1. Early stress confers lifelong vulnerability causing alterations in a specific brain region

    June 28, 2017 by Ashley

    From the Mount Sinai Hospital / Mount Sinai School of Medicine:

    Early life stress encodes lifelong susceptibility to stress through long-lasting transcriptional programming in a brain reward region implicated in mood and depression, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published June 15 in the journal Science.

    The Mount Sinai study focuses on epigenetics, the study of changes in the action of genes caused not by changes in DNA code we inherit from our parents, but instead by molecules that regulate when, where, and to what degree our genetic material is activated. Such regulation derives, in part, from the function of transcription factors — specialized proteins that bind to specific DNA sequences in our genes and either encourage or shut down the expression of a given gene.

    Previous studies in humans and animals have suggested that early life stress increases the risk for depression and other psychiatric syndromes, but the neurobiology linking the two has remained elusive until now.

    “Our work identifies a molecular basis for stress during a sensitive developmental window that programs a mouse’s response to stress in adulthood,” says Catherine Peña, PhD, lead investigator of the study. “We discovered that disrupting maternal care of mice produces changes in levels of hundreds of genes in the VTA that primes this brain region to be in a depression-like state, even before we detect behavioral changes. Essentially, this brain region encodes a lifelong, latent susceptibility to depression that is revealed only after encountering additional stress.”

    Specifically, Mount Sinai investigators identified a role for the developmental transcription factor orthodenticle homeobox 2 (Otx2) as a master regulator of these enduring gene changes. The research team showed that baby mice that were stressed in a sensitive period (from postnatal day 10-20) had suppressed Otx2 in the VTA. While Otx2 levels ultimately recovered by adulthood, the suppression had already set in motion gene alterations that lasted into adulthood, indicating that early life stress disrupts age-specific developmental programming orchestrated by Otx2.

    Furthermore, the mice stressed during the early-life sensitive time period were more likely to succumb to depression-like behavior in adulthood, but only after additional adult stress. All mice acted normally before additional adult social stress, but a “second hit” of stress was more likely to trigger depression-like behavior for mice stressed during the sensitive time period.

    To test the prediction that Otx2 was actually responsible for the stress sensitivity, the research team developed viral tools that were used to either increase or decrease Otx2 levels. They found that suppression of Otx2 early in life was both necessary and sufficient for increased susceptibility to adult stress.

    “We anticipated that we would only be able to ameliorate or mimic the effects of early life stress by changing Otx2 levels during the early sensitive period.” says Dr. Peña. “This was true for long-lasting effects on depression-like behavior, but somewhat to our surprise we could also change stress sensitivity for short amounts of time by manipulating Otx2 in adulthood.”

    While early-life critical periods have been understood for processes such as language learning, little is known about whether there are sensitive periods in childhood when stress and adversity most impacts brain development and particularly emotion-regulation systems. This study is the first to use genome-wide tools to understand how early life stress alters development of the VTA, providing new evidence for sensitive windows in emotion development.

    “This mouse paradigm will be useful for understanding the molecular correlates of increased risk of depression resulting from early life stress and could pave the way to look for such sensitive windows in human studies,” says Eric J. Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of the Friedman Brain Institute at Mount Sinai and senior investigator of the study. “The ultimate translational goal of this research is to aid treatment discoveries relevant to individuals who experienced childhood stress and trauma.”


  2. Study suggests there are genes that up insomnia risk

    June 25, 2017 by Ashley

    From the Vrije Universiteit Amsterdam press release:

    An international team of researchers has found, for the first time, seven risk genes for insomnia. With this finding the researchers have taken an important step towards the unravelling of the biological mechanisms that cause insomnia. In addition, the finding proves that insomnia is not, as is often claimed, a purely psychological condition. Today, Nature Genetics publishes the results of this research.

    Insomnia is probably the most common health complaint. Even after treatment, poor sleep remains a persistent vulnerability for many people. By having determined the risk genes, professors Danielle Posthuma (VU and VUmc) and Eus Van Someren (Netherlands Institute for Neuroscience, VU and VUmc), the lead researchers of this international project, have come closer to unravelling the biological mechanisms that cause the predisposition for insomnia.

    Hope and recognition for insomniacs

    Professor Van Someren, specialized in sleep and insomnia, believes that the findings are the start of a path towards an understanding of insomnia at the level of communication within and between neurons, and thus towards finding new ways of treatment.

