1. Twin study suggests nearly 80% of schizophrenia risk is heritability

    October 11, 2017 by Ashley

    From the Elsevier press release:

    In the largest study of twins in schizophrenia research to date, researchers at the University of Copenhagen, Denmark, estimate that as much as 79% of schizophrenia risk may be explained by genetic factors. The estimate indicates that genetics have a substantial influence on risk for the disorder.

    Published in Biological Psychiatry, the study used a new statistical approach to address one of the factors that contributes to inconsistencies across previous studies — usually studies of heritability require that people be classified as either having schizophrenia or not, but some people at risk could still develop the disease after the study ends. Drs. Hilker, Helenius and colleagues applied a new method to take this problem into account, making the current estimates likely the most accurate to date.

    “The new estimate of heritability of schizophrenia, 79%, is very close to the high end of prior estimates of its heritability,” said Dr. John Krystal, Editor of Biological Psychiatry, referring to previous estimates that have varied between 50% and 80%. “It supports the intensive efforts in place to try to identify the genes contributing to the risk for developing schizophrenia,” said Dr. Krystal, which have been built on the idea that schizophrenia is highly heritable based on the findings of generations of twin studies.

    The study took advantage of the nationwide Danish Twin Register — a record of all twins born in Denmark since 1870 — coupled with information from the Danish Psychiatric Central Research Register, to assess genetic liability in over 30,000 pairs of twins.

    Because the diagnosis of schizophrenia is based on a narrow definition of symptoms, the researchers also estimated heritability using a broader illness category including related disorders on the schizophrenia spectrum. They found a similar estimate of 73%, indicating the importance of genetic factors across the full illness spectrum.

    Dr. Hilker explained, “This study is now the most comprehensive and thorough estimate of the heritability of schizophrenia and its diagnostic diversity. It is interesting since it indicates that the genetic risk for disease seems to be of almost equal importance across the spectrum of schizophrenia,” even though the clinical presentation may range from severe symptoms with lifelong disability to more subtle and transient symptoms. “Hence, genetic risk seems not restricted to a narrow illness definition, but instead includes a broader diagnostic profile,” she added.


  2. Epigenetic study untangles addiction and relapse in the brain

    October 6, 2017 by Ashley

    From the Medical University of South Carolina press release:

    Why do some drug users continue to seek out drugs despite the prospect of losing family, friends, health or livelihood?

    There are notable features — cues — of the early drug-using environment that often develop into persistent and powerful triggers for relapse. Epigenetic factors — enzymes in the brain that alter the packaging and accessibility of genes without changing the genes themselves — influence this process, according to research at the Medical University of South Carolina (MUSC) appearing online on September 27, 2017 in Neuron.

    A major challenge in addiction science is to understand how transient experiences lead to long-lasting risk for relapse in users who try to quit, according to MUSC professor Christopher W. Cowan, Ph.D., William E. Murray SmartState® Endowed Chair in Neuroscience, and senior researcher on the project. “Our goal was to discover the brain mechanisms responsible for the rewarding effects of the drug and the motivation to seek it even after long periods of abstinence,” says Cowan.

    The brains of drug users who have progressed to addiction differ markedly from those of early or casual users. Long-lasting associations form between the early use of a drug and different aspects of the early drug-using environment, such as the location in which a drug was first taken or the emotions a user was experiencing at the time. This can cause addicted users who have quit to experience cravings when in a similar setting. Understanding these connections could lead to better treatments for addiction.

    Cowan’s challenge was to determine which genes were activated in the early drug-using environment. Cowan and his fellow researchers had previously found that the epigenetic enzyme histone deacetylase 5 (HDAC5) slows the rodent brain from forming associations between cocaine and simple cues in the environment, such as light and sound. HDAC5 is found in high amounts in neurons in the nucleus accumbens, part of the reward center of the brain that reacts strongly to cocaine, opioids and alcohol — both in rodents and humans. When HDACs are in the nucleus of neurons, they change the way genomic DNA is packaged in the cell nucleus and often block the ability of certain genes to be turned on.

    In the new study, rodents were trained to press a lever to receive a dose of cocaine. Each time they received a dose, a lamp went on above the lever and a brief sound was generated. These served as simple environmental cues for drug use. Next, some rodents were given a form of HDAC5 that traveled straight to the nuclei of neurons. Those rodents still pressed the lever just as many times to receive drug, meaning that HDAC5, on its own, was likely not blocking genes that promoted early drug-seeking behavior.

