06-07-2017: 'Twin tots reveal autism traits arise mostly from genes' (click to visit spectrumnews.org)
14-06-2017:International consortium reports genetic variants that provide insight into the regulation of the heart rhythm in health and disease - click here to read the press release (PDF)
24-04-2017: Study identifies hundreds of genes that influence timing of puberty and alter risk of several cancers
The largest genomic analysis of puberty timing in men and women conducted to date has identified 389 genetic signals associated with puberty timing, four times the number that were previously known.
The study, published today in Nature Genetics is a large collaborative project with researchers from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, the Netherlands Twin Register and others in the international ReproGen consortium. The researchers also found evidence linking earlier timing of puberty to higher risk of several cancers known to be sensitive to sex-hormones in later life, including breast, ovary and endometrial cancers in women, and prostate cancer in men. These influences remained after controlling for body weight, which is important as body weight itself influences both the timing of puberty and the risk of some cancers.
John Perry, Senior Investigator Scientist from the MRC Epidemiology Unit at the University of Cambridge and senior author on the paper says:
"Previous studies suggested that the timing of puberty in childhood was associated with risks of disease decades later, but until now it was unclear if those were circumstantial observations, for example secondary to other factors such as body weight. Our current study identifies direct causal links between earlier puberty timing itself and increased cancer risk. This link could possibly be explained by higher levels of sex hormones throughout life, but we need to do more work to understand the exact mechanisms involved. We aim to understand these disease links and thereby contribute to the prevention of diseases in later life."
The timing of puberty varies widely between individuals but tends to run closely within families. Data from the Netherlands Twin Register indicated for example that differences among women in age at menarche are highly heritable, with genetic factors explaining at least 70% of the variation (S.M. van den Berg and D.I. Boomsma, Behavior Genetics, 2007).
By performing detailed assessments of genetic variants across the whole genome in 329,345 women, the new study published today identified 389 independent genetic signals for age at puberty in women. This observation was then confirmed in a further 39,543 women from the deCODE study, Iceland. These findings shed light on the mechanisms that regulate puberty timing.
Dr. Hamdi Mbarek, co-author, Assistant Professor at the Department of Biological Psychology at the Vrije Universiteit Amsterdam, says: These results emphasize the importance of genetic factors in the regulation of puberty timing, one of the multiple aspects of fertility status. Furthermore, they support the mechanistic links with known adverse health outcomes like sex steroid-sensitive cancers in women and men.
One of the more remarkable findings concerns the role of imprinted genes, which are only active in your body when inherited specifically from one parent but not the other. We identified rare variants in two genes, which both lower the age of puberty when inherited from your father, but have no effect when inherited from your mother.
Felix R. Day, Deborah J. Thompson, Hannes Helgason et al. “Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk” Nature Genetics 2017
05-12-2016: Collaborating on big data to unravel disease processes
Patients with the same illness often receive the same treatment, even if the cause of the illness is different for each person. Six Dutch universities are combining forces to chart the different disease processes for a range of common conditions. This represents a new step towards ultimately being able to offer every patient more personalised treatment. The results of this study have been published in two articles in the authoritative scientific journal Nature Genetics.
The researchers were able to make their discoveries thanks to new techniques that make it possible to simultaneously measure the regulation and activity of all the genes of thousands of people, and to link these data to millions of genetic differences in their DNA. The combined analysis of these ‘big data’ made it possible to determine which molecular processes in the body become dysregulated for a range of different diseases, from prostate cancer to inflammatory bowel disease, before the individuals concerned actually become ill. “The emergence of ‘big data’, ever faster computers and new mathematical techniques means it’s now possible to conduct extremely large-scale studies and gain an understanding of many diseases at the same time,” explains Lude Franke (UMCG), head of the research team in Groningen. The researchers show how thousands of disease-related DNA differences disrupt the internal working of a cell and how their effect can be influenced by environmental factors. And all this was possible without the need for a single lab experiment.
Large-scale collaboration in the Netherlands
The success of this research is the result of the decision taken six years ago by biobanks throughout the Netherlands to share data and biomaterials. This decision meant it became possible to gather, store and analyse data from blood samples of a very large number of volunteers. The present study illustrates the tremendous value of large-scale collaboration in the field of medical research in the Netherlands. Bas Heijmans (LUMC), research leader in Leiden and initiator of the partnership: “The Netherlands is leading the field in sharing molecular data. This enables researchers to carry out the kind of large-scale studies that are needed to gain a better understanding of the causes of diseases. This result is only just the beginning: other researchers with a good scientific idea will be given access to this enormous bank of anonymised data once they have undergone a screening.”
Mapping the various molecular causes for a disease is the first step towards a form of medical treatment that better matches the disease process of individual patients. To reach that ideal, however, we still have a long way to go. The large-scale molecular data that have been collected for this research are the cornerstone of even bigger partnerships. The third research leader, Peter-Bram ’t Hoen (LUMC), says: “Large quantities of data should eventually make it possible to give everyone personalised health advice, and to determine the best treatment for each individual patient.”
