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
Common drug class may increase risk of heart disease
The risk of cardiovascular disease increased in line with how much anticholinergic medication the participants used each year. Those with the highest exposure had a 71 per cent higher risk of a cardiovascular event than people who did not use anticholinergic medication at all.
People who use drugs with anticholinergic effects, including certain antidepressants, drugs for urinary incontinence and common antihistamines, are at higher risk of developing cardiovascular disease.
This is shown in a study from Karolinska Institutet published in BMC Medicine.
Anticholinergic drugs reduce the effect of the neurotransmitter acetylcholine and are commonly prescribed to middle-aged and older people. This large group of drugs includes antihistamines used for allergic conditions, anxiety or insomnia, drugs for urinary incontinence, and certain antidepressants, where tricyclic antidepressants have a strong anticholinergic effect, whereas SSRIs have a weaker effect. A high cumulative use of these drugs, referred to as anticholinergic burden (see fact box), has previously been linked to impaired cognitive ability.
May affect heart regulation
The new study suggests that the drugs may also affect the parasympathetic nervous system and thereby the regulation of the cardiovascular system. The results show that it may be important to monitor the total drug burden in everyday clinical practice.
The study included more than 500,000 people in Stockholm, Sweden, who were 45 years of age or older and had no prior cardiovascular disease, except for hypertension, at the start of the study. The researchers followed the participants for up to 14 years and analysed how the use of anticholinergic drugs was associated with the development of cardiovascular disease.
“Many of these drugs are used by older people and by people with multiple medical conditions. We wanted to investigate whether the total exposure had any significance for the risk of developing cardiovascular disease over time,” says Nanbo Zhu, postdoctoral researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.
71 per cent higher cardiac risk
The study showed that the risk of cardiovascular disease increased in line with how much anticholinergic medication the participants used each year. Those with the highest exposure had a 71 per cent higher risk of a cardiovascular event than people who did not use anticholinergic medication at all. The association was seen for all types of cardiovascular disease but was particularly clear for heart failure and various forms of arrhythmia.
“Our results indicate that the cumulative drug burden can affect heart regulation, not only in the short term but also over the long term. This does not mean that the drugs should always be avoided, but that exposure should be monitored carefully,” says Hong Xu, assistant professor at the Department of Neurobiology, Care Sciences and Society.
The researchers point out that the study is observational, meaning it cannot establish a causal relationship. Other factors, such as underlying diseases, may also influence the associations.
The work was carried out within the Stockholm CREAtinine Measurements project in collaboration between several research groups at Karolinska Institutet and Region Stockholm. The study was funded by the Swedish Research Council, the Center for Innovative Medicine Foundation, and other foundations. Some researchers report assignments for the pharmaceutical industry, which are disclosed in the scientific publication.
NewsMakers
Mindfulness practices found to significantly reduce depression symptoms, especially for those with early-life adversity
Mindfulness interventions help by regulating our emotions better when different challenges come up. For someone who has experienced childhood neglect or abuse, mindfulness training can help us make sense of that and respond skillfully to this moment in time.
A new study reveals that mindfulness practices may significantly reduce depression symptoms, particularly in people who have experienced early-life adversity, such as childhood abuse and neglect.
Led by Eric Loucks, professor of medicine, epidemiology, and of behavioral and social sciences and director of the Mindfulness Center at Brown, the study enrolled 201 participants, 101 of whom were randomized into the Mindfulness-Based Blood Pressure Reduction Program, while 100 were randomized into an enhanced usual care control, which included home blood-pressure monitors, physician access and health-education materials. Researchers also had a measure of participants’ early-life adversity, particularly their exposure to abuse or neglect.
Loucks and his team followed participants for six months to assess changes in blood pressure, health behaviors and mental health, finding that those in the mindfulness program showed significant improvements in their depression symptoms. Additionally, participants who experienced childhood neglect showed greater improvements in depression symptoms than those who had not. A similar, though less pronounced, trend was observed among people with a history of childhood abuse.
