proteomic targets associated with pain intensity, which the investigators said could help researchers investigate new biological mechanisms of pain and look for new drug targets.

“Not all genes that may be identified are transcribed in all situations in all brain regions, so understanding each step of the biology gives you more insights. In the end, the protein is the ultimate effector in pain,” said Kranzler.

Overall, one note of caution with all of the study’s findings is that while the Million Veteran Program dataset is a diverse one, Smith said it did have some limitations.

“The study is almost all male – 91.2% – which limits the [generalizability of the results]. We know there are genetic and biological differences in pain between men and women, so the study will have missed a lot of genes that are important in pain more generally,” said Smith.

Repurposing existing drugs?
The researchers were able to assign SNPs to 156 genes most likely to have causal effects on pain intensity in the European American group. They examined the status of those genes in the druggable genome database – the set of genes that encode proteins that have potential to be modulated by drugs.

The analysis found that a number of genes associated with pain intensity were present in the druggable genome database. These genes are targets for a variety of drugs, such as anticonvulsants, β-blockers, and calcium channel blockers, that are already licensed or in clinical trials. The findings raise the possibility that such drugs could be repurposed to treat chronic pain and perhaps migraine.

“What they’ve done very successfully here is find some very commonly used drugs that might be of value in treating some pain conditions,” said Smith.

“Now, the authors haven’t said that these drugs are going to be useful straight away,” Smith continued, “but they’ve uncovered the possibility, and that means that research can now look at whether these drugs are useful, for example, through clinical trials,” said Smith.

Kranzler said the findings have relevance for the migraine field: “One drug that does leap to mind from the analysis is topiramate. It’s approved in the US as a prophylaxis for migraine, and it’s one of the drugs that we identified in the drug repurposing analysis. So it does seem to be useful for migraine,” he said.

In terms of the study’s broader relevance to headache and migraine, while the authors didn’t look specifically at headache pain, Kranzler said people who reported it were included in their sample. But the researchers haven’t yet separated the data out into different phenotypes.

“Headache is certainly one of the pain phenotypes we looked at, but not directly. Our next step will be to look at different pain phenotypes, including migraine, as we go forward, ” he said.

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred

Reference
A multi-ancestry genetic study of pain intensity in 598,339 veterans.
Toikumo et al.
Nat Med. 2024 Apr;30(4):1075-84.

Image credit: 123RF Stock Photo.

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Fred Schwaller is a science writer and communicator based in Berlin, Germany. Fred spent a decade in pain research during his doctoral degree at University College London, UK, and his postdoc at the Max Delbrück Centre in Berlin, Germany. After transferring to science communication in 2020, he has been writing and podcasting about life sciences and medicine, specializing in somatosensation and pain. Follow him on Twitter @SchwallerFred.

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