The two scientific articles will be published on 5 December in Nature Genetics (http://dx.doi.org/10.1038/ng.3721 & dx.doi.org/10.1038/ng.3737). The research has been made possible thanks to the cooperation within the BBMRI biobank consortium (Biobanking and BioMolecular resources Research Infrastructure) of six long-running Dutch population studies carried out by the university medical centres in Groningen (LifeLines), Leiden (Leiden Longevity Study), Maastricht (CODAM Study), Rotterdam (Rotterdam Study), Utrecht (Netherlands Prospective ALS Study) and by the Vrije Universiteit (Netherlands Twin Register) plus the national centralised computational facility of SURFsara and the ErasmusMC Human Genomics Facility HuGE-F. The study links in with the Personalised Medicine route of the Dutch National Research Agenda.
31-10-2016: 12 DNA areas 'linked with the age at which we have our first child and family size'
Researchers have identified 12 specific areas of the DNA sequence that are robustly related with the age at which we have our first child, and the total number of children we have during the course of our life. The study, led by the University of Oxford, working together with the Universities of Groningen, The Netherlands and Uppsala, Sweden, includes an analysis of 62 datasets with information from 238,064 men and women for age at first birth, and almost 330,000 men and women for the number of children. Until now, reproductive behaviour was thought to be mainly linked to personal choices or social circumstances and environmental factors. However, this new research shows that genetic variants can be isolated and that there is also a biological basis for reproductive behaviour. The paper is co-authored by over 250 sociologists, biologists, and geneticists from institutions worldwide, and has been published in the journal Nature Genetics.
Lead author Professor Melinda Mills, from the Department of Sociology and Nuffield College at the University of Oxford, comments: 'For the first time we now know where to find the DNA areas linked to reproductive behaviour. For example, we found that women with DNA variants for postponing parenthood also have bits of DNA code associated with later onset of menstruation and later menopause. One day it may be possible to use this information so doctors can answer the important question: "How late can you wait?" based on the DNA variants. It is important to put this into perspective, however, as having a child still strongly depends on many social and environmental factors that will always play a bigger role in whether or when we have babies.'
The study shows that DNA variants linked with the age at which people have their firstborn are also associated with other characteristics reflecting reproduction and sexual development, such as the age at which girls have their first period, when the voice breaks in boys, and at what stage women experience their menopause.
Co-authors Dr Hamdi Mbarek of the Department of Biological Psychology at the VU University Amsterdam, explains: "The identification of these genes that influence our reproductive behaviour as well as the newly identified genes that increase the chance for mothers to have fraternal twins, helps us to better understand the genetic and biological architecture of fertility."
The researchers calculated that variants in the 12 areas of the DNA together predict less than 1% of the timing at which men and women have their first child and of the number of children they have in the course of their lifetime. The paper says that while these numbers seem 'extremely small', their modelling shows that in some cases when the variants are combined, they can be used to predict the probability of women remaining childless. Importantly, by examining the function of the 12 DNA regions and the genes in these regions in detail, the researchers have identified 24 genes that are likely to be responsible for the effects of the 12 DNA variants on reproductive behaviour. Some of these genes were already known to influence infertility, while others have not yet been studied.
28-09-2016:How baby's genes influence birth weight and later life disease
New research finds genetic differences that help to explain why some babies are born bigger or smaller than others. It also reveals how genetic differences provide an important link between an individual's early growth and their chances of developing conditions such as type-2 diabetes or heart disease in later life.
The large-scale study, published in Nature, could help to target new ways of preventing and treating these diseases.
The new study was done by a large team of researchers from including the several universities from the Netherlands. The research involved more than 160 international researchers from 17 countries who are members of the Early Growth Genetics (EGG) Consortium. The research concluded that a substantial proportion (at least one-sixth) of the variation in birth weight is down to genetic differences between babies. This is seven to eight times more variation than can be explained by environmental factors already known to influence birthweight, such as the mother smoking during pregnancy or her body mass index (a measure of obesity) before pregnancy starts.
Dr Rachel Freathy, a Sir Henry Dale Fellow at the University of Exeter Medical School, who is one of the lead authors, said: "This study has revealed how the small genetic differences between individuals can collectively have quite large effects on birth weight, and how those same genetic differences are often linked to poor health in later life. Weight at birth is influenced by many factors, including the baby's genes and those of its parents, as well as by the nutrition made available and the environment provided by the mother. We now have a much more detailed view of the ways in which these genetic and environmental elements work together to influence early growth and later disease."
It has been known for some time that babies whose birthweight is well below, or well above, average have a markedly increased risk of diabetes many decades later. Until now, many researchers have assumed that this link reflects the long-term impact of the nutritional environment in which the fetus develops: in other words, that events in early life can "set up" an individual's body in ways that make them more prone to disease in later life.
In this new study, the researchers uncovered a substantial overlap in the genetic regions linked to differences in birth weight and those that are connected to a higher risk of developing diabetes or heart disease. Most of this overlap involves the baby's genetic profile, but the team found that the mother's genes also played an important role in influencing her baby's birth weight, most likely through the ways in which they alter the baby's environment during pregnancy.
