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.  

More information:
narsad.com
palga.nl

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.

More articles on the research can be found at the ScienceDaily and Wellcome Trust websites.