    Yet the next experiment proved that HDAC5 reduced drug-seeking behavior during abstinence. To simulate withdrawal and abstinence, rodents were given rest without cocaine for one week, followed by a period during which they had access to the lever again. To simulate relapse, the rodents were shown the environmental cues again, this time without having pressed the lever. The presentation of the cues triggered robust lever pressing, indicating drug seeking, in control animals, proving that the associations between drug and environment persisted in their brains. In contrast, animals who had the nuclear form of HDAC5 did not press the lever nearly as often, even after the experimenters gave the animals a small priming dose of cocaine, which often produces strong drug-seeking behaviors.

    HDAC5, the gene suppressor, did not prevent addiction-like behaviors from forming, but it did prevent later drug seeking and relapse during abstinence — at least in rodents.

    The researchers next used a cutting-edge technique that encourages epigenetic enzymes to bind to DNA, allowing them to identify all the genes inhibited by HDAC5. The gene for NPAS4 was a top hit, and significant for an important reason: it is an early-onset gene, meaning that its effects could be exerted on the brain rapidly unless HDAC5 was there to inhibit it — just the molecular event Cowan and his team were seeking.

    In similar experiments, animals with less NPAS4 in the nucleus accumbens took more time to form those early connections between environmental cues and cocaine, but they still sought the drug just as often during later simulated relapse. Apparently, NPAS4 accounts for some addiction-related learning and memory processes in the brain, but not all of them, meaning that HDAC5 must be regulating additional genes that reduce relapse events. Cowan thinks uncovering additional downstream genes could help researchers untangle the details of how the brain transitions from early drug use to addiction, and how new treatments might be developed to reduce relapse in individuals suffering from substance use disorders.

    Animals in the research setting may not mimic the full complexity of human addiction. However, abstinent patients report cravings when given reminders of their drug-associated environment or cues, and animals and humans share similar enzyme pathways and brain structures. Perhaps most exciting for addiction research is that these processes may be similar in the transition to cocaine, alcohol and opioid addictions. “We might have tapped into a mechanism with relevance to multiple substance use disorders,” says Cowan.


  3. Study reveals gender-specific risk of autism occurrence among siblings

    October 5, 2017 by Ashley

    From the Harvard Medical School press release:

    Having one child with autism is a well-known risk factor for having another one with the same disorder, but whether and how a sibling’s gender influences this risk has remained largely unknown.

    Now new research led by scientists at Harvard Medical School has for the first time successfully quantified the likelihood that a family who has one child with autism would have another one with the same disorder based on the siblings’ gender.

    Overall, the results, published Sept. 25 in JAMA Pediatrics, reveal that having an older female child diagnosed with autism spelled elevated risk for younger siblings and that the risk was highest among younger male siblings. They also affirm past research findings that having one child with autism or an autism spectrum disorder (ASD) portends higher risk for subsequent children, that the disorder is somewhat rare — slightly more than 1.2 percent of children in the study were affected — and that boys have a notably higher overall risk than girls.

    The findings can arm physicians and genetic counselors with information useful in counseling families and clarifying the risk for younger siblings in families who already have one child with autism.

    “Our results give us a fair degree of confidence to gauge the risk of autism recurrence in families affected by it based on a child’s gender,” said study first author Nathan Palmer, instructor in biomedical informatics at Harvard Medical School. “It is important to be able to provide worried parents who have one child with the condition some sense of what they can expect with their next child. That information is critical given how much better we’ve become at screening for the disease earlier and earlier in life.”

    Such knowledge, the researchers added, could be particularly important in light of physicians’ growing ability to detect autism’s manifestations early in a child’s life and intervene promptly.

    “This study is a powerful example of how big data can illuminate patterns and give us insights that allow us to empower parents and pediatricians to implement anticipatory and far more precise medicine,” said study senior author Isaac Kohane, head of the Department of Biomedical Informatics at Harvard Medical School.

    The newly published results stem from the largest study of its kind. Researchers analyzed de-identified health insurance records of more than 1.5 million U.S. families with two children between the ages of 4 and 18, tracking patterns of recurrence among siblings over a year or longer. Of the more than 3.1 million children in the study, some 39,000, or about 1.2 percent — 2 percent of boys and 0.5 percent of girls — received a diagnosis of autism or an ASD.