These findings provide vital clues to the some of the processes that act over decades of life to influence an individual's chances of developing diabetes and heart disease. These should highlight new approaches to treatment and prevention. Understanding the contributions of all of these processes will also tell us how much we should expect the many, wonderful improvements in antenatal care to reduce the burden of future diabetes and heart disease.
The researchers analysed genetic differences throughout the genomes of nearly 154,000 people from across the world. The Netherlands Twin Register based at the Vrije Universiteit Amsterdam also took part. The Netherlands Twin Register collects information from twins and their non-twin family members and for this paper it was the non-twin group of participants who provided the information used in the study on birth weight.
By matching the information on birth weight to genetic profiles, the researchers could identify sixty regions of the genome that were clearly driving differences in birthweight. They then analysed data from previous studies on conditions including diabetes and heart disease, and found that many of the same genomic regions were implicated.
Dorret Boomsma from the Netherlands Twin Register says: "These results point to the key role played by genetic differences in connecting variation in early growth to future risk of disease. Next steps will be to gather more pieces of the puzzle, including a better understanding of how the genetic profiles of mother and baby act together to modify the baby's weight and later disease risk as well as investigating which role these genes play in determining birth weight in twins, who usually are born with a lower birth weight than singleton children."
The paper, "Genome-wide associations for birth weight and correlations with adult disease", is published in Nature on Wednesday September 28.
20-06-2016: Large-scale genetic study provides new insight into the causes of migraine
An international research consortium has identified almost 30 new genetic risk factors for common migraine. Many of these risk variants localize inside or close to genes that regulate the vascular system. The results provide further support for the theory that an abnormal function of the blood vessels of the brain is an important component in driving migraine attacks.
The results of the largest genetic study on migraine thus far were published online in the journal Nature Genetics today, June 20. The study was based on DNA samples of 375,000 European, American and Australian participants, including large group of participants from the Netherlands Twin Register. Almost 60,000 of them suffer from migraine.
The researchers combined data from 22 genome-wide association studies including new data from around 35,000 migraine sufferers. From the millions of genetic variants analyzed, 38 independent genomic regions were shown to be associated with migraine. Only ten of these regions have been implicated in migraine susceptibility before.
The study was conducted by members of the International Headache Genetics Consortium including migraine research groups from Australia, Denmark, Estonia, Finland, Germany, Iceland, the Netherlands, Norway, Spain, Sweden, the UK and USA.
Our consortium is devoted to uncovering the genetic causes of migraine and during the past few years we have been able to identify many risk variants. Yet, in this latest, large-scale study, tens of new genetic risk factors were discovered. Because all of these variants modify the disease risk only slightly, the effect could only be seen when this large amount of samples became available, said Professor Aarno Palotie, leader of the International Headache Genetics Consortium. We simply can’t overstate the importance of international collaboration when studying genetics of complex, common diseases.
Migraine is a debilitating disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood which makes developing new treatments challenging. When the researchers took a closer look on the genomic areas pinpointed in the study, they noticed that most of them overlap with known genes. Interestingly, as many as nine of the genes have been previously associated with some vascular disease and four more are known to be involved in the regulation of vascular tone, supporting the importance of blood vessels in migraine attacks.
Doctors have known for a long time that migraine patients differ from each other and the drugs that work for some patients are completely inefficient for others. In the future, we hope that this information can be utilized in dividing the patients into different genetic susceptibility groups.
Original publication: Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine (2016). Padhraig Gormley, Verneri Anttila, Bendik S Winsvold et al. Nature Genetics. dx.doi.org/10.1038/ng.3598
29-04-2016:Twinning consortium reports genetic variants that influence human dizygotic twinning and provide insight into female fertility and reproduction
Découverte de la cause génétique de jumeaux fraternels et lien avec la fertilité
Also available in Arabic
The publication of this article generated a lot of attention in the press:
31-03-2016: Researchers discover genes that influence cannabis use
Researchers from the AMC, Vrije Universiteit Amsterdam (Netherlands Twin Register) and Radboud University have discovered four genes that play a role in the use of cannabis. An article about their findings, co-written by colleagues from the USA and Europe, is being published in this week’s Translational Psychiatry. The research involved almost 40,000 participants in 17 different studies, who together make up the ‘International Cannabis Consortium’.
One in every four Dutch people has used cannabis at some time in his/her life. While cannabis can be a fairly harmless drug for some, it can lead to mental and physical problems or even addiction in others. Previous research on twins showed that hereditary factors play a major role (accounting for 45%) in people’s tendency to use cannabis. Until now, however, researchers did not know which genes were responsible.
Cannabis and nicotine addiction
The researchers found four genes that showed a variation in cannabis users that was not seen in people who never use cannabis. “One of these four genes, NCAM1, was particularly interesting because previous studies had shown that it also plays a role in nicotine addiction,” say researchers Prof. Eske Derks (AMC) and Prof. Jacqueline Vink (Radboud University). NCAM1 plays a role in the transfer of dopamine in the brain. This hormone, which gives people a sense of reward, plays an important part in addiction. They now have to find out whether this applies to cannabis too. The researchers also revealed that the genetic risk factors for cannabis use largely overlap the risk factors for nicotine use.
The discovery of these four genes gives insight into the biological processes governing cannabis use. Further research will focus on how the genes affect cannabis use and whether they play a role in addiction.
Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32?330 subjects from the International Cannabis Consortium,Translational Psychiatry (2016) 6, e769; doi:10.1038/tp.2016.36
Both awards endorse van Bergen’s academic talent and will allow her to study the interplay between genes and environment on reading ability.
On 17th July 2015 in Hawaii (US), Elsje van Bergen received the Sandak Young Investigator Award of the international Society for the Scientific Study of Reading (SSSR). That same day the Netherlands Organisation for Scientific Research (NWO) announced that Van Bergen was also awarded a prestigious Veni fellowship for her research ‘Decoding the gene-environment interplay of reading ability’.
Researchers within the international Society for the Scientific Study of Reading (SSSR) study reading ability, varying from the role of genes and brain processes to dyslexia interventions. The award is intended to recognize a gifted young reading researcher who shows outstanding promise and dedication to the field. The award includes a certificate and a monetary award of 500 dollar. The award shows that Elsje van Bergen is also internationally recognized as a promising and talented scientist.
Two academic prizes on one day
On the same that that she got the SSSR award, NWO announced that she is among the winners of the prestigious Veni fellowship. Van Bergen will use this three-year fellowship of €250.000,- to study the interplay of genes and environment on reading ability. She will conduct her research at the Department of Biological Psychology (Faculty of Behavioural and Movement Sciences) and the Netherlands Twin Register. Van Bergen is delighted with both prizes: “These awards give an impetus to both genetic reading research in the Netherlands as well as my academic career.”
Intertwining of genes and environment
We read all day long: from study books to subtitles and whatsapp messages. Given the importance of reading, we know surprisingly little about the interplay between genes and environment that influences reading development. For instance, families with a strong genetic predisposition to dyslexia may have fewer books in the home because they do not enjoy reading. In her research van Bergen would like to uncover how genes and environments are intertwined. To do so, she will study reading of thousands of twin families and apply sophisticated statistics.
The Royal Netherlands Academy of Arts and Sciences (KNAW) has just announced that one of the two the prestigious Academy Professor Prizes will be awarded to NTR researcher prof. dr. Dorret Boomsma (VU FPP Biological Psychology). The other Prize is for prof. dr. Egbert Meijer (TU/e, Organic Chemistry). Both scientists receive EUR 1 million to spend on a scientific goal of their own choice. More on the EMGO website.
13-04-2014: NTR and NESDA Cohorts Create Roadmap for Gene Expression
Researchers at the Netherlands Twin Register (NTR) and the Netherlands Study of Depression and Anxiety (NESDA) have taken the first steps toward creating a roadmap that may help scientists narrow down the genetic cause of numerous diseases. Their work also sheds new light on how heredity and environment can affect gene expression (please click for the full press release).
12-08-2013: New study shows genetic overlap between schizophrenia and depression for the first time
Psychiatric disorders account for around one-third of disability worldwide and cause enormous personal and societal burdens; affecting almost every one of us, either directly or through friends and family. Despite their importance in our society, psychiatric disorders are amongst the most intractable in medicine and their underlying causes are mostly unknown. Unlike most other diseases and disorders there are no biological markers to aid diagnosis and the organ of relevance, the brain, cannot be biopsied and so is difficult to study. Led by Dr Lee and Professor Naomi Wray from The University of Queensland in Australia, the study links, for the first time, common psychiatric disorders like depression with less common disorders like schizophrenia and bipolar disorder.
A worldwide consortium has found that genetic factors give rise to a general susceptibility to psychiatric disorders. Data from large Dutch studies including the Netherlands Study of Depression and Anxiety (led by Professor Brenda Penninx) and the Netherlands Twin Register (led by Professor Dorret Boomsma) - contributed to this finding.
The study analysed the genetic information of more than 75,000 people, looking specifically at a type of genetic variation called single nucleotide polymorphisms (SNPs). A SNP is one of the most common genetic changes and involves the replacement of a single unit that makes up our DNA with another. The consortium investigated whether any of these small genetic changes were associated with susceptibility across different psychiatric disorders. The study was published in the latest issue of the prestigious journal, Nature Genetics. The large sample size was only achievable through major international collaboration; with more than 300 authors representing over 250 institutions.
Boomsma says: “Twin studies and family history both signify genetic inheritance as a recognised risk factor for psychiatric disorders and it has been hypothesised that psychiatric diagnoses are categorisations of a psychiatric spectrum. The current results support of this hypothesis”.
“The last five years have seen important progress made in our understanding of the genetic underpinning of psychiatric disorders, but major depression has been a harder nut to crack, partly because it is so common and it is likely that multiple combinations of genetic and environmental factors lead to the same diagnosis. These results provide clear guidance on what we need to do next to help unravel the complexity of depression”, Penninx said.
The results indicate that even larger sample sizes of depressed patients who have donated DNA and for whom there is information for a breadth of symptoms will be needed to probe the complexity of major depression. Evidence from other diseases clearly shows that genetic factors underpin differences between individuals in their response to drug treatment. Understanding these differences may contribute to personalizing treatment options in the long term.
