NewsMakers
Study finds rare, but influential, genetic changes related to height
In the largest, deepest search to date, the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium has uncovered 83 new DNA changes that affect human height. These changes are uncommon or rare, but they have potent effects, with some of them adjusting height by more than 2 cm (almost 8/10 of an inch).
In the largest, deepest search to date, the international Genetic Investigation of Anthropometric Traits (GIANT) Consortium has uncovered 83 new DNA changes that affect human height. These changes are uncommon or rare, but they have potent effects, with some of them adjusting height by more than 2 cm (almost 8/10 of an inch). The 700,000-plus-person study also found several genes pointing to previously unknown biological pathways involved in skeletal growth. Findings were published online by Nature.
“While our last study identified common height-related changes in the genome, this time we went for low-frequency and rare changes that directly alter proteins and tend to have stronger effects,” says Joel Hirschhorn, MD, PhD, of Boston Children’s Hospital and the Broad Institute of MIT and Harvard, chair of the GIANT Consortium and co-senior investigator on the study together with researchers at the Montreal Heart Institute, Queen Mary University, the University of Exeter, UK, and nearly 280 other research groups. “To identify these protein-altering changes, some of them very uncommon, required tremendous statistical power, which we achieved thanks to a strong international collaboration.”
Applying a new technology
In 2014, GIANT, studying roughly 250,000 people, brought the total number of known genetic variants to nearly 700 — in more than 400 spots in the genome. This effort involved a powerful method called genome-wide association study (GWAS), which rapidly scans across the genomes of large populations for markers that track with a particular trait. GWAS are good at finding common genetic variants, but nearly all of the identified variants alter height by less than 1 mm (less than 1/20 of an inch). GWAS studies are not as good at capturing uncommon genetic variants, which can have larger effects. Finally, the common variants that track with traits tend to lie mostly outside the protein-coding parts of genes, making it harder to figure out which genes they affect.
So in the new study, the GIANT investigators used a different technology: the ExomeChip, which tested for a catalogue of nearly 200,000 known variants that are less common and that alter the function of protein-coding genes. These variants point more directly to genes and can be used as a shortcut to figuring out which genes are important for a specific disease or trait. Most had not been assessed in prior genetic studies of height.
Using ExomeChip data from a total of 711,428 adults (an initial 460,000 people and about 250,000 more to validate the findings), the investigators identified 83 uncommon variants associated with adult height: 51 “low-frequency” variants (found in less than 5 percent of people) and 32 rare variants (found in less than 0.5 percent).
With these new findings, 27.4 percent of the heritability of height is now accounted for (up from 20 percent in earlier studies), with most heritability still explained by common variants.
Twenty-four of the newly discovered variants affect height by more than 1 cm (4/10 of an inch), larger effects than typically seen with common variants. “This finding matches a pattern seen in other genetic studies, where the more potent variants are rarer in the population,” says Hirschhorn, who is also an endocrinologist at Boston Children’s and a professor of pediatrics and genetics at Harvard Medical School.
Rare but potent clues to new biology
These rare variants not only had large effects but also pointed to dozens of genes as important for skeletal growth. Some of these genes were already known, but many (including SUSD5, GLT8D2, LOXL4, FIBIN, and SFRP4) have not previously been connected with skeletal growth.
One gene of particular interest, STC2, had two different DNA changes that both had larger effects on height. Though the variants are quite rare (frequency of 0.1 percent), people with either of these changes were 1-2 cm taller than non-carriers. Further investigations by co-authors Troels R. Kjaer and Claus Oxvig of Aarhus University (Denmark) suggested that the variants influence height by affecting the availability of growth factors in the blood. “The STC2 protein serves as a brake on human height, validating it as a potential drug target for short stature,” says Hirschhorn.
Height: A window into complex genetics
Why study height? Height is the “poster child” of complex genetic traits, meaning it is influenced by multiple genetic variants working together. It’s easy to measure, so makes a relatively simple model for understanding traits produced by not one gene, but many.
