The European Society
of Human Genetics

Press Releases

2016 Press Releases

Loss of Y chromosome in blood cells is associated with developing Alzheimer’s disease: new research could lead to a simple test to identify those at risk

Embargo: 00.01 hrs CEST Tuesday 24 May 2016

Barcelona, Spain:  Men with blood cells that do not carry the Y chromosome are at greater risk of being diagnosed with Alzheimer’s disease (AD), and this is in addition to an increased risk of death from other causes, including many cancers, the annual conference of the European Society of Human Genetics will hear today (Tuesday). The paper is published today in the American Journal of Human Genetics*. The loss of the Y chromosome, or LOY, is known to affect up to 20% of men who are aged over 80, and is the most common genetic mutation acquired during a man’s lifetime.

Professors Lars Forsberg and Jan Dumanski, from the Department of Immunology, Genetics and Pathology at Uppsala University, Uppsala, Sweden, and colleagues from Sweden, France, the UK, the US and Canada, investigated LOY in over 3200 men with an average age of 73, and an age range of 37-96. Around 17% of them showed LOY in blood cells, and this increased with age. The researchers found that those with an existing diagnosis of AD had a higher degree of LOY, and that LOY was also a marker for the likelihood of developing the disease during the follow-up period.

“The idea for this research project came to me when I was writing our first paper on the relationship between LOY and the development of non-blood cancers,” Prof Forsberg explains. “In thinking about the process known as immunosurveillance – the body’s ability to fight disease development throughout life – I found that it had been well studied in AD, and hence it occurred to me that LOY might be involved in this disease too.”

Using standard molecular techniques, the identification of LOY in blood is easy to determine when it occurs in 10% or more of blood cells with a nucleus containing DNA. As well as being relatively common in older men, it also occurs less frequently in those who are younger.

Since women do not carry a Y chromosome, and men have, on average, shorter lives, it is possible that LOY may be related to the earlier death of men. However, the researchers say, the mechanisms and causes for their findings are still not properly understood.  They are currently investigating the functional effects of LOY, and looking at its role in different groups of men and in other diseases, in order to understand better which types of cancer are associated with LOY, as well as whether there is a link with early signs of dementia, for example mild cognitive impairment.

Another question to be answered relates to how LOY in blood cells can be related to disease in other organs. “The blood cells we studied are involved in the immune system, and the fact that LOY in them is associated with disease in other tissues is striking. We therefore hypothesise that the loss of LOY in blood cells leads them to lose part of their immune function,” says Prof Forsberg.

Previous research by the same group has shown that smoking greatly increases the risk of acquiring LOY, by as much as 400%. However, smoking appears to have a transient effect, and is also dose-dependent, so quitting could reverse the effect. This could be important to emphasise in smoking-cessation programmes, the researchers say.

More difficult to tackle is the question of diagnosis and treatment of serious conditions such as AD and cancer. This currently based on identifying clinical symptoms, and the development of diagnostic tools for their earlier detection could lead to strategies aimed at preventing their development before symptoms occur. For example, in the future it might be possible to use an LOY test to identify men at risk and then carry out oncological or neurological evaluations to try to detect early, mild, symptoms of disease. LOY might also become an important diagnostic tool in combination with other biomarkers that may be used to predict risks for various diseases.

“The addition of LOY testing in the general population could give medical practitioners the possibility of using preventive strategies in men at risk,” says Prof Forsberg. “For example, in cancer, primary tumours are usually not deadly; it is the metastatic process that it normally responsible for deaths. If we could predict which men have an increased risk of cancer, we could watch them closely for the development of disease and also use appropriate preventive treatments. In short, the widespread use of LOY testing could radically decrease male mortality rates, and even perhaps eliminate the difference in life expectancy between the sexes.”


Abstract no:  C23.1:  Mosaic loss of chromosome Y (LOY) in peripheral blood is associated with age, smoking, shorter survival and increased risk of cancer and Alzheimer’s disease


The research was funded by the European Research Council (ERC), Stiftelsen Olle Engkvist Byggmästare Foundation, Swedish Research Council (VR), the Wellcome Trust, Swedish Cancer Society, Swedish Heart-Lung Foundation, Science for Life Laboratory at Uppsala University, Uppsala University Hospital, Uppsala University, Heart and Lung foundation, GenomEUtwin, NIH, Swedish Foundation for Strategic Research (SSF), French National Fondation on Alzheimer’s disease and related disorders, Fondation pour la récherche sur le cerveau (FRC), Lille Métropole Communauté urbaine, LABEX and DISTALZ.