    The results confirm previous research showing that, overall, boys have a higher risk of autism and related disorders than girls.

    The results, however, also reveal a curious pattern of recurrence based on gender: Siblings born after a female child with autism or a related disorder had a higher risk than siblings born after a male child with autism. Male children were, overall, more susceptible to autism than females. In other words, boys with older female siblings with autism had the highest risk for autism themselves, while female siblings with older brothers with autism had the lowest risk.

    For every 100 boys with an older female sibling with autism, 17 received a diagnosis of autism or a related disorder. Male children with older male siblings with ASD had a 13 percent risk of an ASD diagnosis, followed by younger female siblings with older male siblings with ASD (7.6 percent). The lowest risk — 4 percent — was observed among younger female siblings who had an older brother with autism or an ASD.

    The investigators caution that families should keep the risk in perspective because autism and related disorders remain relatively rare, affecting roughly 1 percent of the general population.

    Even for the group at highest risk — males with an older female sibling with autism — the odds are still about five to one that the child will be unaffected,” Palmer said. “What we have provided here is context for families who already have children with autism or another similar disorder and need a clearer perspective on recurrence risk.”

    The results, the researchers said, underscore the notion that autism and related disorders likely arise from the complex interplay between genes and environment and, for reasons yet to be understood, these conditions disproportionately affect more males than females even within families. The stark gender variance, however, hints at a possible role of inherent biological sex differences that may precipitate the development of such disorders under the right environmental conditions, the research team said.

    Autism-spectrum disorders are neurodevelopmental conditions that typically emerge in the first few years. They are marked by a range of brain problems, impaired social interactions and compromised communication skills. The Centers for Disease Control and Prevention estimate that autism spectrum disorders affect 1 in 68 children in the United States, with males having four times greater risk than females — an observation also borne out in the new study.

    Yet exactly what portion of these diagnoses are strictly rooted in genetic mutation and how many are influenced by environmental factors has long mystified scientists. While some forms of autism arise from a single genetic mutation, most cases appear to be the result of a complex interplay between genes and environment.


  4. Study identifies a new genetic marker for schizophrenia

    September 25, 2017 by Ashley

    From the Osaka University press release:

    Schizophrenia is a complicated disease that often appears in early adulthood. Although scientists have not traced the genetic causes, more than 80% of schizophrenia cases are considered to have a hereditary cause. In a new report published in Translational Psychiatry, Japanese researchers report that a rare genetic variant, RTN4R, may have a fundamental role in the disease.

    “Schizophrenia is a disease caused by disturbances in neural circuits. Myelin-related genes are associated with the disease,” explains Osaka University Professor Toshihide Yamashita, one of the authors of the studies.

    Myelin acts as a conductor of signals for the neural circuits. Yamashita hypothesized that myelin-related genes could contribute to the pathology of schizophrenia.

    RTN4R is a subunit of RTN4, which regulates crucial functions for neural circuits, namely, axon regeneration and structural plasticity.

    Moreover, “RTN4 is a promising candidate gene for schizophrenia because it is located at chromosome 22q11.2, a hotspot for schizophrenia,” he said.

    Rare variants describe mutations that have low frequency but a large effect. Yamashita and his colleagues searched for rare variants of RTN4. Screening the DNA of 370 schizophrenia patients, he found a single missense mutation, R292H, that changed the amino acid of this protein from arginine to histidine in two patients.

    R292H is located in the domain of RTN4R that binds to ligands, so a change in even a single amino acid could have profound effects on RTN4 function. To test this possibility, the scientists expressed the mutation in chick retinal cells, which only weakly express the gene, finding a significant change in myelin-dependent axonal behavior. Computer simulations showed that the mutation reduced the interaction between RTN4 and its partner protein, LINGO1, by increasing the distance between the two.

    Yamashita is convinced that rare variants could act as risk factors for schizophrenia.

    “There is growing evidence that rare variants contribute to neurodevelopment diseases. The R292H mutation was not found in any existing databases. Our findings strengthen the evidence that rare variants could contribute to schizophrenia,” he said.