“Mastering the complex genetics of height may give us a blueprint for studying multifactorial disorders that have eluded our complete understanding, such as diabetes and heart disease,” says Hirschhorn. “This study has shown that rare protein-altering variants can be helpful at finding some of the important genes, but also that even larger sample sizes will be needed to completely understand the genetic and biologic basis of human growth and other multifactorial diseases.”
Indeed, the GIANT consortium is already embarking on a GWAS of height with more than 2 million people, and other studies involving sequencing data are underway. “We predict that these more comprehensive studies will continue to enhance our understanding of human growth and how best to attain the biological insights that will inform treatments for common diseases,” says Hirschhorn.
In addition to Hirschhorn, the study’s co-senior authors include Timothy Frayling of the University of Exeter, Panos Deloukas of the Queen Mary University of London and Guillaume Lettre of the University of Montreal. Co-first authors were Eirini Marouli of Queen Mary University; Mariaelisa Graff of the University of North Carolina, Chapel Hill; Carolina Medina-Gomez of Erasmus Medical Center (Rotterdam, Netherlands); Ken Sin Lo of the Montreal Heart Institute; Andrew R Wood of the University of Exeter (U.K.), Troels R. Kjaer of Aarhus University (Denmark), Rebecca S. Fine of the Broad Institute, Boston Children’s Hospital and Harvard Medical School; and Yingchang Lu of Vanderbilt University (Nashville, TN) and the Icahn School of Medicine at Mount Sinai (New York). The study’s numerous funding sources include the National Institutes of Health, the Wellcome Trust, MRC, the European Research Council, the European Union, the Canadian Government, the Canadian Institutes of Health Research, the Danish Council, Novo Nordisk and the Lundbeck Foundation.
NewsMakers
Study links coffee consumption to metabolic health and sex hormones
Despite having a similar body mass index (BMI), individuals with higher coffee consumption had lower total and visceral fat and greater skeletal muscle mass than those who consumed less coffee.
Coffee is one of the world’s most widely consumed beverages, and previous research has linked its consumption to a lower risk of conditions such as type 2 diabetes and cardiovascular disease. However, the biological mechanisms behind these benefits remain unclear. A new Finnish study links habitual coffee consumption to healthier body composition and metabolic markers, while revealing distinct associations with sex hormones in men and women.
The study, conducted at the University of Oulu, analysed data from 2,264 participants aged 46 in the Northern Finland Birth Cohort 1966. Researchers examined how habitual coffee consumption was associated with circulating metabolites, cardiometabolic risk markers and sex hormones.
Despite having a similar body mass index (BMI), individuals with higher coffee consumption had lower total and visceral fat and greater skeletal muscle mass than those who consumed less coffee.
In both men and women, higher coffee consumption was correlated with lower circulating levels of branched-chain amino acids, biomarkers that have previously been linked to insulin resistance and an increased risk of type 2 diabetes when chronically elevated.
The strongest sex-specific associations were observed in men. Higher coffee consumption was linked to a more favourable glucose–insulin profile, higher concentrations of total and bioavailable testosterone, and increased levels of sex hormone-binding globulin (SHBG). At the same time, free testosterone and the free androgen index were modestly lower. In women, hormonal associations were more limited and were primarily characterised by higher SHBG and lower measures of free androgens.
“Coffee is consumed by millions of people every day, yet we still know surprisingly little about how it relates to our metabolism and hormones. What stood out in our findings was a distinct hormonal signature that didn’t disappear even after we took into account BMI and lifestyle factors, with several of these associations differing between men and women,” says Luca Verroest, lead author of the study and Doctoral Researcher at the University of Oulu.
The results suggest that hormonal pathways may partly explain the relationship between coffee consumption and metabolic health. However, as this was an observational study, the findings demonstrate associations rather than cause-and-effect relationships.
The study is particularly relevant in Finland, one of the world’s highest coffee-consuming countries, where annual consumption averages around 11.8 kilograms per person.
The researchers say the findings provide a foundation for future studies aimed at determining whether coffee itself drives these biological changes and identifying the compounds responsible. These questions are currently being investigated in animal models, with the long-term goal of progressing to human intervention studies. Further research will be needed before the findings could inform dietary recommendations.