    He also hopes that the findings will help with the recognition of insomnia. “As compared to the severity, prevalence and risks of insomnia, only few studies targeted its causes. Insomnia is all too often dismissed as being ‘all in your head’. Our research brings a new perspective. Insomnia is also in the genes.”

    In a sample of 113,006 individuals, the researchers found 7 genes for insomnia. These genes play a role in the regulation of transcription, the process where DNA is read in order to make an RNA copy of it, and exocytosis, the release of molecules by cells in order to communicate with their environment. One of the identified genes, MEIS1, has previously been related to two other sleep disorders: Periodic Limb Movements of Sleep (PLMS) and Restless Legs Syndrome (RLS). By collaborating with Konrad Oexle and colleagues from the Institute of Neurogenomics at the Helmholtz Zentrum, München, Germany, the researchers could conclude that the genetic variants in the gene seem to contribute to all three disorders. Strikingly, PLMS and RLS are characterized by restless movement and sensation, respectively, whereas insomnia is characterized mainly by a restless stream of consciousness.

    Genetic overlap with other characteristics

    The researchers also found a strong genetic overlap with other traits, such as anxiety disorders, depression and neuroticism, and low subjective wellbeing. “This is an interesting finding, because these characteristics tend to go hand in hand with insomnia. We now know that this is partly due to the shared genetic basis,” says neuroscientist Anke Hammerschlag (VU), PhD student and first author of the study.

    Different genes for men and women

    The researchers also studied whether the same genetic variants were important for men and women. “Part of the genetic variants turned out to be different. This suggests that, for some part, different biological mechanisms may lead to insomnia in men and women,” says professor Posthuma. “We also found a difference between men and women in terms of prevalence: in the sample we studied, including mainly people older than fifty years, 33% of the women reported to suffer from insomnia. For men this was 24%.”

    The risk genes could be tracked down in cohorts with the DNA and diagnoses of many thousands of people. The UK Biobank — a large cohort from England that has DNA available — did not have information as such about the diagnosis of insomnia, but they had asked their participants whether they found it difficult to fall asleep or to have an uninterrupted sleep. By making good use of information from slaapregister.nl (the Dutch Sleep Registry), the UK Biobank was able, for the first time, to determine which of them met the insomnia profile. Linking the knowledge from these two cohorts is what made the difference.


  3. Epigenetic changes at birth could explain later behavior problems

    June 24, 2017 by Ashley

    From the King’s College London press release:

    Epigenetic changes present at birth — in genes related to addiction and aggression — could be linked to conduct problems in children, according to a new study by King’s College London and the University of Bristol.

    Conduct problems (CP) such as fighting, lying and stealing are the most common reason for child treatment referral in the UK, costing an estimated £22 billion per year. Children who develop conduct problems before the age of 10 (known as early-onset CP) are at a much higher risk for severe and chronic antisocial behaviour across the lifespan, resulting in further social costs related to crime, welfare dependence and health-care needs.

    Genetic factors are known to strongly influence conduct problems, explaining between 50-80 per cent of the differences between children who develop problems and those who do not. However, little is known about how genetic factors interact with environmental influences — especially during fetal development — to increase the risk for later conduct problems.

    Understanding changes in DNA methylation, an epigenetic process that regulates how genes are ‘switched on and off’, could aid the development of more effective approaches to preventing later conduct problems.

    The study, published in Development & Psychopathology, used data from Bristol’s Avon Longitudinal Study of Parents and Children (ALSPAC) to examine associations between DNA methylation at birth and conduct problems from the ages of four to 13.

    The researchers also measured the influence of environmental factors previously linked to early onset of conduct problems, including maternal diet, smoking, alcohol use and exposure to stressful life events.

    They found that at birth, epigenetic changes in seven sites across children’s DNA differentiated those who went on to develop early-onset versus those who did not. Some of these epigenetic differences were associated with prenatal exposures, such as smoking and alcohol use during pregnancy.

    One of the genes which showed the most significant epigenetic changes, called MGLL, is known to play a role in reward, addiction and pain perception. This is notable as previous research suggests conduct problems are often accompanied by substance abuse, and there is also evidence indicating that some people who engage in antisocial lifestyles show higher pain tolerance. The researchers also found smaller differences in a number of genes previously associated with aggression and antisocial behaviour, including MAOA.