  5. Study explains why stress hormone can prevent disorders after exposure to traumatic event

    by Ashley

    From the Universitat Autònoma de Barcelona press release:

    People who have suffered from traffic accidents, war combat, terrorist attacks and exposure to other traumatic events have an increased likelihood of developing diseases. These diseases can be psychological and physical, such as heart problems and cancer. The current preventive treatments based on psychological support and drugs are effective in some cases. Unfortunately, these treatments do not work for many individuals. It is also known that the earlier the treatment starts the better to prevent future negative consequences.

    Researchers at the Institut de Neurociències of the Universitat Autònoma de Barcelona (INc-UAB, Spain) have discovered in a study with mice and humans that the Ppm1f (Protein phosphatase 1f) gene expression is one of the most highly regulated after exposure to traumatic stress. Moreover, Ppm1f is associated with posttraumatic stress disorder (PTSD), depression and anxiety. The main function of Ppm1f is to regulate the activity of the protein Camk2 (Calmodulin-dependent protein kinase 2), which is key in many processes of the human body such as memory, the heart’s functioning and the immune system.

    According to Dr. Raül Andero Galí, lead researcher in this study, “Once we discovered the relationship between the Ppm1f gene and different psychological disorders after exposure to traumatic stress, we wanted to find an effective drug to prevent these changes and its negative consequences on the brain.” Dr Andero is scientist at the INc-UAB. It was already known that dosing the stress hormone — a glucocorticoid — few hours after exposure to a traumatic event may decrease the likelihood of developing psychological disorders. Thus, the scientists administered the hormone to mice one hour after exposure to stress. “The results confirmed a decrease in the symptoms of anxiety and depression, and also that this effect is because the Ppm1f gene changes are prevented,” explains Dr. Eric Velasco, researcher at the INc-UAB and co-author of the study.

    “The apparent contradiction that the stress hormone decreases the likelihood of developing diseases after exposure to traumatic stress is one of the greatest paradoxes of current medicine” Andero says. “This study sheds light on this paradox and uncovers a way by which the stress hormone could prevent diseases, at least psychologically, through regulation of the Ppm1f gene” he adds.

    Until now, the stress hormone has been administered to people in very few cases. “Our discovery opens the door to a broader application and to the development of treatments aimed specifically at regulating this gene’s functions,” says Antonio Florido, researcher of the INc-UAB and also co-author of the paper.

    The study was carried out in collaboration with the universities of Harvard and Emory (United States). This work is published in Biological Psychiatry, one of the most important journals in Neuroscience. The UAB researchers are currently interested in collaborating with other laboratories and obtaining funding to continue the studies of Ppm1f associated with other disorders such as cardiovascular diseases and cancer in order to verify whether their results are comparable in other diseases and potentially prevent them.


  6. Study suggests another gene that may significantly influence development of dementia and Alzheimer’s

    September 21, 2017 by Ashley

    From the University of Southern California press release:

    The notorious genetic marker of Alzheimer’s disease and other forms of dementia, ApoE4, may not be a lone wolf.

    Researchers from USC and the University of Manchester have found that another gene, TOMM40, complicates the picture. Although ApoE4 plays a greater role in some types of aging-related memory ability, TOMM40 may pose an even greater risk for other types.

    TOMM40 and APOE genes are neighbors, adjacent to each other on chromosome 19, and they are sometimes used as proxies for one another in genetic studies. At times, scientific research has focused chiefly on one APOE variant, ApoE4, as the No. 1 suspect behind Alzheimer’s and dementia-related memory decline. The literature also considers the more common variant of APOE, ApoE3, neutral in risk for Alzheimer’s disease.

    USC researchers believe their new findings raise a significant research question: Has TOMM40 been misunderstood as a sidekick to ApoE4 when it is really a mastermind, particularly when ApoE3 is present?

    “Typically, ApoE4 has been considered the strongest known genetic risk factor for cognitive decline, memory decline, Alzheimer’s disease or dementia-related onset,” said T. Em Arpawong, the study’s lead author and a post-doctoral fellow in the USC Dornsife College of Letters, Arts and Sciences Department of Psychology. “Although prior studies have found some variants of this other gene TOMM40 may heighten the risk for Alzheimer’s disease, our study found that a TOMM40 variant was actually more influential than ApoE4 on the decline in immediate memory – the ability to hold onto new information.”

    Studies have shown that the influence of genes associated with memory and cognitive decline intensifies with age. That is why the scientists chose to examine immediate and delayed verbal test results over time in conjunction with genetic markers.

