Genetic risks for nicotine dependence span a range of traits and diseases

"Genetic studies may help reduce some of the stigma society has against substance use disorders, while also making treatment more accessible," says Victoria Risner, first author of the new study on nicotine dependence, who did the work as an Emory undergraduate.

By Carol Clark 

Some people casually smoke cigarettes for a while and then stop without a problem, while others develop long-term, several packs-per-day habits. A complex mix of environmental, behavioral and genetic factors appear to raise this risk for nicotine dependence. 

Studies of groups of twins suggest that 40 to 70 percent of the risk factors are heritable. Until recently, however, studies have only explained about 1 percent of the observed variation in liability to nicotine dependence, using a genetic score based on how many cigarettes a person smokes per day. 

A study led by psychologists at Emory University offers a new model for examining this genetic risk. It leveraged genome wide association studies for a range of different traits and disorders correlated with nicotine dependence and explained 3.6 percent of the variation in nicotine dependence. 

The journal Nicotine & Tobacco Research published the finding. 

Higher polygenetic scores for a risk for schizophrenia, depression, neuroticism, self-reported risk-taking, a high body mass index, alcohol use disorder, along with a higher number of cigarettes smoked per day were all indicators of a higher risk for nicotine dependence, the study found. And polygenetic scores associated with higher education attainment lowered the risk for nicotine dependence, the results showed. 

“If you look at the joint effect of all of these characteristics, our model accounts for nearly 4 percent of the variation in nicotine dependence, or nearly four times as much as what we learn when relying solely on a genetic index for the number of cigarettes someone smokes daily,” says Rohan Palmer, senior author of the study and assistant professor in Emory’s Department of Psychology, where he heads the Behavioral Genetics of Addiction Laboratory. 

“What we’re finding,” Palmer adds, “is that to better leverage genetic information, we need to go beyond individual human traits and disorders and think about how risk for different behaviors and traits are interrelated. This broader approach can give us a much better measure for whether someone is at risk for a mental disorder, such as nicotine dependence.” 

Rohan Palmer heads the Department of Psychology's Behavioral Genetics of Addiction Laboratory that is developing new methods to better understand what makes people vulnerable to substance use disorders.

“All of the traits and diseases we looked at are polygenic, involving multiple genes,” adds Victoria Risner, first author of the study, who did the work as an Emory undergraduate majoring in neuroscience and behavioral biology. “That means that millions of genetic variants likely go into a complete picture for all of the heritable risks for nicotine dependence.” 

The researchers hope that others will build on their multi-trait, polygenetic model and continue to boost the understanding of the risk for such complex disorders. “The more we learn, the closer we can get to one day having a genetic test that clinicians can use to inform their assessment of someone’s risk for nicotine dependence,” Palmer says. 

Although the hazards of smoking are well established, about 14 percent of Americans report daily use of tobacco. Around 500,000 people die each year in the United States from smoking or exposure to smoke, and another 16 million live with serious illnesses caused by tobacco use, including cancer, cardiovascular disease and pulmonary disease. While the toxic chemicals produced during smoking and vaping are what cause harmful health effects, it’s the addictive component of nicotine that hooks people on these habits. 

Risner worked on the current paper for her honors thesis. “Nicotine dependence was interesting to me because the vaping scene was just arriving while I was an undergraduate,” she says. “I saw some of my own friends who were into vaping quickly becoming dependent on it, while some others who were using the same products didn’t. I was curious about the genetic underpinnings of this difference.” 

The project leveraged genome-wide association studies for a range of traits and disorders. The researchers then looked for matching variants in genetic data from a national representative sample of Americans diagnosed with nicotine dependence. The results showed how polygenetic scores for the different traits and disorders either raised or lowered the risk for that dependence. The number of cigarettes smoked per day, self-perceived risk-taking and educational attainment were the most robust predictors. 

The multi-variant, polygenetic model offers a road map for future studies. A clearer picture of heritability for nicotine dependence, for instance, may be gained by adding more risk associations to the model (such as nicotine metabolism) and clusters of polygenic traits (such as anxiety along with neuroticism). 

“As we continue to zero in on who is most at risk for becoming nicotine dependent, and what inter-related factors, whether genetic or environmental, may raise their risk, that could help determine what intervention might work best for an individual,” Palmer says. 

“Just a few decades ago, it was not well understood that nicotine dependence could have a genetic component,” Risner says. “Genetic studies may help reduce some of the stigma society has against substance use disorders, while also making treatment more accessible.” 

