Foetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And foetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes foetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.

Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with foetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.

Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signalling pathway that might determine genetic susceptibility for the development of FASD.

‘Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity,’ said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. ‘And importantly, identifying those mothers whose foetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy.’

The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to foetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbours. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).
Charness and his team went on to develop multiple cell lines from that first culture, and that’s where they encountered the riddle: In some of those lines, alcohol disrupted L1’s adhesive effect, while in others it did not.

‘How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?’ asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.

Clearly, something else was affecting the protein’s sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. ‘That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition,’ Charness said.

In the current study, Charness’ team and collaborators at the University of North Carolina School of Medicine in Chapel Hill conducted cell culture experiments to identify specific molecular events that contribute to the alcohol sensitivity of L1 adhesion molecules. They focused on what was happening to the L1 molecule inside a cell that could affect an event outside the cell such as disruption by alcohol.

‘We found that phosphorylation events that begin inside the cell can render the external portion of the L1 adhesion molecule more vulnerable to inhibition by alcohol,’ said Xiaowei Dou, HMS instructor in neurology in the Charness Lab and first author on the new study. ‘Phosphorylation was controlled by the enzyme ERK2, and occurred at a specific location on the internal portion of the L1molecule.’

Phosphorylation plays a significant role in a wide range of cellular processes. By adding a phosphate group to a protein or other molecule, phosphorylation turns many protein enzymes on and off, and thereby alters their function and activity.

The researchers also found that variations in ERK2 activity correlated with differences in L1 sensitivity to alcohol that they observed across cell lines and among different strains of mice. ‘Dou showed that he could take these cells that had been insensitive to alcohol for 13-14 years, and make them sensitive by ramping up the activity of this kinase’ Charness said.

These variations suggest that genes for ERK2 and the signalling molecules that regulate ERK2 activity might influence genetic susceptibility to FASD. Moreover, their identification of a specific locus that regulates the alcohol sensitivity of L1 might facilitate the rational design of drugs that block alcohol neurotoxicity.

‘The only thing this modification blocked was alcohol’s ability to inhibit L1,’ Charness said. ‘If you’re looking for a drug, ideally you’re looking for it to block the effects of the toxin without interfering with the target molecule of the toxin.’

The findings will also help guide an international consortium in its search for genes linked to families with fetal alcohol spectrum disorders. Harvard Medical School

A JDRF-funded study out of Switzerland has shown that a single gene called SIRT1 may be involved in the development of type 1 diabetes (T1D) and other autoimmune diseases. The study represents the first demonstration of a mono-genetic defect leading to the onset of T1D.

The research began when Marc Donath, M.D., endocrinologist and researcher at the University Hospital Basel in Switzerland, discovered an interesting pattern of autoimmune disease within the family of one of his patients, a 26-year-old male who had recently been diagnosed with T1D. The patient showed an uncommonly strong family history of T1D; his sister, father, and paternal cousin had also been diagnosed earlier in their lives. Additionally, another family member had developed ulcerative colitis, also an autoimmune disease.

‘This pattern of inheritance was indicative of dominant genetic mutation, and we therefore decided to attempt to identify it,’ Dr. Donath said.

Four years of analysis using three different genotyping and sequencing techniques pointed to a mutation on the SIRT1 gene as the common indicator of autoimmune disease within the family. The SIRT1 gene plays a role in regulating metabolism and protecting against age-related disease. To gain more understanding of how this genetic change in SIRT1 leads to T1D, Dr. Donath and his team performed additional studies with animal models of T1D. When the mutant SIRT1 gene found in the families was expressed in beta cells, those beta cells generated more mediators that were destructive to them. Furthermore, knocking out the normal SIRT1 gene in mice resulted in their becoming more susceptible to diabetes with greatly increased islet destruction. Dr. Donath speculates that the beta cell impairment and death due to the SIRT1 mutation subsequently activates the immune system toward T1D.

‘The identification of a gene leading to type 1 diabetes could allow us to understand the mechanism responsible for the disease and may open up new treatment options,’ Dr. Donath explained.

Patricia Kilian, Ph.D., director of the Beta Cell Regeneration Program at JDRF, concurred, and said that the development is exciting for many reasons: ‘While the change in the genetic makeup within this family with type 1 diabetes is rare, the discovery of the role of the SIRT1 pathway in affecting beta cells could help scientists find ways to enhance beta cell survival and function in more common forms of the disease. This study also reinforces increasing evidence that abnormal beta cell function has a role in the development of type 1 diabetes, and that blocking or reversing early stages of beta cell dysfunction may help prevent or significantly delay the disease’s onset. Drug companies are already in the process of developing SIRT1 activators, which could eventually speed our ability to translate these new research findings into meaningful therapies for patients.’ JDRF