    “An example of immediate recall is someone tells you a series of directions to get somewhere and you’re able to repeat them back,” explained Carol A. Prescott, the paper’s senior author who is a professor of psychology at USC Dornsife College and professor of gerontology at the USC Davis School of Gerontology. “Delayed recall is being able to remember those directions a few minutes later, as you’re on your way.”

    The study was published in the journal PLOS ONE on Aug. 11.

    Prescott and Arpawong are among the more than 70 researchers at USC who are dedicated to the prevention, treatment and potential cure of Alzheimer’s disease. The memory-erasing illness is one of the greatest health challenges of the century, affecting 1 in 3 seniors and costing $236 billion a year in health care services. USC researchers across a range of disciplines are examining the health, societal and political effects and implications of the disease.

    In the past decade, the National Institute on Aging has nearly doubled its investment in USC research. The investments include an Alzheimer Disease Research Center.

    Tracking memory loss

    For the study, the team of researchers from USC and The University of Manchester utilized data from two surveys: the U.S. Health and Retirement Study and the English Longitudinal Study of Ageing. Both data sets are nationally representative samples and include results of verbal memory testing and genetic testing.

    The research team used verbal test results from the U.S. Health and Retirement Survey, collected from 1996 to 2012, which interviewed participants via phone every two years. The researchers utilized the verbal memory test scores of 20,650 participants, aged 50 and older who were tested repeatedly to study how their memory changed over time.

    To test immediate recall, an interviewer read a list of 10 nouns and then asked the participant to repeat the words back immediately. For delayed recall, the interviewer waited five minutes and then asked the participant to recall the list. Test scores ranged from 0 to 10.

    The average score for immediate recall was 5.7 words out of 10, and the delayed recall scoring average was 4.5 words out of 10. A large gap between the two sets of scores can signal the development of Alzheimer’s or some other form of dementia.

    “There is usually a drop-off in scores between the immediate and the delayed recall tests,” Prescott said. “In evaluating memory decline, it is important to look at both types of memory and the difference between them. You would be more worried about a person who has scores of 10 and 5 than a person with scores of 6 and 4.”

    The first person is worrisome because five minutes after reciting the 10 words perfectly, he or she can recall only half of them, Prescott said. The other person wasn’t perfect on the immediate recall test, but five minutes later, was able to remember a greater proportion of words.

    To prevent bias in the study’s results, the researchers excluded participants who reported that they had received a likely diagnosis of dementia or a dementia-like condition, such as Alzheimer’s. They also focused on participants identified as primarily European in heritage to minimize population bias. Results were adjusted for age and sex.

    The researchers compared the U.S. data to the results of an independent replication sample of participants, age 50 and up, in the English Longitudinal Study of Aging from 2002 to 2012. Interviews and tests were conducted every two years.

    Genetic markers of dementia

    To investigate whether genes associated with immediate and delayed recall abilities, researchers utilized genetic data from 7,486 participants in the U.S. Health and Retirement Study and 6,898 participants in the English Longitudinal Study of Ageing.

    The researchers examined the association between the immediate and delayed recall results with 1.2 million gene variations across the human genome. Only one, TOMM40, had a strong link to declines in immediate recall and level of delayed recall. ApoE4 also was linked but not as strongly.

    “Our findings indicate that TOMM40 plays a larger role, specifically, in the decline of verbal learning after age 60,” the scientists wrote. “Further, our analyses showed that there are unique effects of TOMM40 beyond ApoE4 effects on both the level of delayed recall prior to age 60 and decline in immediate recall after 60.”

    Unlike ApoE4, the ApoE3 variant is generally thought to have no influence on Alzheimer’s disease or memory decline. However, the team of scientists found that adults who had ApoE3 and a risk variant of TOMM40, were more likely to have lower memory scores. The finding suggests that TOMM40 affects memory – even when ApoE4 is not a factor.

    The team suggested that scientists should further examine the association between ApoE3 and TOMM40 variants and their combined influence on decline in different types of learning and memory.

    “Other studies may not have detected the effects of TOMM40,” Prescott said. “The results from this study provide more evidence that the causes of memory decline are even more complicated than we thought before, and they raise the question of how many findings in other studies have been attributed to ApoE4 that may be due to TOMM40 or a combination of TOMM40 and ApoE4.”