The study, Associations of habitual coffee intake with testosterone and cardiometabolic markers: the Northern Finland Birth Cohort 1966 study, has been published in the European Journal of Nutrition.
NewsMakers
Scheduling dental care during prenatal visits boosts oral health care during pregnancy
Scheduling a dental appointment during prenatal clinic visits—a simple, no-cost task that doesn’t require extra staff—increases the likelihood that patients later see a dentist during pregnancy.
Prenatal visits might include bloodwork, discussions of due dates and vitamins, and ultrasounds. What if these visits could also improve oral health care among pregnant patients?
New research shows that scheduling a dental appointment during prenatal clinic visits—a simple, no-cost task that doesn’t require extra staff—increases the likelihood that patients later see a dentist during pregnancy.
The study, published in the American Journal of Public Health, demonstrates the benefit of coordination among health providers and integrating oral health into prenatal care, especially for vulnerable patient populations.
Historically, dentists avoided treating women during pregnancy unless it was an emergency, or only provided care during the second trimester. This guidance changed once studies showed that routine and emergency dental care is safe during pregnancy—and current obstetric and dental guidelines stress that dental care can and should be provided during this critical period.
Moreover, pregnancy increases the risk of some oral health conditions, including gum inflammation and sometimes tooth decay, making routine dental care even more important during pregnancy. Some oral health issues may affect the fetus or even be transmissible to the child after birth.
Marginalized groups, including low-income individuals and those insured by Medicaid, are known to have higher rates of dental disease. Yet women enrolled in Medicaid are far less likely to see a dentist for a cleaning during pregnancy compared to women with private insurance.
“Many of those vulnerable to oral disease enter pregnancy with dental disease, and this may worsen during pregnancy,” said study author Stefanie Russell, associate professor at Rutgers School of Dental Medicine and an adjunct associate professor at NYU College of Dentistry, who led this research while at NYU.
One way to try and increase dental care among pregnant women is to reach them where they already are: their prenatal appointments. To bridge this gap, researchers and clinicians at NYU College of Dentistry teamed up with neighboring NYC Health + Hospitals/Bellevue, the oldest public hospital in the US, to create the New York University/Bellevue Prenatal Oral Health Program.
During weekly sessions at Bellevue’s prenatal clinic, pregnant patients receive a standardized screening to assess their oral health. Those with dental needs are referred to NYU College of Dentistry for follow-up care, educated about the importance and safety of dental care during pregnancy, and informed that Medicaid covers dental care in New York.
From 2018 to 2020, 420 prenatal patients with Medicaid coverage were referred to NYU Dentistry for follow-up dental care; the majority were Hispanic, and roughly half spoke Spanish as their first language. Referrals for dental care took two forms: immediately scheduled dental appointments made before the patient left the prenatal clinic or through a patient navigator. The patient navigator—a bilingual professional—educated patients regarding oral health, reminded patients of their upcoming dental appointments, and followed up after to identify any issues.
Nearly 44 percent of patients referred to NYU College of Dentistry followed through with a dental appointment. Both immediate appointment scheduling and the patient navigator increased the chances of a patient receiving dental care, but those who had appointments scheduled at their prenatal visit were 2.6 times more likely to see a dentist than those without appointments scheduled—even more likely than those who worked with the patient navigator.
“This suggests that immediately scheduled dental appointments can be an effective way to increase dental care utilization during pregnancy, without needing to hire extra staff,” said study author Shulamite Huang, assistant professor of epidemiology and health promotion at NYU College of Dentistry.
The authors conclude that integrating oral health screening in a prenatal clinic is feasible and increases engagement with dental care during pregnancy. They are continuing their research to measure whether this care improves oral health outcomes and to better understand how dental screening can be successfully integrated with prenatal care in other settings.
“A warm hand-off is key for addressing part of the barriers to dental care during pregnancy. Our team plans to further investigate and optimize interventions addressing both patient-, provider-, and healthcare system-level barriers to dental care during pregnancy,” said Huang.