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes.
The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work was led by Drs. Aristotle Voineskos and James Kennedy.
Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalised for years, while others respond well to treatment.
‘What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur,’ explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. ‘In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment.’
‘Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic basis of this condition that affects thousands of Canadians and their families,’ says Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.
Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.
‘We showed that this gene has a bigger effect on age-at-onset than one’s gender has,’ said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. ‘This may be a paradigm shift for the field.’
The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.
‘Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult,’ said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. ‘This can have major impact on disease outcome.’
In a separate part of the study involving 213 people, the researchers used magnetic resonance brain imaging (MRI) and diffusion tensor-MRI (DT-MRI). They found that individuals with the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, that serve as the information highways of the brain.
Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.
‘We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have,’ said Dr. Voineskos. ‘This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalised treatment options right from the start.’
This research was funded by the Canadian Institutes of Health Research, the Brain & Behavior Research Foundation and the Ontario Mental Health Foundation. Centre for Addiction and Mental Health (CAMH)

A professor from Case Western Reserve University School of Medicine is one of the lead authors of a study identifying seven new regions of the human genome that are associated with increased risk of age-related macular degeneration (AMD), a leading cause of blindness among older adults.

The AMD Gene Consortium, a network of international investigators representing 18 research groups, also confirmed the existence of 12 other regions—called loci—that had been identified in previous studies..

‘This work represents a big step forward toward solving why some people get AMD, while others do not,’ said Sudha Iyengar, professor of epidemiology and biostatistics at Case Western Reserve School of Medicine and a member of the consortium’s senior executive committee. ‘This disease is not caused by a single change in the DNA, but represents many events that accumulate over the lifetime of a patient. Identification of these genes provides molecular windows into the AMD disease process.’

AMD affects the macula, a region of the retina responsible for central vision. The retina is the layer of light-sensitive tissue in the back of the eye that houses rod and cone photoreceptor cells. Compared with the rest of the retina, the macula is especially dense with cone photoreceptors; humans rely on the macula for tasks that require sharp vision, such as reading, driving, and recognising faces. As AMD progresses, such tasks become more difficult and eventually impossible. Some kinds of AMD are treatable, but no cure exists

Since the 2005 discovery that certain variations in the gene for complement factor H—a component of the immune system—are associated with major risk for AMD, research groups around the world have conducted genome-wide association studies to identify other loci that affect AMD risk. These studies were made possible by tools developed through the Human Genome Project, which mapped human genes, and related projects, such as the International HapMap Project, which identified common patterns of genetic variation within the human genome.

The consortium’s analysis included data from more than 17,100 people with the most advanced and severe forms of AMD, which were compared to data from more than 60,000 people without AMD. The 19 loci that were found to be associated with AMD implicate a variety of biological functions, including regulation of the immune system, maintenance of cellular structure, growth and permeability of blood vessels, lipid metabolism, and atherosclerosis.

As with other common diseases, such as Type 2 diabetes, an individual person’s risk for getting AMD is likely determined not by one but many genes. Further comprehensive DNA analysis of the areas around the 19 loci identified by the AMD Gene Consortium could turn up undiscovered rare genetic variants with a disproportionately large effect on AMD risk. Discovery of such genes could greatly advance scientists’ understanding of AMD pathogenesis and their quest for more effective treatments.

‘This compelling analysis by the AMD Gene Consortium demonstrates the enormous value of effective collaboration,’ said NEI director Paul A. Sieving, MD, PhD. ‘Combining data from multiple studies, this international effort provides insight into the molecular basis of AMD, which will help researchers search for causes of the disease and will inform future development of new diagnostic and treatment strategies.’ Case Western Reserve University

​Can the length of strands of DNA in patients with heart disease predict their life expectancy?
Researchers from the Intermountain Heart Institute at Intermountain Medical Center in Salt Lake City, who studied the DNA of more that 3,500 patients with heart disease, say yes it can.
In the new study, the researchers were able to predict survival rates among patients with heart disease based on the length of strands of DNA found on the ends of chromosomes known as telomeres—the longer the patient’s telomeres, the greater the chance of living a longer life.
Previous research has shown that telomere length can be used as a measure of age, but these expanded findings suggest that telomere length may also predict the life expectancy of patients with heart disease.

Telomeres protect the ends of chromosome from becoming damaged. As people get older, their telomeres get shorter until the cell is no longer able to divide. Shortened telomeres are associated with age-related diseases such as heart disease or cancer, as well as exposure to oxidative damage from stress, smoking, air pollution, or conditions that accelerate biologic ageing.

‘Chromosomes by their nature get shorter as we get older,’ said John Carlquist, PhD, director of the Intermountain Heart Institute Genetics Lab. ‘Once they become too short, they no longer function properly, signalling the end of life for the cell. And when cells reach this stage, the patient’s risk for age-associated diseases increases dramatically.’

Dr. Carlquist and his colleagues from the Intermountain Heart Institute at Intermountain Medical Center tested the DNA samples from more than 3,500 heart attack and stroke patients.

‘Our research shows that if we statistically adjust for age, patients with longer telomeres live longer, suggesting that telomere length is more than just a measure of age, but may also indicate the probability for survival. Longer telomere length directly correlate with the likelihood for a longer life—even for patients with heart disease,’ said Dr. Carlquist. Intermountain Medical Center Heart Institute