  7. Using DNA to predict schizophrenia, autism

    September 15, 2017 by Ashley

    From the Osaka University press release:

    Osaka University researchers show in a multi-institute collaboration that a single amino acid substitution in the protein CX3CR1 may act as predictor for schizophrenia and autism.

    Huntington’s disease, cystic fibrosis, and muscular dystrophy are all diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy — You have the mutation? Then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. A new multi-institutional study by Japanese researchers shows a potential rare gene mutation that could act as a predictor for two neurodevelopmental disorders, schizophrenia and autism.

    “Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism,” says Osaka University Professor Toshihide Yamashita, one of the authors of the study. “Microglia contribute to the structure and function of synapse connectivities.”

    Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. They have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders.

    Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7000 schizophrenia and autism patients and healthy subjects, finding one mutant candidate, a single amino acid switch from alanine to threonine, as a candidate marker for prediction.

    “Rare variants alter gene function but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause,” said Yamashita, who added the alanine threonine substitution was a rare variant.

    The structure of CX3CR1 includes a domain known as Helix 8, which is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling.

    “The variant changes the region from hydrophobic to hydrophilic and destabilize Helix 8. We overexpressed the mutation in cells and found Akt signaling was disrupted,” explains Yamashita.

    According to Yamashita, the findings are the first to connect a genetic variation in microglia with neurodevelopment disorders. Moreover, he hopes that the discovery could become a basis for predictive diagnostics.

    “There is no reliable way to diagnose schizophrenia or autism in asymptomatic patients. Deeper understanding of the genetic risk factors will help us develop preventative measures.”


  8. Manipulating a single gene defines a new pathway to anxiety

    September 9, 2017 by Ashley

    From the University of Utah Health press release:

    Removing a single gene from the brains of mice and zebrafish causes these animals to become more anxious than normal. Researchers from University of Utah Health show that eliminating the gene encoding Lef1 disrupts the development of certain nerve cells in the hypothalamus that affect stress and anxiety. These results are the first implication that Lef1 functions in the hypothalamus to mediate behavior, knowledge that could prove useful for diagnosing and treating human brain disorders.

    “Anxiety is an essential behavior that is much more complex than we thought,” says first author Yuanyuan Xie, Ph.D., who led the research in collaboration with senior author Richard Dorsky, Ph.D., professor of Neurobiology and Anatomy at U of U Health. Lef1 is a component of the Wnt signaling pathway, which has roles in animal development, physiology, and disease.

    “This work is making us think about how brain structures control behavior in a different way,” Xie says. The study appears in PLOS Biology on Aug. 24.

    Humans, mice, fish, and even flies exhibit anxiety, triggering behaviors that heighten awareness. Despite its reputation, the uneasy feeling can be a good thing: in the case of zebrafish causing them to freeze in their tracks so they can hide in plain sight from predators. But being anxious at inappropriate times is counterproductive and can be a sign of unnecessary stress, a characterization that holds true not only for fish but also for people.

    When Xie and Dorsky started their investigation, they had no reason to believe that Lef1 had a specific role in anxiety. Brains of fish missing the gene were relatively normal except there were cells missing from a region called the hypothalamus. This part of the brain controls many “hard-wired” behaviors such as sleep and feeding, as well as hormone release through the pituitary gland. “Before we did the experiments we had no idea that the neurons impacted by Lef1 would preferentially impact one type of behavior,” says Dorsky.

    Tallying the genes that were most perturbed by loss of Lef1 in this brain region revealed that over 20 were involved in mood disorders like depression and anxiety. The scientists then noticed that the fish had telltale signs consistent with these disorders. The animals were reluctant to explore their environment when placed into a new tank, preferred to remain immobile at the bottom. And they grew slowly, another condition often related to elevated stress.

    Different Paths to One Behavior

    Despite the fact that brain structure and complexity vary greatly from flies to humans, Lef1 appears to mediate anxiety across species. The new study shows that unexpectedly, the gene utilizes diverse mechanisms to get the job done.

    Similar to zebrafish, mice in which Lef1 had been removed from the hypothalamus showed signs of anxiety, including being smaller and a reluctance to explore. They also had fewer brain cells in the region where Lef1 is normally present. However, the missing cells make Pro-melanin concentrating hormone (Pmch), a brain signal that was not perturbed in zebrafish. By contrast, zebrafish and Drosophila fruit flies lacking their versions of Lef1 are missing cells that make Corticotropin releasing hormone binding protein (Crhbp), and these cells were unaffected in mice.