The results of our research are still a long way away from impacting those affected by psychiatric disorders in terms of diagnosis, prognosis or treatment, but we are now glimpsing the possibility that the advances in genomic technology could have on our understanding of common mental illnesses. This also indicates that there is a further need to gather and combine genetic and detailed psychiatric information on a large scale. Boomsma and Penninx aim to contribute to this purpose by including more patients with depression and also healthy controls through large collaborative biobank projects in the Netherlands. The article can be found here:
Study Identifies New Gene Variations Associated With Heart Rate
Researchers Discover 14 New Loci Which May Provide Insight for the Treatment of Cardiovascular Disease
New genetic variations associated with heart rate have been identified in a collaborative genome-wide study in which 268 researchers from 211 institutions ia joined forces, including the Netherlands Twin Registry at the VU University. Since heart rate is a marker of cardiovascular health, researchers anticipated that a better understanding of its genetic regulation might provide a first step towards identifying targets for new drugs to treat cardiovascular disease. The study titled, “Identification of Heart Rate-Associated Loci and Their Effects on Cardiac Conduction and Rhythm Disorders” was published online this week in the April issue of Nature Genetics.To gain new insights into the genetic regulation of heart rate, the researchers spent three years working on a genome-wide association study using data from 181,171 participants from 65 studies during 2009-2012. This effort resulted in the discovery of 14 new genetic variations that are associated with heart rate. “Without any prior hypothesis, we studied the entire human genome, hoping to identify new genetic variations that no one before had even imagined would play a role in the regulation of heart rate,” said Dr. Loos, senior author of the study at the Icahn School of Medicine at Mount Sinai.
Experimental down-regulation of gene expression was then conducted on fruit flies and zebrafish, to better understand how genetic variations might affect heart rate. These experiments identified 20 genes with a role in heart rate regulation, signal transmission, embryonic development of the heart, as well cardiac disorders, such as dilated cardiomyopathy, congenital heart failure and sudden heart failure. “Our findings in humans as well as in fruit flies and zebrafish provide new insights into mechanisms that regulate heart rate,” said Dr. Marcel den Hoed, post-doctoral fellow at the Medical Research Council Epidemiology Unit in Cambridge, UK and lead author.
The study also showed that a genetic susceptibility for higher heart rate is associated with altered cardiac conduction and a reduced risk of sick sinus syndrome, a common indicator for pacemaker implantation. “Our study tripled the number of genetic variations that are known to be associated with heart rate, some of which are also associated with other cardiovascular risk factors and with heart rhythm disorders,” said Dr. Loos. “These discoveries are just the beginning of something new and exciting and can hopefully be used to identify new drugs for the treatment of heart rhythm disorders.”
The role of genes and environment in attention problems throughout aging
Genes link growth in the womb with adult metabolism and disease
Researchers have identified four new genetic regions that influence birth weight, providing further evidence that genes as well as maternal nutrition are important for growth in the womb. Three of the regions are also linked to adult metabolism, helping to explain why smaller babies have higher rates of chronic diseases later in life.
It has been known for some time that babies born with a lower birth weight are at higher risk of chronic diseases such as type 2 diabetes and cardiovascular disease. Three genetic regions have already been identified that influence birth weight, two of which are also linked to an increased susceptibility to type 2 diabetes.
The latest study analysed almost 70,000 individuals of European, Arab, Asian and African American descents from across 50 separate studies of pregnancy and birth. Their findings confirmed the three regions previously identified and also revealed four new genetic regions that are associated with birth weight. The study was part-funded by by the Wellcome Trust, the Netherlands Organisation for Scientific Research, the European Union, the Medical Research Council (UK), the Academy of Finland and the National Institute of Health (USA).
One of the new genetic regions is also associated with blood pressure in adulthood, providing the first evidence of a genetic link between birth weight and blood pressure. Two of the regions are known to be linked to adult height, showing that genes involved in growth begin to take effect at a very early stage.
Professor Mark McCarthy, a co-author of the study from the Wellcome Trust Centre for Human Genetics, said: “Our findings add to the growing evidence that events during early growth in the womb can have a significant impact on our health as adults. However, these genes tell only part of the story. It’s important that we understand how much is down to genetics and how much is due to the environment in which we grow so that we can target efforts to prevent disease later in life.”
It’s not clear how the genetic regions identified affect both birth weight and adult metabolism, although the findings do offer some clues as to the biological pathways involved. For example, the two genetic regions linking birth weight with type 2 diabetes risk are also associated with reduced levels of insulin. Insulin is the hormone responsible for regulating sugar levels in the blood, but it is also known to have an important role in early growth.
Dr. Rachel Freathy, co-lead author and a Sir Henry Wellcome Postdoctoral Fellow from the University of Exeter Medical School, said: “These discoveries give us important clues to the mechanisms responsible for the control of a baby’s growth in the womb, and may eventually lead to a better understanding of how to manage growth problems during pregnancy.”
Together, the newly identified genetic regions have a surprisingly large effect on birth weight when compared with known environmental influences. Dr. Inga Prokopenko, co-lead author from the University of Oxford explained: “Birth weight is subject to powerful influences from many environmental factors. It was a surprise to see that the genetic effects in combination have a similar impact to that of maternal smoking in pregnancy, which itself is well known to lead to lower birth weight babies.”