Discovery of new disease gene will lead to better screening for severe paediatric heart disease

Embargo: 00.01 hrs Tuesday 24 May 2016

Barcelona, Spain:  Cardiomyopathy, or a deterioration of the ability of the heart muscle to contract, generally leads to progressive heart failure. It is frequently inherited, and, because approximately 40% of children born with it are likely to die within five years of diagnosis, being able to identify its genetic basis is particularly important. Now, an international team of researchers has identified a new disease gene which is implicated in the development of severe paediatric cardiomyopathies. The gene is probably also involved in a milder, adult-onset form of the condition.

Presenting the results of the study to the annual conference of the European Society of Human Genetics today (Tuesday) Johanna Herkert, MD, a clinical geneticist at the University Medical Centre of Groningen, The Netherlands, will describe how analysis of the exomes (the parts of the genome that produce proteins) of children who were seriously ill with early-onset cardiomyopathies led to the finding that a mutation in the gene alpha-kinase 3 (ALPK3) had been inherited from both their fathers and mothers. In cases where both parents carry the mutation, the risk of having a child with a severe cardiomyopathy is 25%. Since the child does not carry a normal copy of gene the condition will develop at an early age.

“However, several family members who carried only one mutated gene copy also developed cardiac disease, albeit at a later stage in life,” says Dr Herkert. “The identification of these mutations enables us to provide genetic counselling, predictive testing of family members, and prenatal testing in future pregnancies. It also allows us to provide early treatment, and a potential target for drug development in the future.”

The researchers studied five children with cardiomyopathy from three unrelated families of different ethnic backgrounds. The families had previously been screened for mutations in other cardiomyopathy-related genes. Four patients were diagnosed during foetal life, or within hours of birth, and the fifth only developed symptoms at four years old. Three of the children died between 35 weeks of gestation and five days of birth; the other two were still alive at 11 years old, but showed signs of severe cardiomyopathy.

“We knew that mice without a functional ALPK3 gene displayed very similar cardiomyopathy related features to those observed in our paediatric patients,” says Dr Herkert, “but we did not quite know how dramatic its effect would be in humans. Our findings show that we now should include this gene in routine diagnostic screening in order to be able to identify affected children and their family members at risk. This will also give us an insight into the prevalence of ALPK3-related cardiomyopathy in the general population.”

Although the possibility of treating an affected foetus in the womb is still a long way off, the gene could provide a drug development target for a medicine to be administered immediately after birth before the disease has a chance to develop further. Affected family members with only one ALPK3 mutation could also be treated later in life.

“We are currently studying the effect of the ALPK3 mutations on the production of the protein in heart muscle, but also in skeletal muscle, as ALPK3 gene mutations may result in skeletal muscle problems too. Moreover, a large genome study has shown a possible link between ALPK3 and cardiac hypertrophy, or thickening of the heart muscle. We would like to explore this finding further as it may well mean that ALPK3 is implicated in other heart diseases in the general population, and once again this could suggest new treatment possibilities.

“Better knowledge of the precise role of the gene in disease development, as well as the elucidation of the molecular pathways involved, should lead us towards improved clinical care from the point of view of screening and surveillance, and to targeted drug development,” Dr Herkert will conclude.


Abstract no:  C22.2

Dietary experiments in mice point the way to early detection of cancer development in humans

Embargo: 00.01 hrs CEST Monday 23 May 2016

Barcelona, Spain:  Colorectal cancer is the second most common cause of cancer-related deaths in the Western world, mainly because it is usually diagnosed too late. Finding ways to identify those people who are at increased risk of developing colon cancer is therefore crucial, a researcher will tell  the annual conference of the European Society of Human Genetics today (Monday).

Marjaana Pussila, a PhD student in the ‘DNA mismatch repair and cancer’ group at the University of Helsinki, Finland, will explain how her team’s work in genetically-engineered mice has helped to reveal the role played by a Western-style diet, rich in fat and low in fibre, vitamin D and folate, in the development of colorectal cancer.  Interactions between genetic and environmental factors, including diet, are thought to play a crucial role in its development, but the earliest changes in normal colonic mucosa that could lead to early detection and prevention of cancer development remain to be elucidated.

Using a mouse model of Lynch syndrome, the most common form of inherited colon cancer, the researchers carried out a long-term diet experiment. The Lynch syndrome mouse carries a mutation in MIh1, a mismatch repair gene, which is one of the main susceptibility genes in the disease. Each time cells divide, DNA has to replicate itself. It is during this process that mistakes can be made, leading to genomic instability and potentially to cancer. Lynch syndrome carriers have inherited one healthy and one mutated mismatch repair gene, and about an 80% risk of developing cancer.