    Dr Edward Barker, senior author from King’s College London, said: ‘We know that children with early-onset conduct problems are much more likely to engage in antisocial behaviour as adults, so this is clearly a very important group to look at from a societal point of view.

    ‘There is good evidence that exposure to maternal smoking and alcohol is associated with developmental problems in children, yet we don’t know how increased risk for conduct problems occurs. These results suggest that epigenetic changes taking place in the womb are a good place to start.’

    Dr Charlotte Cecil, first author from King’s College London, said: ‘Our study reveals significant epigenetic changes which differentiate children who go on to develop conduct problems and those who don’t. Although these findings do not prove causation, they do highlight the neonatal period as a potentially important window of biological vulnerability, as well as pinpointing novel genes for future investigation.

    ‘Given that the postnatal environment is also crucial for children’s development, future research should examine whether positive environmental experiences can help to modify these epigenetic changes.’


  4. Study suggests anorexia nervosa has a genetic basis

    by Ashley

    From the Medical University of Vienna press release:

    A large-scale, international whole-genome analysis has now revealed for the first time that anorexia nervosa is associated with genetic anomalies on chromosome 12. This finding might lead to new, interdisciplinary approaches to its treatment. The study was led by the University of North Carolina and has been published in the American Journal of Psychiatry. Child and adolescent psychiatrist Andreas Karwautz from MedUni Vienna’s Department of Child and Adolescent Psychiatry was responsible for the Austrian contribution.

    There are currently around 7,500 adolescents in Austria suffering from anorexia nervosa. Girls make up around 95% of those suffering from this serious and protracted disease, which leads to serious health problems due to excessive weight loss. The disease is currently curable in 80% of cases but is still associated with an annual mortality rate of 0.5%. At the present time, the Department of Child and Adolescent Psychiatry at MedUni Vienna is treating around 70 seriously ill adolescents, both as in-patients and out-patients.

    Although we already knew from genetic tests on monozygotic twins that genes are approximately 60% responsible for the development of anorexia nervosa, we did not know with any certainty which gene loci were involved. A study initiated by the US University of North Carolina has now been conducted worldwide, involving 220 researchers in international medical centres analysing the genetic material of 3,500 anorexics. It was found that, compared with the control group of 11,000 people, anorexics had a significant locus on chromosome 12 that contributes towards an elevated risk of developing anorexia nervosa.

    The researchers also explored whether there was any correlation with other disorders. This revealed that the significant locus lies on chromosome 12, in a region associated with Type I diabetes and autoimmune disorders, as well as insulin metabolism. Moreover, genetic correlations were found between anorexia nervosa, neuroticism and schizophrenia, supporting the idea that anorexia is a psychiatric illness.

    Child and adolescent psychiatrist Karwautz regards the findings of this study as significant proof that, in addition to the psychosocial component, biological factors also play an extremely important role in the onset of anorexia nervosa. This has huge implications in terms of improving treatment. Says Karwautz: “Such studies form a basis for providing patients and their relatives with a logical and realistic explanation for this persistent disorder, which is the third commonest disorder in this adolescent age group. Prevention programmes will also benefit from these new findings.”


  5. Social experience tweaks genome function to modify future behavior

    June 18, 2017 by Ashley

    From the Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign press release:

    Mice have a reputation for timidity. Yet when confronted with an unfamiliar peer, a mouse may respond by rearing, chasing, grappling, and biting — and come away with altered sensitivity toward future potential threats.

    What changes in the brain of an animal when its behavior is altered by experience? Research at the University of Illinois led by Professor of Cell and Developmental Biology Lisa Stubbs is working toward an answer to this question by focusing on the collective actions of genes. In a recent Genome Research publication (DOI: 10.1101/gr.214221.116), Stubbs and her colleagues identified and documented the activity of networks of genes involved in the response to social stress.

    “The goal of this study was to understand the downstream events in mice, and how they are conveyed across interacting brain regions . . . how they might set the stage for emotional learning in response to social threat,” said Stubbs. Answers to these questions could help scientists understand how the brains of other animals, including humans, generate social behavior, as well as what goes wrong in disorders of social behavior.