The findings are published online in the journal Nature Genetics. The international research team was led by scientists from the UK, Finland, the Netherlands and the United States.
Genome wide study into new gene functions in the formation of platelets (click to read the press release)
Genes and blood pressure
High blood pressure affects 1 billion people worldwide and is a major modifiable risk factor for stroke and heart diseases. The International Consortium for Blood Pressure Genome-Wide Association Studies (ICBP-GWAS) which includes over 400 investigators from over 200 centers in 24 countries across the U.S., Europe, Asia and Australia – analyzed genetic data from over 200,000 individuals from around the world and identified common variants in twenty-eight regions of DNA associated with blood pressure. Sixteen of the identified regions have not previously been implicated in blood pressure regulation, although some were suspected.
In their study, published in Nature, the ICBP-GWAS investigators conducted a meta-analysis of 30 genome-wide association studies that included measurements of participants’ blood pressure. Analysis of 2.5 million DNA sequence variants in more than 69,000 individuals of European ancestry identified several chromosomal regions with modest evidence for influence on blood pressure. To confirm the results of the first stage meta-analysis, the researchers genotyped variants with the strongest signals in more than 133,000 additional individuals of European descent. Combining the results from over 200,000 individuals of European ancestry identified twenty-eight gene regions associated with both systolic and diastolic blood pressure, of which 16 were novel. While 6 of the regions include genes suspected to influence blood pressure, the other twenty-two loci were not previously known to contribute to blood pressure regulation.
A genetic risk score combining the blood pressure variants identified in Europeans were associated with blood pressure in individuals of East Asian, South Asian, and African ancestries. The genetic risk score was associated with risk of stroke and coronary heart disease, including myocardial infarction.
A report published in Nature Genetics simultaneously, identifies new gene regions for two further blood pressure measurements; pulse pressure (PP) and mean arterial pressure (MAP). Both measurements can predict hypertension and cardiovascular disease. This research uncovered four new gene regions for pulse pressure and two for mean arterial pressure and shows the importance of looking at different measures of blood pressure in order to identify new genetic variants that affect levels of blood pressure in the population. Pulse pressure in particular is a marker of the stiffness of the arteries that carry blood from the heart round the body.
These findings represent a major advance in our understanding of blood pressure regulation and point the way to novel targets for treatment.
Genetic discovery suggests potential new asthma treatment
An international study, including the Netherlands Twin Register, featured in The Lancet, has identified two new genetic variants that increase the risk of asthma. The findings suggest that a drug currently used to treat rheumatoid arthritis may be effective to treat asthma. “Asthma impacts one in 10 people and can have a debilitating effect on their quality of life. Despite this, we still know very little about what causes asthma, which is essential to develop improved treatments”. Dr Ferreira, QIMR Brisbane, Australia, leads the study of asthma genetics – which has brought together the top asthma experts from several countries to try to identify genes that increase the risk of developing asthma. “In this study, we compared the DNA of thousands of asthma patients with that of individuals who do not suffer from asthma” Dr Ferreira said.
“After combining our results with other international studies, we identified two regions of the DNA that were consistently different between asthmatics and non-asthmatics: one is located in the interleukin-6 receptor (IL6R) gene on chromosome 1 and the other near a gene called GARP on chromosome 11. Of these two, the first is particularly interesting because interleukin-6 is a signalling molecule that plays an important role in the immune system and inflammation. It is involved in many diseases, including rheumatoid arthritis. Together with previous findings, our results indicate that because of this genetic difference, asthma patients produce more interleukin-6 receptor than non-asthmatics which, in turn, contributes to airway inflammation. This suggests that a drug used to block the interleukin-6 receptor for treatment of rheumatoid arthritis could be considered for clinical trials to prevent or reduce the airway inflammation associated with asthma. Although it is too early to tell whether a safe and effective interleukin-6 asthma therapy will indeed emerge in the near future, results from this study already provide key biological insights into the complex mechanisms that cause asthma.”
The paper is published in The Lancet: Ferreira MAR, Matheson MC, Duffy DL, Marks GB, Hui J, Le Souëf P, Danoy P, Baltic S, Nyholt DR, Jenkins M, Hayden C, Willemsen G, Ang W, Kuokkanen M, Beilby J, Cheah F, Geus de EJC, Ramasamy A, Vedantam S, Salomaa V, Madden PA, Heath AC, Hopper JL, Visscher PM, Musk B, Leeder SR, Jarvelin M-R, Pennell C, Boomsma DI, Hirschhorn JN, Walters H, Martin NG, James A, Jones G, Abramson MJ, Robertson CF, Dharmage SC, Brown MA, Montgomery GW, Thompson PJ. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. The Lancet, Volume 378, Number 9795, 1006-1014, 2011 and available online here.
Dorret I Boomsma (Netherlands Twin Register VU University, Amsterdam) received a “Distinguished Investigator” grant from the “Brain and Behavior Research Foundation” (formerly NARSAD)
The grant focuses on establishing a link between two large databases in the Netherlands: The Netherlands Twin Register (NTR) and the Pathological Anatomy National Automated Archive (PALGA) and aims to study the association between early prenatal factors and developmental outcomes in childhood.