“We wanted to be able to spot cancer-predicting events in the colon mucosa before tumours developed,” Ms Pussila explains. “For this reason, we decided to use a mouse model which was already known to have a susceptibility to colon cancer. We reasoned that in mutation carriers requiring just a second hit of the inherited susceptibility gene for malignant transformation, it might be possible to detect the earliest changes, perhaps even preceding the second hit, and distinguish these from alterations occurring later in cancer development.

“Interestingly, our results showed that the gene expression profiles of normal mucosa in those mice that developed colon cancer were very different from those of the mice that did not. This seems to indicate that there is a colon-wide effect of events that predispose to cancer.  And the Western-style diet seemed to be a severe risk factor, since 80% of cancers were detected in WD fed mice,” says Ms Pussila.

Surprisingly, no typical Lynch syndrome tumour characteristics, such as lack of MIh1 protein or microsatellite instability – a kind of genetic hyper-mutability – were detected, although MIh1 gene expression was already severely decreased in the mucosa. This suggests that a decrease in MIh1 gene expression may be sufficient to induce the development of tumours, even where the DNA mismatch repair mechanism that recognises and corrects mistakes in DNA replication is still operating well enough to avoid microsatellite instability.

“It has been generally assumed that the development of cancer in Lynch syndrome carriers needs an inactivation of both the mismatch repair gene alleles, or pairs, involved, thus causing microsatellite instability. However, our studies have shown that this is not necessarily the case, since a severely decreased amount of MIh1 without loss of the second allele and without microsatellite instability appears to be enough to provoke the development of tumours,” says Ms Pussila.

“Now, by studying the gene expression profiles of Mlh1 low mucosa we hope to be able to  further identify cancer predisposing changes which may help in early detection of tumours,” Ms Pussila will conclude.


Abstract no:  C14.1 – Lynch syndrome mouse: A model for colon carcinogenesis


The research was funded by grants from the European Research Council (2008-AdG-232635) and the Jenny and Antti Wihuri Foundation.

How does obesity cause disease in organs distant from those where fat accumulates? New genetic evidence points the way

Embargo: 00.01 hrs CEST Sunday 22 May 2016

Barcelona, Spain:  Obesity is on the rise throughout the world, and in some developed countries two-third of the adult population is either overweight or obese. This brings with it an increased risk of serious conditions such as heart disease, stroke, cancer and osteoarthritis. Many of these conditions do not appear to affect the parts of the body where the excess fat accumulates, but rather to involve body systems that are remote from the fat accumulation. Now an international group of scientists has taken an important step towards understanding the links between obesity and the related, yet physically distant, diseases it causes, the annual conference of the European Society of Human Genetics will hear today (Sunday).

Ms Taru Tukiainen, D.Sc., a postdoctoral researcher working at the Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland and colleagues from the UK and US, set out to study the relationship between body mass index (BMI), a common-used way of measuring obesity, and gene expression in 44 different tissue types, including some that are rarely accessible in large sample sizes, for example the brain and internal organs. “Most tissue sampling is invasive, but we were able to use the GTEx* dataset of tissues from autopsy donors, and therefore sample a far wider range than is usually possible,” Ms Tukiainen explains. “This is the first time that such changes in human tissue function in response to alterations in BMI have been explored among so many body systems simultaneously.”

The researchers found simultaneous changes in response to obesity in almost all the tissues studied. “These results show that obesity really is a systemic condition, and particularly a condition of systemic inflammation. Interestingly, though, the changes in tissue function appeared to be only partially shared between different types of tissues; some tissues clearly act in pairs with one half of the pair compensating for – or enhancing - the dysfunction of the other. For instance, adipose tissue and adrenal glands, which are both organs secreting hormones essential to metabolism, often react to changes in BMI in completely opposite ways, including a decrease in metabolic activity in the former and an increase in the latter,” Ms Tukiainen will say.

Although lifestyle changes are the most effective way to combat obesity, they can be hard work and difficult to maintain. Therefore the biological processes identified by the researchers may help the treatment of obesity by identifying potential drug targets, and particularly tissue-specific targets, they say. The results may also help to distinguish groups of individual who are at higher risk of developing complications, and lead toward personalised care.

“Our research highlights the burden of overweight and obesity on the digestive system. Although this is unsurprising, given the role of digestive system tissues in food processing, we found alarming links between BMI-related changes in different parts of the digestive tract and genes implicated in some diseases, for example Crohn’s disease.

“An association between two variables does not necessarily imply there is a causal link and, from the gene expression results alone, we cannot tell which is driving which. Do changes in BMI or changes in gene expression come first? We can, however, address the potential causes by using genetic variants known to be associated with BMI in combination with our data on gene expression,” says Ms Tukiainen.