    The new results are part of a large-scale research project funded by the Simons Foundation that is headed by Stubbs and includes many of her coauthors, including first authors Michael Saul and Christopher Seward. Stubbs, Saul, Seward, and other coauthors are members of the Carl R. Woese Institute for Genomic Biology (IGB); Saul is an IGB Fellow and Seward is a graduate student.

    An aggressive encounter between two mice is just one strand of the web of interactions that connects a population of social animals. Like individuals in a community, the genes in a genome cannot be completely understood until their relationships to one another are examined in context, including how those relationships may change across different tissues and over time.

    Stubbs’ team wanted to gather information that would allow them to construct this type of comprehensive gene network to reflect how the brain of a social animal responds to an aggressive encounter. They staged a controlled encounter between pairs of mice; one mouse in its home cage, and a second, unfamiliar mouse introduced behind a screen. The presence of the intruder mouse created a social challenge for the resident mouse, while the screen prevented a physical encounter.

    The researchers then quantified the activity of genes in several different regions of the brain associated with social behaviors — the frontal cortex, hypothalamus, and amygdala — and at several time points in the two hours following the encounter. In analyses of the resulting data, they looked for groups of genes acting together. In particular, they sought to identify transcription factors, genes whose protein products help control other genes, that might be orchestrating the brain’s molecular response.

    Stubbs was excited to discover that the results mirrored and expanded upon previous work in other species by collaborators at the IGB, including work by the laboratory of Director Gene Robinson in honey bees.

    “As we examined the regulatory networks active in the mouse brain over time, we could see that some of the same pathways already explicated in honey bees… were also dysregulated similarly by social challenge in mice,” she said. “That cross-species concordance is extremely exciting, and opens new doors to experimentation that is not being pursued actively by other research groups.”

    Among the genes responding to social challenge were many related to metabolism and neurochemical signaling. In general terms, it appeared that cells in the brains of challenged mice may alter the way they consume energy and communicate with one another, changes that could adjust the neural response to future social experiences.

    The researchers looked for associations between genes’ responses to social experience and their epigenetic state. How different regions of DNA are packaged into the cell (sometimes referred to as chromatin structure) can influence the activity of genes, and so-called epigenetic modifications, changes to this structure, help to modify that activity in different situations.

    “We found that the chromatin landscape is profoundly remodeled over a very short time in the brain regions responding to social challenge,” said Stubbs. “This is surprising because chromatin profiles are thought to be relatively stable in adult tissues over time.” Because such changes are stable, they are sometimes hypothesized to reinforce long-term behavioral responses to experience.

    Stubbs and her colleagues hope that by identifying genomic mechanisms of social behavior that are basic enough to be shared even between distantly related animal species, they can discover which biological mechanisms are most central.

    “The most exciting thing in my view is using [comparisons between species] to drill through the complex response in a particular species to the ‘core’ conserved functions,” she said, “thereby providing mechanistic hypotheses that we can follow by exploiting the power of genetic models like the mouse.”


  6. Exposure to specific toxins and nutrients during late pregnancy and early life correlate with autism risk

    June 15, 2017 by Ashley

    From the The Mount Sinai Hospital / Mount Sinai School of Medicine press release:

    Using evidence found in baby teeth, researchers from The Senator Frank R. Lautenberg Environmental Health Sciences Laboratory and The Seaver Autism Center for Research and Treatment at Mount Sinai found that differences in the uptake of multiple toxic and essential elements over the second and third trimesters and early postnatal periods are associated with the risk of developing autism spectrum disorders (ASD), according to a study published June 1 in the journal Nature Communications.

    The critical developmental windows for the observed discrepancies varied for each element, suggesting that systemic dysregulation of environmental pollutants and dietary elements may serve an important role in ASD. In addition to identifying specific environmental factors that influence risk, the study also pinpointed developmental time periods when elemental dysregulation poses the biggest risk for autism later in life.

    According to the U.S. Centers for Disease Control and Prevention, ASD occurs in 1 of every 68 children in the United States. The exact causes are unknown, but previous research indicates that both environmental and genetic causes are likely involved. While the genetic component has been intensively studied, specific environmental factors and the stages of life when such exposures may have the biggest impact on the risk of developing autism are poorly understood. Previous research indicates that fetal and early childhood exposure to toxic metals and deficiencies of nutritional elements are linked with several adverse developmental outcomes, including intellectual disability and language, attentional, and behavioral problems.