The NTR has recruited newborn twins in the Netherlands since 1989. PALGA is a national database with abstracts of pathology reports, including information on chorionicity in twins and multiples.
Prior twin studies have examined specific prenatal and perinatal risk factors (e.g. maternal smoking, birth weight) and their interactions with genetic factors in the etiology of behavioral problems in children, but have important limitations. There is detectable variation in the similarity of twins’ prenatal environment. Depending on the timing of the zygote splitting in two, MZ twins can be mono-amniotic, di-amniotic mono-chorionic, or di-amniotic di-chorionic (DA-DC). DZ twins also vary in their prenatal similarity based on the degree of placental fusing. Information on chorion and placental type in large twin registers is very rare. Thus there is an entire range of prenatal similarity, in twins which can be used to estimate the importance of prenatal environment, separate from that of the post-natal environment.
Beyond the genetics of addiction
Dr. Jacqueline M. Vink receives ERC starting grant of € 1,5M
'My proposal seeks to explain the complex interplay between genetic and environmental causes of individual variation in substance use and the risk for abuse. Substance use is common. Substances like nicotine and cannabis have well-known negative health consequences, while alcohol and caffeine use may be both beneficial and detrimental, depending on the quantity and frequency of use. Twin studies (including my own) demonstrated that both heritable and environmental factors play a role in substance use and in the risk for abuse. Understanding the balance between genetic and environmental causes may hold the key to further reductions in the disease burden and mortality due to substance use.
My proposal on substance use (nicotine, alcohol, cannabis and caffeine) is organized around several key objectives: 1. To unravel the interplay between genetic and environmental influences on substance use by using extended twin family designs; 2. To identify and confirm genes and gene networks involved in substance use by using DNA-variant data; 3. To explore differential gene expression patterns associated with substance use; 4. To test the added value of biomarkers for substance use (measured in blood or urine) in understanding the individual variation in substance use; 5. To unravel relation between substance use and health by linking twin-family data to national medical databases.
To realize these aims I will use the extensive resources of the Netherlands Twin Register (NTR); including both the longitudinal phenotype database and the biological samples collected in the NTR biobank. I have been involved in data collection, coordination of data collection and analyzing the data since 1999. With my comprehensive experience in data collection, data analyses and my knowledge in the field of behavior genetics and addiction research I will be able to successfully lead this cutting-edge project. Additional phenotype data crucial for the project will be collected by my team. Large samples will be available for this study and state-of-the art methods will be used to analyze the data. All together, my project will offer powerful approaches to unravel the complex interaction between genetic and environmental causes of individual differences in substance use and the risk for abuse and will give new opportunities for health promotion, prevention and intervention'.
Meta-analysis gives ‘hit’ on new gene linked to alcohol consumption
Two VU/VUmc studies (Netherlands Twin Register - NTR and the Netherlands Study of Depression and Anxiety - NESDA) together with Imperial College London and King’s College London in a collaborative meta-analysis study report on a new gene finding for alcohol consumption.
The scientists including the groups of Prof. Boomsma and Prof. Penninx have identified a gene that appears to play a role in regulating how much alcohol people drink, in a study of over 47,000 people published today in Proceedings of the National Academy of Sciences. The researchers claim that finding a common genetic variation influencing levels of alcohol consumption may lead to a better understanding of mechanisms underlying alcohol drinking behaviour in the general population.
The gene, called “autism susceptibility candidate 2”, or AUTS2, has previously been linked to autism and attention deficit hyperactivity disorder, but its function is not known. Today’s study found that there are two versions of the AUTS2 gene, one three times more common than the other. People with the less common version drink on average five per cent less alcohol than people with the more common version. The gene is most active in parts of the brain associated with neuropsychological reward mechanisms, suggesting that it might play a part in regulating the positive reinforcement that people feel when they drink alcohol. Alcohol consumption is known to be partly determined by genes but until now the only gene known to make a notable contribution was the gene encoding alcohol dehydrogenase, an enzyme that breaks down alcohol in the liver.
The researchers analysed DNA samples from over 26,000 volunteers to search for genes that appeared to affect alcohol consumption, and then checked their findings in another 21,000 people. The volunteers reported how much alcohol they drank in questionnaires. Once the researchers had identified AUTS2, they examined how much messenger RNA –a copy of the gene’s code that is used to make a protein – was present in samples of donated human brain tissue. They found that the people with the version of the gene associated with lower alcohol consumption produced more of the messenger RNA, meaning that the gene was more active.
The researchers also investigated strains of mice that had been selectively bred according to how much alcohol they drink voluntarily. They found that there were differences in the AUTS2 gene activity levels among different breeds of mice that drink more or less alcohol. In addition, the researchers found that blocking the effect of a related gene in fruit flies made the flies less sensitive to alcohol. These results indicate that AUTS2 seems to be involved in regulation of alcohol intake in a number of different species.
Journal reference: G. Schumann et al. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proceedings of the National Academy of Sciences, published online 4 April 2011.
