1. Study identifies gene variant that protects against Alzheimer’s disease

    December 11, 2017 by Ashley

    From the Brigham Young University press release:

    Research published Wednesday in Genome Medicine details a novel and promising approach in the effort to treat Alzheimer’s disease.

    Brigham Young University professors Perry Ridge and John Kauwe led the discovery of a rare genetic variant that provides a protective effect for high-risk individuals — elderly people who carry known genetic risk factors for Alzheimer’s — who never acquired the disease.

    In other words, there’s a specific reason why people who should get Alzheimer’s remain healthy. Study authors believe this genetic function could be targeted with drugs to help reduce the risk of people getting the disease.

    “Instead of identifying genetic variants that are causing disease, we wanted to identify genetic variants that are protecting people from developing disease,” said Ridge, assistant professor of biology at BYU. “And we were able to identify a promising genetic variant.”

    That former approach to Alzheimer’s disease has been generally effective in producing a list of genes that might impact risk for the disease, but it leaves researchers without sufficient data on what to do next. In this new approach, Ridge and Kauwe develop the biological mechanism by which a genetic variant actually impacts Alzheimer’s disease.

    Using data from the Utah Population Database — a 20-million-record database of the LDS Church’s genealogical records combined with historical medical records from Utah — Ridge and Kauwe first identified families that had a large number of resilient individuals: those who carried the main genetic risk factor for Alzheimer’s (E4 Allele) but remained healthy into advanced age.

    Using whole genome sequencing and a linkage analysis methodology, they then looked for the DNA that those resilient individuals shared with each other that they didn’t share with loved ones who died of Alzheimer’s. They discovered the resilient subjects shared a variant in the RAB10 gene while those who got the disease did not share the genetic variant.

    Once the researchers identified the potentially protective gene variant, they over expressed it in cells and under expressed it in cells to see the impact on Alzheimer’s disease related proteins. They learned that when this gene is reduced in your body, it has the potential to reduce your risk for Alzheimer’s.

    “There are currently no meaningful interventions for Alzheimer disease; No prevention, no modifying therapies, no cure,” Kauwe said. “The discoveries we’re reporting in this manuscript provide a new target with a new mechanism that we believe has great potential to impact Alzheimer’s disease in the future.”


  2. Tracking down genetic influences on brain disorders

    December 8, 2017 by Ashley

    From the Universität Basel press release:

    New findings will help to identify the genetic causes of brain disorders: researchers at the Universities of Basel, Bonn and Cologne have presented a systematic catalog of specific variable locations in the genome that influence gene activity in the human hippocampus, as they report in the journal Nature Communications.

    Individual differences in gene regulation contribute to the development of numerous multifactorial disorders. Researchers are therefore attempting to clarify the influence of genetic variants (single-nucleotide polymorphisms, or SNPs) on gene expression and on the epigenetic modification of regulatory sections of the genome (DNA methylation). The German-Swiss team has now studied the genetic determinants of gene expression, as well as the process of DNA methylation in the human hippocampus.

    Three million genomic locations analyzed

    The researchers have presented an extensive catalog of variable locations in the genome — that is, of SNPs — that affect the activity of genes in the human hippocampus. Specifically, they have analyzed the influence of more than three million SNPs, spread throughout the genome, on activity in nearby genes and the methylation of adjacent DNA sections.

    The special thing about their work is that the researchers used freshly frozen hippocampus tissue obtained during surgery on 110 treatment-resistant epilepsy patients. They extracted DNA and RNA from the hippocampus tissue and, for all of the obtained samples, used microchips to determine several hundred thousand SNPs, as well as the degree of methylation at several hundred thousand locations (known as CpG dinucleotides) in the genome. Among other analyses, they measured the gene expression of over 15,000 genes using RNA microchips.

    Development of schizophrenia

    The researchers also demonstrated the preferred areas in which variably methylated CpG dinucleotides appear in the genome, and they were able to assign these to specific regulatory elements, revealing a link to brain disorders: a significant proportion of the identified SNPs that individually influence DNA methylation and gene expression in the hippocampus also contribute to the development of schizophrenia. This underlines the potentially significant role played by SNPs with a regulatory effect in the development of brain disorders.

    The study’s findings will make it considerably easier to interpret evidence of genetic associations with brain disorders in the future. Of the SNPs involved in the development of brain disorders, many of those identified in recent years are located in the non-coding part of the genome. Their functional effect in cells is therefore largely unclear.