Risner graduated from Emory in 2019 and is now in medical school at the University of North Carolina, Chapel Hill. This summer, she’s applying the coding and analytical skills she learned at Emory to conduct research into genetic factors that may raise the risk for pre-term births. 

Emory co-authors of the Nicotine & Tobacco Research article include graduate student Lauren Bertin; post-doctoral fellow Chelsie Benca-Bachman; and Alicia Smith, associate professor in the School of Medicine. Additional authors include researchers from the University of Helsinki; Brown University; the Providence VA Medical Center; the Jackson Laboratory in Bar Harbor, Maine; Purdue University; and the University of Colorado at Boulder. 

The work on the Nicotine & Tobacco Research article was funded by the National Institute on Drug Abuse and the Academy of Finland.

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New molecule found in chestnut leaves disarms dangerous staph bacteria

"We're laying the groundwork for new strategies to fight bacterial infections at the clinical level," says Emory ethnobotanist Cassandra Quave, shown gathering samples of chestnut leaves in Italy. "We urgently need these new strategies."

By Carol Clark

Scientists isolated a molecule, extracted from the leaves of the European chestnut tree, with the power to neutralize dangerous, drug-resistant staph bacteria. Frontiers in Pharmacology published the finding, led by scientists at Emory University. 

The researchers dubbed the molecule Castaneroxy A, after the genus of the European chestnut, Castanea. The use of chestnut leaves in traditional folk remedies in rural Italy inspired the research. 

“We were able to isolate this molecule, new to science, that occurs only in very tiny quantities in the chestnut leaves,” says Cassandra Quave, senior author of the paper and associate professor in Emory’s Center for the Study of Human Health and the School of Medicine’s Department of Dermatology. “We also showed how it disarms Methicillin-resistant Staphylococcus aureus by knocking out the bacteria’s ability to produce toxins.” 

Methicillin-resistant Staphylococcus aureus (MRSA) causes infections that are difficult to treat due to its resistance to antibiotics. It is one of the most serious infectious disease concerns worldwide, labeled as a “serious threat” by the Centers for the Disease Control and Prevention. In the United States alone, nearly 3 million antibiotic-resistant infections occur each year, killing more than 35,000 people. 

Antibiotics work by killing staph bacteria, which can lead to greater resistance among those few bacteria that survive, spawning “super bugs.” The Quave lab has identified compounds from the Brazilian peppertree, in addition to the European chestnut tree, that simply neutralize the harmful effects of MRSA, allowing cells and tissue to naturally heal from an infection without boosting resistance. 

“We’re trying to fill the pipeline for antimicrobial drug discovery with compounds that work differently from traditional antibiotics,” Quave says. “We urgently need these new strategies.” She notes that antimicrobial infections kill an estimated 700,000 globally each year, and that number is expected to grow exponentially if new methods of treatment are not found. 

First author of the Frontiers in Pharmacology paper is Akram Salam, who did the research as a PhD student in the Quave lab through Emory’s Molecular Systems and Pharmacology Graduate Program.

The European chestnut, also known as the sweet chestnut, is native to Southern Europe and Asia Minor.

Quave is a medical ethnobotanist, researching traditional plant remedies to find promising leads for new drugs. Although many major drugs are plant-based, from aspirin (the bark of the willow tree) to Taxol (the bark of the Pacific yew tree), Quave is one of the few ethnobotanists with a focus on antibiotic resistance.

The story behind the current paper began more than a decade ago, when Quave and her colleagues researched written reports and conducted hundreds of field interviews among people in rural southern Italy. That pointed them to the European, or sweet, chestnut tree, native to Southern Europe and Asia Minor. “In Italian traditional medicine, a compress of the boiled leaves is applied to the skin to treat burns, rashes and infected wounds,” Quave says. 

Quave took specimens back to her lab for analysis. By 2015, her lab published the finding that an extract from the leaves disarms even the hyper-virulent MRSA strains capable of causing serious infections in healthy athletes. Experiments also showed the extract did not disturb normal, healthy bacteria on skin cells. 

Finally, the researchers demonstrated how the extract works, by inhibiting the ability of MRSA bacteria to communicate with one another, a process known as quorum sensing. MRSA uses this sensing signaling system to make toxins and ramp up its virulence. 

For the current paper, the researchers wanted to isolate these active ingredients from the plant extract. The process is painstaking when done manually, because plant extracts typically contain hundreds of different chemicals. Each chemical must be separated out and then tested for efficacy. Large scale fraction collectors, coupled to high-performance liquid chromatographic systems, automate this separation process, but they can cost tens of thousands of dollars and did not have all the features the Quave lab needed. 