Several genes determine puberty timing in women
Scientists have discovered 30 new genes that control the age of sexual maturation in women. Notably, many of these genes also act on body weight regulation or biological pathways related to fat metabolism. It is known that early puberty is a risk factor for a number of later life illnesses and poor health, including obesity. A large new study of more than 100,000 women from Europe, US and Australia highlights several specific genetic links between early puberty and body fat.
The study also found genes involved in hormone regulation, cell development and other mechanisms being linked to age at menarche (the onset of menstrual periods in women), and this shows that puberty timing is controlled by a complex range of biological processes.
The findings are reported in the journal Nature Genetics by the large international ReproGen consortium, with scientists from 104 worldwide institutions, including researchers from the Netherlands Twin Register at the Vrije Universiteit Amsterdam.
NTR author Jouke- Jan Hottenga says “It is interesting that several of the genes for puberty timing have been linked in other studies to body weight gain and obesity. This suggests that women in some families may inherit a joint genetic susceptibility to weight gain and early puberty.”
NTR author Dorret Boomsma explains: “our twin-family studies from the Netherlands Twin register had already demonstrated in the past that individual differences in age at menarche are highly heritable, with additive genetic factors explaining at least 70% of the true variation. An additional 1.5% of the variation can be explained by a genotype-environment interaction effect where environmental factors are more important in individuals genetically predisposed for late menarche. Our studies in female twins and their sisters had shown that the average age at menarche in the Dutch population is 13.5 years, but that there is large variation around this average. We now know the top hits that explain the genetic part of the variation”. (Van den Berg & Boomsma, 2007)
Ken Ong, senior author and paediatrician in Cambridge says “We know that girls who are overweight are more likely to go through puberty at younger ages. Our findings tell us that overweight and puberty are intricately linked. It is important to understand that these ‘common genetic factors’ can be modified by changes in lifestyle. If rates of childhood overweight and obesity continue to rise we will see many more girls with puberty at young ages. Conversely, efforts to prevent or reduce childhood overweight will help avoid early puberty.”
The NTR researchers are extremely grateful to all study participants from the twin families for making this research possible. The Dutch investigators would also like to acknowledge the support provided by the Centre for Systems Biology (CMSB), and the Genetic Association Information Network (GAIN) funded by the NIMH, NWO and ZonMW.
Nature Genetics: apple or pear shape predetermined by your genes
For some people it is much harder than others to watch their weight. Researchers found that people who inherited many genetic factors affecting weight from their parents are 7 to 9 pounds heavier than people who inherited fewer of those factors. Even if you have an apple or pear shape, appears determined in part by your genetic material. The researchers, including several Dutch groups, published their findings in two publications in the international journal Nature Genetics.
The researchers first searched for genetic factors that make people more prone to obesity. Of the 18 new genetic variants that they identified, several appeared to play a role in the development of obesity through the brain. For example, the brain makes you feel hungry and regulates the way food is being processed into fat. It also determines how well you can control yourself and suppress eating binges. The newly found genetic factors and already known factors together explain only a small fraction of the weight variation between people. Other genetic factors will have to be identified by studies of an even larger scale and with a different setup.
In addition, the researchers studied how genetic factors influence the distribution of body fat. Where exactly our body stores fat affects our health. People who have more fat around the waist (the so-called ‘apple shape’) have a greater chance of developing diabetes (type 2) and cardiovascular disease. Storing fat at the thighs and buttocks (‘pear shape’) appears to offer some protection against diabetes and hypertension. The researchers found 13 genetic factors that affect the shape of the body.
There are also clear differences in body shape between men and women, but the processes that determine these differences did not become clear from this study. The study does, however, provide some biological clues. Seven of the thirteen variants found seem to have a much stronger effect in women than in men. This could be of importance for the differences in fat distribution between men and women.
The researchers who were responsible for these findings are part of the so-called Giant Consortia, which is an international co-operation with over 400 scientists from 280 research institutes, financially supported by various organisations. Participating Dutch scientists come from Rotterdam (Erasmus MC), Amsterdam (VU), Leiden (LUMC) and Nijmegen (UMC St. Radboud). They belong to the national biobank co-operations CMSB, NCHA and BBMRI-NL, subsidized by the Dutch government.
Carola Zillikens, internist and researcher at the Erasmus MC, who worked for both studies: "For this study, we investigated nearly one quarter of a million people worldwide. This is the largest study of our genetic material ever. Our findings give more insight into the biological processes that can lead to obesity and body fat distribution. We hope that in due time this can help us find ways to prevent or treat obesity. "
"In the study of complex common diseases such as cardiovascular disease and diabetes we now have reached the stage where only giant global consortia can provide enough power to increase understanding. In the international field the Dutch researchers are welcome guests with their large and well-typed biobanks", says Gertjan van Ommen of the LUMC, leader of CMSB and BBMRI-NL." We increasingly succeed by national and international collaboration where we fail on our own."
Dorret Boomsma, leader of the Netherlands Twin Register at the VU: "From earlier studies, partly in Dutch twins and families, we already knew that inheritance plays an important role in obesity and body shape, and that for some people it is much more difficult than for others to maintain their weight. This large study now shows us us the right direction for characterizing genes that explain the genetic predisposition.