    “We found significant divergences in metal uptake between ASD-affected children and their healthy siblings, but only during discrete developmental periods,” said Manish Arora, PhD, BDS, MPH, Director of Exposure Biology at the Senator Frank Lautenberg Environmental Health Sciences Laboratory at Mount Sinai and Vice Chair and Associate Professor in the Department of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai. “Specifically, the siblings with ASD had higher uptake of the neurotoxin lead, and reduced uptake of the essential elements manganese and zinc, during late pregnancy and the first few months after birth, as evidenced through analysis of their baby teeth. Furthermore, metal levels at three months after birth were shown to be predictive of the severity of ASD eight to ten years later in life.”

    To determine the effects that the timing, amount, and subsequent absorption of toxins and nutrients have on ASD, Mount Sinai researchers used validated tooth-matrix biomarkers to analyze baby teeth collected from pairs of identical and non-identical twins, of which at least one had a diagnosis of ASD. They also analyzed teeth from pairs of normally developing twins that served as the study control group. During fetal and childhood development, a new tooth layer is formed every week or so, leaving an “imprint” of the micro chemical composition from each unique layer, which provides a chronological record of exposure. The team at the Lautenberg Laboratory used lasers to reconstruct these past exposures along incremental markings, similar to using growth rings on a tree to determine the tree’s growth history.

    “Our data shows a potential pathway for interplay between genes and the environment,” says Abraham Reichenberg, PhD, Professor of Psychiatry and Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai. “Our findings underscore the importance of a collaborative effort between geneticists and environmental researchers for future investigations into the relationship between metal exposure and ASD to help us uncover the root causes of autism, and support the development of effective interventions and therapies.”

    Additional studies are needed to determine whether the discrepancies in the amount of certain metals and nutrients are due to differences in how much a fetus or child is exposed to them or because of a genetic difference in how a child takes in, processes, and breaks down these metals and nutrients.


  7. Scientists identify 100 memory genes, open new avenues of brain study

    June 14, 2017 by Ashley

    From the UT Southwestern Medical Center press release:

    Scientists have identified more than 100 genes linked to memory, opening new avenues of research to better understand memory processing in the human brain.

    A study at the Peter O’Donnell Jr. Brain Institute includes the results of a new strategy to identify genes that underlie specific brain processes. This strategy may eventually help scientists develop treatments for patients with memory impairments.

    “Our results have provided a lot of new entry points into understanding human memory,” said Dr. Genevieve Konopka, Assistant Professor of Neuroscience with the O’Donnell Brain Institute at UT Southwestern Medical Center. “Many of these genes were not previously linked to memory, but now any number of labs could study them and understand their basic function in the brain. Are they important for brain development; are they more important for aspects of behavior in adults?”

    The study published in Cerebral Cortex stems from previous research by Dr. Konopka that linked specific genes to resting-state brain behavior. She wanted to use that same assessment to evaluate brain activity during active information processing.

    To do so, she collaborated with Dr. Bradley Lega, a neurosurgeon with the O’Donnell Brain Institute conducting memory research on epilepsy patients while helping to locate the source of their seizures. Dr. Lega maps the brain waves of these patients to understand what patterns are critical for successful memory formation.

    Combining their techniques, the doctors found that a different group of genes is used in memory processing than the genes involved when the brain is in a resting state. A number of them had not previously been linked to any brain process, Dr. Konopka said.

    Dr. Lega is hopeful the findings can help scientists better understand and treat a range of conditions involving memory impairment, from epilepsy to Alzheimer’s disease.

    He also hopes the study’s success in combining genetics and cognitive neuroscience will encourage more scientists to reach beyond their areas of expertise to elevate their research.

    “This kind of collaboration is not possible unless high-quality neuroscience research and academically minded clinicians are in close physical and intellectual proximity. I don’t think either of us working or thinking independently would’ve come up with this type of analysis. Ideally, the O’Donnell Brain Institute will be a natural incubator for these sorts of collaborations for a number of neuroscience fields,” said Dr. Lega, Assistant Professor of Neurological Surgery, Neurology and Neurotherapeutics, and Psychiatry.


  8. Brain anatomy differs in people with 22q genetic risk for schizophrenia, autism

    June 7, 2017 by Ashley

    From the University of California – Los Angeles press release:

    A UCLA study characterizes, for the first time, brain differences between people with a specific genetic risk for schizophrenia and those at risk for autism, and the findings could help explain the biological underpinnings of these neuropsychiatric disorders.