Additional study authors include Richard Heyman and Mary Kang of NYU Dentistry; Belkys Saba, formerly of NYU Dentistry; Chloe Bird of the Tufts University School of Medicine; and Chengwu Yang of the Florida Atlantic University Schmidt College of Medicine.
NewsMakers
Why a UTI hurts — and why that might be a good thing
Australian researchers have discovered a previously overlooked group of bladder nerves that help detect urinary tract infections (UTIs) and trigger the body’s response to clear them, providing a potential new target for future bladder pain therapies.
Australian researchers have discovered a previously overlooked group of bladder nerves that help detect urinary tract infections (UTIs) and trigger the body’s response to clear them, providing a potential new target for future bladder pain therapies.
The study shows that bladder nerves located close to the lining of the bladder act as a frontline infection sensor, helping the body recognise UTIs and trigger responses that reduce the severity and spread of infection.
UTIs are among the most common bacterial infections worldwide, with more than 400 million cases reported every year. Nearly one in three women will experience UTIs before the age of 24, and many elderly people and those with bladder issues from spinal cord injuries can experience multiple UTIs in a single year.
Symptoms often include frequent urination, a sudden urge to urinate, pain during urination, and pelvic discomfort can be debilitating for some patients.
Flinders University’s Dr Luke Grundy says that while scientists have long understood how the bladder senses as it fills and triggers urination, the role of a specialised group of bladder nerves near the bladder lining has remained unclear.
“Most bladder nerves act like a fuel gauge, telling the brain when the bladder is filling up and needs emptying,” says Dr Grundy, Head of the NeuroUrology Research Group at Flinders University.
“The nerves we studied in this research are different. They sit close to the bladder lining and appear to act more like an early warning system, detecting infection and inflammation.
“They don’t just sense infection. They help coordinate the body’s response to it by triggering pain and urinary frequency, behaviours that appear to help clear bacteria from the bladder as part of the body’s defence system.”
Lead author and recently graduated PhD student Dr Cindy Tay says the discovery changes how these nerves are understood.
“These mucosal nerves have puzzled scientists for almost two decades because they stay quiet while the bladder fills and empties, which is the main job of the bladder,” says Dr Tay.
“What we’ve found is that they have a hidden job — acting as an early warning system that springs into action the moment infection takes hold.”
The research team developed a novel method to selectively study a specialised group of sensory nerves in the bladder lining of mice, revealing that while these nerves play little role in normal bladder function, they become highly responsive during a UTI and help detect and respond to infection.
“When the bladder is healthy, these nerves are relatively quiet, but during a urinary tract infection they become highly sensitive and respond to the presence of bacteria and inflammation,” says Dr Grundy.
“It may feel unpleasant, but urinating more frequently actually helps clear the infection by flushing out the harmful bacteria.”
The study also helps explain why people with conditions affecting nerve function may be more prone to recurrent or severe UTIs.
“If the nerves that detect infection aren’t working properly, the body may not respond as effectively,” says Dr Grundy.
Building on previous research, the new study reveals a deeper understanding of how UTIs affect bladder function and the nervous system, and could help develop new treatments that target these nerves to relieve UTI-related symptoms.
“Our findings provide new insight into how the bladder detects and responds to infection, helping explain the biological processes that drive the pain, urgency and discomfort commonly experienced during UTIs,” says Dr Grundy
Researchers say the next challenge is to develop therapies that ease the pain and urgency associated with UTIs while preserving the protective role these nerves play in fighting infection.
The paper, ‘Bladder mucosal afferents detect UTI and aid pathogen clearance,’ by Cindy Tay, Harman Sharma, Stewart Ramsay (University of Adelaide), Georgia Bourlotos, Sarah K Manning, Natalie E Stevens, Sophie J Miller, Geraint B Rogers, David J Lynn, Feargal J Ryan, Andrea M Harrington (University of Adelaide), Vladimir Zagorodnyuk, Steven L Taylor and Luke Grundy was published in Proceedings of the National Academy of Sciences (PNAS).
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