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Newswise — Genome wide association studies (GWAS) have identified hundreds of genome regions containing thousands of genetic variants associated with asthma, but it’s still not clear which variants have an actual causal link to the disease. This “variant-to-function” gap is one of the biggest challenges to the usefulness of these genomic studies and has motivated researchers to develop new tools to make sense of GWAS results.

A new study by researchers from the University of Chicago combines genetic data and improved computational tools to look more closely at GWAS results for both adult-onset and childhood-onset asthma. The research identified many genetic variants with a high likelihood of having a causal effect on both types of asthma, paving the way for further studies to target the genes connected to these variants as potential treatments.

The study, published in Genome Medicine, also found significant differences in the sets of genes that could be linked to adult-onset and childhood-onset asthma, with relatively little overlap between the two.

“The real uniqueness of our study is that the differences between childhood- and adult-onset asthma were evident at every level that we looked at,” said Carole Ober, PhD, the Blum-Riese Distinguished Service Professor and Chair of Human Genetics at UChicago, and co-senior author of the paper. “You find out it’s actually different variants that are contributing to asthma. Even when the GWAS locus looks the same, the genes functionally linked to these variants are also different. So, they’re really quite different diseases.”

Fine-mapping causal variants

Researchers use GWAS to compare genome sequences from a large group of people with a disease to another set of sequences from healthy individuals. The differences identified in the disease group could point to genetic variants that increase risk for that disease and warrant further study. Most human diseases—including asthma—are not caused by a single genetic variant, however. Instead, they are the result of complex interactions among multiple genes, environmental factors, and host of other variables. As a result, GWAS often identifies too many variants across the genome to be of use without further refinement.

GWAS also identifies association only, not causality. In a typical genomic region, many variants are highly correlated with each other, due to a phenomenon called linkage disequilibrium. This is because DNA is passed from one generation to the next in entire blocks, not as individual variants. Therefore, variants nearby each other tend to be correlated. To make the problem more difficult, most of the genetic variants associated with diseases are located in non-coding regions of the genome, making their effects difficult to interpret.

In the new study, Ethan Zhong, a graduate student working with Ober and Xin He, PhD, Associate Professor of Human Genetics and another co-senior author of the paper, wanted to bridge the variant-to-function gap and find more concrete biological insights from different sets of asthma GWAS data. He worked with data from the UK Biobank, a large-scale biomedical database and research resource containing de-identified genetic data from nearly 500,000 people in the United Kingdom. Using a statistical method called “fine-mapping,” he was able to estimate the probability that a given genetic variant has a causal relationship to asthma.

The new estimates incorporated data on the accessibility of chromatin, the bundle of DNA and proteins that make up chromosomes. When a region is involved in regulating gene expression, the chromatin “opens” to become more accessible. The amount of open chromatin can be measured and used as an indicator of regulatory activity; when combined with statistical evidence, it builds an even stronger case that the variant is causally linked to asthma.

“The GWAS associations provide sets of variants associated with the disease,” Zhong said. “So, when those variants overlap with open chromatin regions in cell types that are relevant to asthma pathogenesis like lung epithelial cells, we think that they are more likely to be causal to these asthma phenotypes.”

Zhong also included data on expression quantitative trait loci (eQTLs), genetic variants associated with differences in gene expression, and chromatin interactions from blood and lung cell types, to link fine-mapped variants to their target genes. Using this information, he built a list of likely causal genes supported by genetic evidence.

Closing the gap

The fine-mapping analysis uncovered 21 independent sets of variants (called credible sets) for adult-onset asthma and 67 for childhood-onset, with only 16% shared between the two. Zhong also looked for cis-regulatory elements (CREs), short DNA sequences that control expression of nearby genes, that were linked to asthma and found 62 and 169 candidate genes for adult-onset and childhood-onset, respectively. More than 60% of these had open chromatin in different cell types, including many genes involved in immune and inflammatory responses.

The team selected six of the candidate CREs and tested them in bronchial epithelial cells to see if the variants had a regulatory effect; four of the six did, meaning their efforts are getting closer to the mark in the right kind of cells involved in asthma. The variant-to-function gap closes ever so slightly, opening the door to further studies of these candidate genes as potential targets for treatment.

The study was supported in part by a National Institutes of Health grant to discover genes in asthma and allergy, in collaboration with Marcelo Nobrega, MD, PhD, A.N. Pritzker Professor of Human Genetics at UChicago, Nathan Schoettler, MD, PhD, Assistant Professor of Medicine, and Anne Sperling, PhD, formerly of UChicago and now Professor of Medicine at the University of Virginia.