    These results suggested that Lef1 could regulate anxiety through two different nerve cell signals. Support for this scenario was unexpectedly found in humans, where expression of Crhbp and Pmch are extremely closely linked in the hypothalamus, indicating they may actually be present in the same cells and together act downstream of Lef1 to regulate behavior.

    “When you think about genes with a conserved function you think everything that gene does must be the same in all animals. But our study shows that that isn’t necessarily true,” says Dorsky.

    The observation could explain how a gene that specifies a particular behavior can adapt to accommodate changes in brain circuitry that happen over evolutionary time. “Our results suggest that during evolution, the brain can innovate different ways to get to the same outcome,” Dorsky explains.

    The findings highlight specific sets of genes and the brain cells they affect as being involved in regulating anxiety. Future work will focus on determining whether these pathways may define a subset of human behavioral and mood disorders.


  9. Altered mitochondria associated with increased autism risk

    September 7, 2017 by Ashley

    From the Children’s Hospital of Philadelphia press release:

    Mitochondria, the tiny structures inside our cells that generate energy, may play a key role in autism spectrum disorders (ASD). A provocative new study by Children’s Hospital of Philadelphia (CHOP)’s pioneering mitochondrial medicine team suggests that variations in mitochondrial DNA (mtDNA) originating during ancient human migrations may play an important role in predisposition to ASDs.

    “Our findings show that differences in mitochondrial function are important in ASD,” said study leader Douglas C. Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine at CHOP. “Our team demonstrates that a person’s vulnerability to ASD varies according to their ancient mitochondrial lineage.”

    Wallace and colleagues, including Dimitra Chalkia, Larry Singh and others, published their findings in JAMA Psychiatry.

    The scientists conducted a cohort study of genetic data from 1,624 patients and 2,417 healthy parents and siblings, representing 933 families in the Autism Genetic Resource Exchange (AGRE). The Center for Applied Genomics at CHOP had previously performed genome-wide association studies on this AGRE cohort, and partnered in this study.

    Mitochondria contain their own DNA, distinct from the more familiar nuclear DNA (nDNA) inside the cell nucleus. The mtDNA codes for essential genes governing cellular energy production, and those genes exchange biological signals with nDNA to affect our physiology and overall health.

    The current study analyzed single-nucleotide functional variants — base changes in the cohort’s mtDNA that characterize mitochondrial haplogroups. Haplogroups are lineages of associated mtDNA variants that reflect the ancient migration patterns of early human bands that spread out of Africa to the rest of the world during prehistory. Based on his seminal 1980 discovery that the human mtDNA is inherited only through the mother, Wallace’s surveys over the years, covering mtDNA variation among indigenous populations around the world, have permitted the reconstruction of human worldwide migrations and evolution patterns over hundreds of millennia.

    The current study found that individuals with European haplogroups designated I, J, K, X, T and U (representing 55 percent of the total European population) had significantly higher risks of ASD compared to the most common European haplogroup, HHV. Asian and Native American haplogroups A and M also were at increased risk of ASD.

    These mitochondrial haplogroups originated in different global geographic areas, adapted through evolution to specific regional environments. However, subsequent changes, such as migration, changes in diet, and other environmental influences, can create a mismatch between the physiology of a particular mtDNA lineage and the individual’s environment, resulting in predisposition to disease. Additional nDNA genetic factors or environmental insults may further reduce an individual’s energy output until it is insufficient to sustain normal brain development and function, resulting in disease.

    As the wiring diagram for cellular power plants, mtDNA is crucial in supplying energy to the body. The brain is particularly vulnerable to even mild energy deficiencies because of its high mitochondrial energy demand. Wallace’s previous studies have shown that mitochondrial dysfunction can disturb the delicate balance between inhibition and excitation in brain activity — a crucial factor in ASDs and other neuropsychiatric disorders. “There may be a bioenergetic threshold,” says Wallace, adding that an individual already predisposed to ASD based on their mitochondrial haplogroup may be pushed below that threshold by the chance occurrence of additional genetic variants or environmental insults.