Marco Caputo, a research specialist in the lab, solved the problem. Using a software device from a child’s toy, the LEGO MINDSTORMS robot creator, a few LEGO bricks, and some components from a hardware store, Caputo built an automated liquid separator customized to the lab’s needs for $500. The lab members dubbed the invention the LEGO MINDSTORMS Fraction Collector. They published instructions for how to build it in a journal so that other researchers can tap the simple, but effective, technology. 

The lab's homemade fraction collector.

The Quave lab first separated out a group of molecules from the plant extract, cycloartane triterpenoids, and showed for the first time that this group actively blocks the virulence of MRSA. The researchers then dove deeper, separating out the single, most active molecule from this group, now known as Castaneroxy A. 

“Our homemade piece of equipment really helped accelerate the pace of our discovery,” Quave says. “We were able to isolate this molecule and derive pure crystals of it, even though it only makes up a mere .0019 percent of the chestnut leaves.” 

Tests on mouse skin infected with MRSA, conducted in the lab of co-author Alexander Horswill at the University of Colorado, confirmed the molecule’s efficacy at shutting down MRSA’s virulence, enabling the skin to heal more rapidly. 

Co-author John Bacsa, director of Emory Department of Chemistry’s X-ray Crystallography Center, characterized the crystal shape of Castaneroxy A. Understanding the three-dimensional configuration of the crystal is important for future studies to refine and optimize the molecule as a potential therapeutic.

“We’re laying the groundwork for new strategies to fight bacterial infections at the clinical level,” Quave says. “Instead of being overly concerned about treating the pathogen, we’re focusing on ways to better treat the patient. Our goal is not to kill the microbes but to find ways to weaken them so that the immune system or antibiotics are better able to clear out an infection.” 

Emory co-authors of the paper also include graduate students Caitlin Risener and Lewis Marquez; post-doctoral fellow Gina Porras; and former staff scientist James Lyles. Additional authors from the University of Colorado are Young-Saeng Cho and Morgan Brown. 

The work was funded by the National Center for Complementary and Integrative Health, Emory’s Department of Dermatology, the National Institute of Allergy and Infectious Diseases and the National Institute of General Medical Sciences.

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Study shows adaptive brain response to stress, and its absence in people with depression

"Learning more about how acute stress and chronic stress affect the brain may help in the development of treatment targets for depression," says Jessica Cooper, first author of the study and a post-doctoral fellow in Emory's Department of Psychology.

By Carol Clark

A new study identifies a novel biomarker indicating resilience to chronic stress. This biomarker is largely absent in people suffering from major depressive disorder, and this absence is further associated with pessimism in daily life, the study finds. 

Nature Communications published the research by scientists at Emory University. 

The researchers used brain imaging to identify differences in the neurotransmitter glutamate within the medial prefrontal cortex before and after study participants underwent stressful tasks. They then followed the participants for four weeks, using a survey protocol to regularly assess how participants rated their expected and experienced outcomes for daily activities. 

“To our knowledge, this is the first work to show that glutamate in the human medial prefrontal cortex shows an adaptive habituation to a new stressful experience if someone has recently experienced a lot of stress,” says Michael Treadway, senior author of the study and professor in Emory’s Department of Psychology and Department of Psychiatry and Behavioral Science. “Importantly, this habituation is significantly altered in patients with depression. We believe this may be one of the first biological signals of its kind to be identified in relation to stress and people who are clinically depressed.” 

“Learning more about how acute stress and chronic stress affect the brain may help in the identification of treatment targets for depression,” adds Jessica Cooper, first author of the study and a post-doctoral fellow in Treadway’s Translational Research in Affective Disorders Laboratory. 

The lab focuses on understanding the molecular and circuit-level mechanisms of psychiatric symptoms related to mood disorders, anxiety and decision-making. 

It’s long been known that stress is a major risk factor for depression, one of the most common and debilitating of mental illnesses. “In many ways, depression is a stress-linked disorder,” Treadway says. “It’s estimated that 80 percent of first-time depressive episodes are preceded by significant, chronic life stress.” 

Around 16 to 20 percent of the U.S. population will meet the criteria for a major depressive disorder during their lifetimes. Experts are predicting rates of depression to climb even further in the wake of the ongoing COVID-19 pandemic. During the pandemic, about four in 10 adults in the United States have reported symptoms of anxiety or depressive disorder, up from one in 10 who reported them in 2019, according to the Kaiser Family Foundation. 

“The pandemic has created more isolation for many people, while also increasing the amount of severe stressors and existential threats they experience,” Treadway says. “That combination puts a lot of people at high risk for becoming depressed.” 