    The research, published May 23 in the Journal of Neuroscience, sheds light on how an excess, or absence, of genetic material on a particular chromosome affects neural development.

    “Notably, the opposing anatomical patterns we observed were most prominent in brain regions important for social functioning,” said Carrie Bearden, lead author of the study and a professor of clinical psychology at UCLA. “These findings provide clues into differences in brain development that may predispose to schizophrenia or autism.”

    Bearden’s earlier research had focused on children with abnormalities caused by missing sections of genetic material on chromosome 22, in a location known as 22q11.2. The disorder, called 22q11.2-deletion syndrome, can cause developmental delays, heart defects and distinct facial features. It also confers the highest-known genetic risk for schizophrenia.

    Then she learned that people with 22q duplication — abnormal repetition, or duplication, of genetic material in chromosome 22 — had learning delays and sometimes autism, but a lower risk for schizophrenia than that found in the general population. In other words, duplication of genetic material in this region seemed to provide some protection against schizophrenia.

    For the current study, Bearden, who is part of the UCLA Semel Institute for Neuroscience and Human Behavior, conducted MRI scans of 143 study participants: 66 with 22q deletions, 21 with 22q duplications, and 56 without the genetic mutation.

    Those in the group with 22q deletion, which carries the risk for schizophrenia, had thicker gray matter, but less brain surface area — a measure which relates to how folded the brain is — compared to those in the duplication group. The people in the 22q duplication group, who at risk for autism, had the opposite pattern, with thinner gray matter and larger brain surface area.

    “The next question is how does brain anatomy — and brain function — relate to psychiatric outcomes? These findings provide a snapshot,” Bearden said. “We are now conducting follow-up studies to track predictors of outcome over time. Those are the puzzle pieces that are next on our list to disentangle.”

    These structures are not sole determinants of schizophrenia or autism, Bearden said, but rather, more dots in the connect-the-dots puzzle of understanding these disorders. Observing this group of people over time could provide insights on how other risk factors or life events, such as puberty, affect the mind.

    Bearden says she and her team are collaborating with other scientists to investigate brain structural differences in animal models, to find out what causes them at the cellular level.


  9. Family history of Alzheimer’s may alter metabolic gene that increases risk for disease

    June 5, 2017 by Ashley

    From the Iowa State University press release:

    A new Iowa State University study may have identified the link that explains years of conflicting research over a mitochondrial gene and the risk for Alzheimer’s disease.

    Auriel Willette, an ISU assistant professor of food science and human nutrition who led the study, says the researcher who initially discovered the gene, TOMM40 (Translocase of Outer Mitochondrial Membrane-40kD), found it increased the risk for Alzheimer’s. However, when multiple studies failed to replicate the results, many researchers dismissed the findings, Willette said.

    Not convinced the gene was a total bust, Willette decided to look at other factors that may be contributing to the mixed results. In the paper published online by Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association as an in press corrected proof, Willette and his colleagues found a dramatic difference in the gene’s impact on memory, general cognitive function and risk based on a family history of Alzheimer’s disease and the length of a specific section of the gene.

    “It was kind of a shot in the dark, but we found if you don’t have a family history of Alzheimer’s disease, then having a longer version of the gene is a good thing. It is related to better memory up to 10 years later and about one-fifth of the risk for developing Alzheimer’s disease,” said Willette, who is also an adjunct assistant professor of neurology at the University of Iowa. “However, if your mom or dad has Alzheimer’s, then having a long version is bad. It’s a complete polar opposite.”

    In the study, late middle-aged people with a family history and longer version of the gene encountered twice as much memory loss up to 10 years later as someone with a family history and a short version of the gene. A similar but stronger finding was seen in a separate group of older adults with and without Alzheimer’s.

    Family history for this study focused specifically on whether a participant’s parents had Alzheimer’s disease. The study also found an association between the gene, family history and mitochondrial function, which creates energy to power cells. Researchers controlled for gender, age and education in their analysis of TOMM40 and family history in study participants.