Additional authors include Robert Mitchell, Christine Billstrand, Emma Thompson, Noboru J. Sakabe, Ivy Aneas, Isabella M. Salamone, and Jing Gu.

E-cigarettes have become increasingly popular over the last two decades, especially among young people. These sleek, deliciously flavored smoking devices are often marketed as a safer alternative to conventional cigarettes, but alarming new research challenges that assumption.

In a study published June 25 in the journal ACS Central Science, researchers tested three popular disposable vape brands for hazardous metals and metalloids such as lead, chromium, antimony, and nickel. Inhaling these toxins can increase the risk of cancer, respiratory disease, and nerve damage. The findings show that e-cigarettes emit dangerously high levels of toxic metals—orders of magnitude higher than levels emitted by traditional cigarettes and other e-cigarettes. One brand released more lead during a day’s use than nearly 20 packs of cigarettes. Given the widespread underage use of vapes, the findings underscore an urgent need for regulatory action, the researchers conclude.

“Our study highlights the hidden risk of these new and popular disposable electronic cigarettes—with hazardous levels of neurotoxic lead and carcinogenic nickel and antimony—which stresses the need for urgency in enforcement,” co-author Brett Poulin, an assistant professor of environmental toxicology at the University of California, Davis, said in a statement. “These risks are not just worse than other e-cigarettes but worse in some cases than traditional cigarettes.”

The Food and Drug Administration (FDA) has cracked down on brands selling flavored, disposable vapes in the U.S. due to concerns about youth access, health risks, and unauthorized sales. Despite issuing warning letters to popular brands, slapping retailers with civil penalties, and blocking e-cigarette imports from other countries such as China, the agency has failed to keep these devices out of the U.S. market.

In the past few years, sales of disposable vapes have overtaken sales of older, refillable vapes. According to the FDA’s Annual National Youth Tobacco Survey for 2025, disposable e-cigarettes are the most commonly used tobacco product among young people. The survey found that 5.9% of middle and high school students (1.63 million) reported current use of e-cigarettes, and of those students, 55.6% use disposable vapes.

Previous studies have investigated the elemental composition of refillable e-cigarettes, but few have looked into these newer devices. To fill that gap, Poulin and his colleagues analyzed the metals and metalloids inside seven disposable vapes made by three brands, including flavored and unflavored liquids. They selected the brands based on popularity and purchased the e-cigarettes from online vendors based in the U.S. All the devices they tested contained nicotine except one, which allowed the researchers to test if nicotine influences the metal concentrations of e-liquids (commonly known as “vape juice”).

The key components of any vape are a battery, e-liquid (commonly known as “vape juice” or “e-juice), and a heating coil. When the user presses a button on the device or—in some cases—simply inhales, the battery heats the coil and turns the e-liquid into an aerosol. These metal components can leach into the e-liquid and thus work their way into the lungs.

The researchers tested the metal concentrations of unused e-liquids and aerosols, using a special instrument to activate the e-cigarettes and generate between 500 and 1,500 puffs per device. They found that “these disposable devices have toxins already present in the e-liquid, or they’re leaching quite extensively from their components into e-liquids and ultimately transferred to the smoke,” lead author Mark Salazar, a PhD candidate in Poulin’s lab, said in the statement.

Some unused e-liquids contained high levels of antimony, a toxic metalloid. Heating coils leached nickel into the e-liquid, while leaded bronze alloy components in some devices leached nickel and lead. The vapors of some devices contained surprisingly high metal levels, including antimony and lead. Interestingly, the metal concentrations of the aerosols increased as the number of puffs increased, suggesting that exposure worsens as the device ages.

Overall, the researchers determined that disposable e-cigarette users are exposed to markedly higher levels of toxic metals and metalloids than those who use refillable vapes, which may lead to increased health risks. Three of the tested vapes produced vapors that contained nickel levels that exceeded cancer risk thresholds, and two emitted potentially cancerous amounts of antimony. Four devices had nickel and lead emissions that surpassed risk thresholds for illnesses besides cancer, such as neurological damage and respiratory disease.

Of the nearly 100 disposable e-cigarette brands available in the U.S., this study tested only three. Despite regulatory efforts, these devices remain wildly popular among adolescents. The researchers hope that their work inspires others to investigate the health risks associated with disposable e-cigarettes, as it would appear they won’t be going away anytime soon.