    The striking tendency for ASD to occur more frequently in males than females may reflect another peculiarity of mitochondrial genetics, added Wallace. Males are four times more likely to suffer blindness from a well-known mtDNA disease, Leber hereditary optic neuropathy (LHON). The lower risk of blindness in females may arise from estrogen effects in mitochondria that increase beneficial antioxidant activity.

    Wallace said that his team’s finding that subtle changes in mitochondrial energetics are important risk factors in ASD suggests potential alternative approaches for therapy. He added, “There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON. If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD.”


  10. Life at home affects kids at school, some more than others

    August 31, 2017 by Ashley

    From The Norwegian University of Science and Technology (NTNU) press release:

    Some children are more susceptible to changes than others. They carry the relationship with their parents to school with them. Genetics can help explain why.

    “When the situation changes at home for these children, the relationship with their teacher changes too,” says researcher and PhD candidate Beate W. Hygen at NTNU Social Research and the Norwegian University of Science and Technology’s (NTNU) Department of Psychology.

    This means that when things are going well at home and in the parent-child relationship, the relationship between the child and the teacher is correspondingly good. However, the teacher-child relationship deteriorates when the child’s home life becomes more difficult.

    Genetic explanation

    “Some children seem to soak up environmental factors at home. This in turn affects the relationship with the teacher. For other children, the conditions at home don’t have much influence on their relationship with the teacher,” says Hygen.

    The explanation may be partly genetic. Hygen is the first author of a recent article that considers whether certain environmental factors affect children’s social development differently depending on what kind of genetic variants the child has.

    Hygen says the researchers are finding a link between children’s susceptibility to such factors and differences in a gene that regulates how individuals are affected by oxytocin. The differences found by the researchers were located in a variant of a receptor gene called OXTR, rs 53576. You can read more about this gene at https://www.snpedia.com/index.php/Rs53576

    Oxytocin is well known, even outside research circles. It is often called the “love hormone,” because it’s triggered when we’re together with someone we love, like a romantic love or our child. But oxytocin levels also increase when a relationship appears to be in danger, so the nickname isn’t totally accurate.

    Oxytocin release, the level of oxytocin in the brain and how oxytocin affects us play a significant role in our human relationships and how we interact and engage with others.

    Study looks at ambience

    Genetic differences in how we are affected by oxytocin can thus create differences in the way we relate to each other. Biology largely determines how we behave, but this study shows that this happens in conjunction with our surroundings.

    Previous surveys that have studied conditions at home versus in school have usually primarily looked at the parents’ situation. Social learning models, Hygen says, approach the issue from a starting point of “if there’s just yelling and negativity at home, some children can take these experiences into other relationships, such as with their teachers.”

    But the researchers in this survey start with the child itself and ask the question, “How vulnerable is the child to environmental factors?”

    “The most susceptible children will bring their home situation — both good and bad — into the school setting,” says Hygen.

    The Norwegian researchers examined 652 children in two age groups: 4-to-6 year olds and 6-to-8 year olds. This data is part of the long-term Tidlig Trygg i Trondheim study conducted by the Regional Centre for Child and Youth Mental Health and Child Welfare (RKBU) of Central Norway. The survey goes into detail about the home ambience. The study aims to identify risk and protection factors for psychosocial development and development of mental health problems in children.

    The researchers also asked the children’s teachers to assess the relationships they had with the children. This last component might be a source of error in the study, the researchers said.

    Different result in the United States

    The Norwegian researchers collaborated with American researchers, who conducted the same analysis in the US. The American researchers included 559 children from different locations in the United States. They did not find the same connection between home and school relationships.

    Hygen believes she has an idea why the Norwegian and American researchers have gotten divergent results.

    “In the United States, the stability of the relationship between teacher and child is often not the same in this age group,” she says.

    Norwegian children in the 6-to-8-year age group often have the same teacher for several years. In the United States, teachers change more often, and a change in the child’s relationship with their teacher over time may therefore be due to a change of teacher, not necessarily an improvement or worsening of the relationship with the same teacher.

    So, according to Hygen, researchers are less sure whether they are able to accurately measure relationship improvement or deterioration in the US, and the more frequent teacher changes may explain why the study doesn’t capture the effect of changes in the parent-child relationship.

    The researchers also assume that the quality of teachers varies a lot more in the United States than in Norway, since the funding of the school system differs from state to state. Greater social inequalities in the United States, which can influence relationships between teachers and children, may also affect the US results.

    The study has been published in the professional journal Developmental Psychology.