    Fuel for the brain and memory loss

    This study is the latest piece of the puzzle Willette and his colleagues are putting together in an effort to lower the risk for Alzheimer’s, and ultimately prevent people from getting the disease. The overall direction of their work focuses on how the body derives and processes energy, he said. While this study examines mitochondria, Willette has also looked at insulin resistance and proteins and enzymes that cause problems regulating energy.

    Separately, it may be harder to grasp the impact of each puzzle piece or individual study. Collectively, researchers are learning what happens to memory and cognitive function when brain cells do not get enough energy to do their job, causing long-term damage, Willette said. With all these different factors, the challenge is pinpointing why some people get Alzheimer’s and others do not.

    “As researchers, it feels like we’re on a train with a thousand different levers and buttons. We as a scientific community are trying to pull every lever and push every button to see which one is the brake,” Willette said. “At the end of the day, this is all about better understanding how and how soon we get the disease. The hope is that knowing this will inform us about new steps we can take to slow down the progression.”

    Identifying changes prior to advanced stages of disease

    Focusing on these metabolic problems would not be possible without years of data on individuals with Alzheimer’s disease, specifically data collected prior to their diagnosis or in people at risk for the disease. For this study, Willette and his colleagues used data from the Wisconsin Registry for Alzheimer’s Prevention study and the Alzheimer’s Disease Neuroimaging Initiative. The Wisconsin group tracks changes in memory loss and cognitive function over time for middle-aged people at risk for Alzheimer’s, while the other group tracks similar changes in older people with and without the disease.

    Willette says without this data, researchers would have little understanding of the disease’s progression. The goal is to identify unifying factors that may trigger the disease by analyzing changes in the brain, the blood and other areas of the body. With this latest study, Willette hopes it will help Alzheimer’s researchers piece together other answers.

    “It’s like trying to solve The New York Times Saturday crossword puzzle, which can be incredibly frustrating. But by finding the correct answer to one question, you can begin to fill in other answers,” Willette said. “My hope is we’re providing the answer to that crossword and other researchers can find additional answers based off this one.”


  10. Researchers implicate genetic locus on chromosome 12 in anorexia nervosa

    May 21, 2017 by Ashley

    From the University of North Carolina Health Care press release:

    A landmark study led by UNC School of Medicine researchers has identified the first genetic locus for anorexia nervosa and has revealed that there may also be metabolic underpinnings to this potentially deadly illness.

    The study, which is the most powerful genetic study of anorexia nervosa conducted to date, included genome-wide analysis of DNA from 3,495 individuals with anorexia nervosa and 10,982 unaffected individuals.

    If particular genetic variations are significantly more frequent in people with a disorder compared to unaffected people, the variations are said to be “associated” with the disorder. Associated genetic variations can serve as powerful pointers to regions of the human genome where disorder-causing problems reside, according to the National Human Genome Research Institute.

    “We identified one genome-wide significant locus for anorexia nervosa on chromosome 12, in a region previously shown to be associated with type 1 diabetes and autoimmune disorders,” said lead investigator, Cynthia Bulik, PhD, FAED, founding director of the UNC Center of Excellence for Eating Disorders and a professor at Karolinska Institutet in Stockholm, Sweden.

    “We also calculated genetic correlations — the extent to which various traits and disorders are caused by the same genes,” said Bulik.

    Anorexia nervosa was significantly genetically correlated with neuroticism and schizophrenia, supporting the idea that anorexia is indeed a psychiatric illness.”

    “But, unexpectedly, we also found strong genetic correlations with various metabolic features including body composition (BMI) and insulin-glucose metabolism. This finding encourages us to look more deeply at how metabolic factors increase the risk for anorexia nervosa,” Bulik said.

    This study was conducted by the Psychiatric Genetics Consortium Eating Disorders Working Group — an international collaboration of researchers at multiple institutions worldwide.

    “In the era of team science, we brought over 220 scientists and clinicians together to achieve this large sample size. Without this collaboration we would never have been able to discover that anorexia has both psychiatric and metabolic roots,” said Gerome Breen, PhD, of King’s College London.

    “Working with large data sets allows us to make discoveries that would never be possible in smaller studies,” said Laramie Duncan, PhD, of Stanford University, who served as lead analyst on the project.

    The researchers are continuing to increase sample sizes and see this as the beginning of genomic discovery in anorexia nervosa. Viewing anorexia nervosa as both a psychiatric and metabolic condition could ignite interest in developing or repurposing medications for its treatment where currently none exist.