Large-scale genome-wide association studies have already identified nearly 100 genetic variants that influence BMI. Analyses by the group that interpret this information further have shown that many of these gene expression changes, particularly in adipose tissue, appear to be caused by increased BMI.

“I believe that our work adds to the weight of evidence, and provides hypotheses for other researchers to follow up in the hope of being able to translate the results into ways of preventing and treating the very serious complications of obesity,” Ms Tukiainen will conclude.


*GTEx is a dataset consisting of thousands of tissue samples in which the RNA from each sample has been sequenced to measure gene expression. Because it is not a dataset collected specifically for obesity research, the donors are representative of the population as a whole, and the obesity epidemic is clearly reflected in that only 31% of GTEx donors are or normal weight; the remainder are either overweight or obese.


Abstract no:  C08.1 – Multi-tissue transcriptome analysis reveals disease-relevant and causal links between obesity and gene expression


GTEx is funded by the US National Institutes of Health. Ms Tukiainen is funded by the Academy of Finland.

Mouse studies hold promise for a simple, non-surgical treatment for an aggressive gastric neuroendocrine tumour

Embargo: 00.01 hrs Friday 20 May 2016

Barcelona, Spain:  Patients with aggressive neuroendocrine tumours (NETs) have limited treatment options and there are few oncologists who are specialised in this relatively rare disease. Normally a total gastrectomy (removal of the stomach) is employed in these cases, with a subsequent dramatic reduction in the quality of life for patients. Now researchers have identified a mutation in the human ATP4a gene that is involved in the gastric acid secretion regulation and has been identified as responsible of an aggressive form of inherited, early-onset gastric NET.  

Dr Oriol Calvete, from the Human Genetics Group at the Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain, will present his work to the annual conference of the European Society of Human Genetics tomorrow (Saturday). “Our research has enabled us to determine important clinical ‘red lights’ for the early diagnosis of patients who will develop these tumours at a younger age, and to identify characteristics that distinguish a good from a poor prognosis for these patients,” he says.

The researchers generated a genetically-engineered mouse carrying the mutation. This developed most of the changes seen in human patients, including not just achlorhydria (a lack of or total absence of gastric secretions in the stomach), but also iron-deficiency anaemia and other pathological changes that replicate the human clinical traits involved, through the presence of which the researchers were able to confirm the mutation as the primary one responsible for the development of gastric NETs.

The researchers were able to restore chlorhydria in affected mice by adding a 3% solution of hydrogen chloride to their drinking water.  Mice that drank this water from birth did not develop gastric NETS, and in those where treatment was started later in the life cycle, the main causative biochemical alterations responsible for their development were blocked. “Gastric acid regulation is quite complicated,” Dr Calvete explains.  “Because gastric secretions are activated by the intake of food via the stomach, there are no signs of being abnormal before birth, but by restoring normal gastric acid balance as soon as possible afterwards, we can eliminate the conditions that lead to the development of tumours.”

NETS develop in the neuroendocrine system that is responsible for producing the hormones that regulate the working of different organs in the body. They are rare, incurable, and treatments for them are limited, especially once they become advanced. Because all NETS are classified as rare diseases by regulatory authorities in the EU and the US, there are few drugs available to treat these patients.

“The younger age of onset – around 30 years - of this particularly aggressive form of gastric NET in humans means that it is particularly important to try to find a treatment that is relatively simple, cheap, and does not compromise quality of life,” says Dr Calvete. “Total gastrectomy at 30 years old can have a devastating effect, and because NETS are highly infiltrating tumours, does not always mean that it will avoid metastasis. We hope that our work has given a lead towards a way of avoiding patients having to undergo this kind of aggressive surgery.”

“Additionally, the genetically-engineered mouse model will allow us to test potential treatments aimed at correcting achlorhydria, not just for gastric NETS, but also for other diseases of the gastrointestinal system such as Barrett’s oesophagus (chronic inflammation of the lower part of the oesophagus), or hiatus hernia,” says Dr Calvete.

The researchers are now intending to carry out further investigations into the genetic causes of other gastric NETS.  “For example, we have studied two more families with similar pathological characteristics, but with no mutation in the ATP4a gene. This implies that other genes may be  responsible and we hope to discover them using a similar methodology,” Dr Calvete will conclude.


Abstract no:  P12.098B


The research was funded by the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER), by the European Commission’s Horizon 2020 (BRIDGES project) and by the Spanish Government’s Proyectos de investigación en Salud (PIS) PI012-00070.