Although the link between stress and depression is clearly established, the mechanisms underlying this relationship are not. Experiments with rodents have shown an association between the response of glutamate — the major excitatory neurotransmitter in the mammalian brain — and stress. The role of glutamate in humans with depression, however, has been less clear. 

The 88 participants in the current study included people without a mental health disorder and unmedicated patients diagnosed with a major depressive disorder. Participants were surveyed about perceived recent stress in their lives before they underwent experiments using a brain scanning technique known as magnetic resonance spectroscopy. 

While in the scanner, participants were required to alternate between performing two tasks that served as acute stressors: Putting their hand up to the wrist in ice water and counting down from the number 2,043 by steps of 17 while someone evaluated their accuracy. 

Brain scans before and after the acute stressor measured glutamate in the medial prefrontal cortex, an area of the brain involved with thinking about one’s state and forming expectations. Previous research has also found that this brain area is involved in regulating adaptive responses to stress. 

Participants submitted saliva samples while in the scanner, allowing the researchers to confirm that the tasks elicited a stress response by measuring the amount of the stress hormone cortisol in the sample. 

In healthy individuals, the brain scans revealed that glutamate change in response to stress in the medial prefrontal cortex was predicted by individual levels of recent perceived stress. Healthy participants with lower levels of stress showed increased glutamate in response to acute stress, while healthy participants with higher levels of stress showed a reduced glutamate response to acute stress. This adaptive response was comparatively absent in the patients diagnosed with depression. 

“The decrease in the glutamate response over time appears to be a signal, or a marker, of a healthy adaptation to stress,” Treadway says. “And if the levels remain high that appears to be a signal for maladaptive responses to stress.” 

The initial result was strong for the adaptation in healthy participants, but was in a modest sample size, so the researchers decided to see if they could replicate it. “Not only did we get a replication, it was an unusually strong replication,” Treadway says. 

The experiment also included a group of healthy controls who underwent scanning before and after performing tasks. Rather than stressful tasks, however, the controls were asked to place a hand into warm water or to simply count out loud consecutively. Their glutamate levels were not associated with perceived stress and they did not show a salivary cortisol response. 

To expand their findings, the researchers followed participants for four weeks after scanning. Every other day, the participants reported on their expected and experienced outcomes for activities in their daily lives. The results showed that glutamate changes that were higher than expected based on an individual’s level of perceived stress predicted an increased pessimistic outlook — a hallmark for depression. 

“We were able to show how a neural response to stress is meaningfully related to what people experience in their daily lives,” Cooper says. “We now have a large, rich data set that gives us a tangible lead to build upon as we further investigate how stress contributes to depression.” 

Emory co-authors of the study include former and current graduate students from the Treadway lab Victoria Lawlor, Shabnam Hossein and Andrew Teer; as well as current and former research assistants Makiah Nuutinen, Brittany DeVries, Daniel Cole, Chelsea Leonard and Emma Hahn. Additional authors include researchers from UCLA, the University of Arkansas, Princeton and McLean Hospital/Harvard Medical School. 

The work was supported by the National Institutes of Mental Health.

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Flow of slushy sea ice predicts glacier calving

A view of Illusiat Glacier shows the ice melange (in the foreground) and the sheered off edge of the glacier where a massive ice sheet just broke away. (Jason Amundson)

Ice mélange, the mass of floating sea ice that buttresses many tidewater glaciers, plays a major role in the timing of calving icebergs, finds a new study published in Nature Geoscience. 

Scientists measured how just a tiny shift in the flow of a mélange, from smooth to slightly more chaotic, can predict up to one hour in advance that a massive hunk of ice will break off from a glacier, then crash into the ocean to form a new iceberg. 

“As a gateway to the ocean, ice mélange is critical to predictions of sea-level rise,” says Justin Burton, associate professor of physics at Emory University and co-author of the paper. “We’ve provided what may be the best, most high-resolution data ever on the dynamics of a mélange leading up to a major calving event. That helps us understand the forces determining how much ice melts into the ocean, and how fast it happens.” 

Ryan Cassotto, a glaciologist from the University of Colorado, Boulder, is lead author of the paper. Co-authors include Jason Amundson from the University of Alaska Southeast, Juneau; and Mark Fahnestock and Martin Truffer, both from the University of Alaska Fairbanks. 

The study’s data was drawn from Ilulissat, a World Heritage Site and the most productive tidewater glacier in Greenland, also known as Jakobshavn Glacier. Kilometer-sized icebergs that calve from Ilulissat often capsize, leading to glacial earthquakes and small tsunamis. 

Read the full story here.

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