“In this program, that was primarily designed to lower blood pressure while addressing whole-person health, we also saw that mental well-being, particularly around depression symptoms, improved in participants that went through the program,” Loucks said. “The findings suggest that cultivating mindful self-regulation skills–such such as self-awareness, attention control and emotion regulation–may help interrupt maladaptive patterns shaped by past experiences.”
Over the last 15 years, Loucks has been studying social determinants of health such as early-life adversity and its impacts on cardiovascular health, body mass index and blood pressure. “I came to a point where I wanted to not just document it, but do something about it, and I wondered if mindfulness training might help,” he said. “I’d gone through a lot of mindfulness training myself outside of work and started to get trained up in mindfulness programs that are specific to health contexts.”
Loucks began to study the Mindfulness-Based Stress Reduction program, running it through two clinical trials that were funded by the NIH and finding that it reduced blood pressure in both trials. He also wanted to look at the intervention from a whole-person perspective.
“If we look at everyday folks out in the world, those that had exposure to early life adversity, like abuse and neglect, tend to have worse mental health and also worse cardiovascular health,” Loucks said. “Mindfulness interventions help by regulating our emotions better when different challenges come up. For someone who has experienced childhood neglect or abuse, mindfulness training can help us make sense of that and respond skillfully to this moment in time.”
Loucks discussed this work during a keynote address at the U.S. DOHaD Society this year. “It felt like a coming-home moment to see that this intervention, originally developed to address psychosocial factors that influence health, had even stronger effects among people with early-life adversity, particularly on depression,” he said. “It’s been about a 15-year arc of research that culminated in these findings.”
NewsMakers
High-fiber diet linked to reduced risk of heart disease in night shift workers
A moderate intake of about 19 grams of fibre per day was linked to a lower risk for those who worked night shifts regularly. For those who worked night shifts sporadically, about 15 grams was enough. The current recommendation for adults is about 25 grams of dietary fibre per day.
People who work at night have a higher risk of coronary artery disease, a type of heart disease. A new study suggests that a higher fibre intake in the diet may help reduce this risk. The study included over 220,000 adults in the UK and is published in the European Journal of Epidemiology.
The human body is built to sleep at night. This means that working during the night goes against this natural pattern, and can place additional strain on the body, including the heart. Previous research has linked night work to an increased risk of coronary artery disease. Since night work is often unavoidable, the researchers wanted to investigate whether certain dietary habits might have a protective effect.
More fibre associated with lower risk
The researchers used data from 220,000 adults in the UK Biobank (2006–2010) and divided the participants into three groups:
- Day workers
- Shift workers who worked night shifts sporadically
- Regular night shift workers
The participants had completed a detailed questionnaire about their dietary habits. During a follow-up after about 12 years, it was found that night shift workers who consumed little fibre in their diet had a higher risk of coronary artery disease than those who consumed more fibre.
“A moderate intake of about 19 grams of fibre per day was linked to a lower risk for those who worked night shifts regularly. For those who worked night shifts sporadically, about 15 grams was enough. The current recommendation for adults is about 25 grams of dietary fibre per day,” says Diana Nôga, lead author and researcher at Uppsala University.
The researchers stress that the figures from the study are not official dietary recommendations. But they do show a pattern in this UK study: a higher dietary fibre intake was linked to a lower risk of heart disease among night shift workers.
“The link between fibre and a lower risk of heart disease is not just because those who eat more fibre generally have a healthier lifestyle. We know this because we adjusted for various lifestyle factors in the analysis. One possible explanation, supported by previous research, is that fibre in the diet can improve intestinal flora and also reduce lipids, which can be particularly good for the heart in people who work at night,” says Christian Benedict, senior author of the study and Professor of Pharmacology at Uppsala University.
Dietary fibre can support heart health
According to the researchers, an increased intake of fibre-rich foods such as whole grains, vegetables, fruit, legumes and lentils may be a simple way to improve heart health for night shift workers. However, this requires that you do not have any medical obstacles to doing this, such as chronic gastrointestinal diseases.
“Dietary changes should be seen as a complement to, not a substitute for, other heart health-promoting habits such as not smoking, remaining physically active, and getting enough sleep,” says Diana Nôga.
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