    An important factor in the project’s success was the close cooperation between the Universities of Basel, Bonn and Cologne. This collaboration is supported by the IntegraMent Consortium, which is sponsored by Germany’s Federal Ministry of Education and Research and coordinated by Professor Markus Nöthen of the University of Bonn.


  3. Genetic study links tendency to undervalue future rewards with ADHD

    December 5, 2017 by Ashley

    From the University of California – San Diego press release:

    Researchers at University of California San Diego School of Medicine have found a genetic signature for delay discounting — the tendency to undervalue future rewards — that overlaps with attention-deficit/hyperactivity disorder (ADHD), smoking and weight.

    In a study published December 11 in Nature Neuroscience, the team used data of 23andme customers who consented to participate in research and answered survey questions to assess delay discounting. In all, the study included the data of more than 23,000 people to show that approximately 12 percent of a person’s variation in delay discounting can be attributed to genetics — not a single gene, but numerous genetic variants that also influence several other psychiatric and behavioral traits.

    “Studying the genetic basis of delay discounting is something I’ve wanted to do for the entirety of my 20 years of research, but it takes a huge number of people for a genetics study to be meaningful,” said senior author Abraham Palmer, PhD, professor of psychiatry and vice chair for basic research at UC San Diego School of Medicine. “By collaborating with a company that already has the genotypes for millions of people, all we needed was for them to answer a few questions. It would have been difficult to enroll and genotype this many research participants on our own in academia — it would’ve taken years and been cost prohibitive. This is a new model for science.”

    According to Palmer, every complicated nervous system needs a way of assessing the value of current versus delayed rewards. Most people think of the “marshmallow experiment,” he said, referring to the classic experiment where children were tested for their ability to delay gratification by giving them the choice between one marshmallow now or two marshmallows a few minutes later.

    “A person’s ability to delay gratification is not just a curiosity, it’s integrally important to physical and mental health,” Palmer said. “In addition, a person’s economic success is tied to delay discounting. Take seeking higher education and saving for retirement as examples — these future rewards are valuable in today’s economy, but we’re finding that not everyone has the same inclination to achieve them.”

    For the study, the team looked at data from 23andMe research participants who answered survey questions that could be used to assess delay discounting. For example, customers were asked to choose between two options: “Would you rather have $55 today or $75 in 61 Days?”

    “In less than four months, we had responses from more than 23,000 research participants,” said Pierre Fontanillas, PhD, a senior statistical geneticist at 23andMe. “This shows the power of our research model to quickly gather large amounts of phenotypic and genotypic data for scientific discovery.”

    By comparing participants’ survey responses to their corresponding genotypes and complementary data from other studies, Palmer’s team found a number of genetic correlations.

    “We discovered, for the first time, a genetic correlation between ADHD and delay discounting,” said first author Sandra Sanchez-Roige, PhD, a postdoctoral researcher in Palmer’s lab. “People with ADHD place less value in delayed rewards. That doesn’t mean that everyone with ADHD will undervalue future rewards or vice versa, just that the two factors have a common underlying genetic cause.”

    The researchers also found that delay discounting is genetically correlated with smoking initiation. In other words, people who undervalue future rewards may be more likely to start smoking and less likely to quit if they did.

    Body weight, as determined by body mass index (BMI), was also strongly correlated with delay discounting, suggesting that people who don’t place a high value on future rewards tend to have a higher BMI.

    The team determined that delay discounting negatively correlated with three cognitive measures: college attainment, years of education and childhood IQ. In other words, the genetic factors that predict delay discounting also predict these outcomes.

    In many studies that rely on surveys, particularly for those in which the participants are paid to fill out the survey, there’s always a chance that some answered randomly or carelessly. Palmer’s survey included three questions to assess how carefully the research participants were answering the questions. For example, one asked “Would you rather have $60 today or $20 today?” There’s only one correct answer and the team saw only 2.1 percent of participants get even one of those three questions wrong, assuring them that the vast majority were answering the questions carefully.

    “We are very thankful to the 23andMe research participants who took the time to complete our survey — they weren’t paid to do it, they are citizen-scientists volunteering their help,” Palmer said. “It’s quite a feeling to think that so many people were willing to help out in this interest of ours.”

    Palmer hopes to expand the study to a larger and more diverse population to strengthen their findings.

    “An even larger study would help start identifying specific genes with a higher level of confidence,” he said. “Then we can do hypothesis-driven studies of this trait with animal or cellular models.”

    While most research studies begin in test tubes, cells grown in the laboratory and animal models before moving to humans, the opposite is true here. After starting with these human observations, Palmer’s team is now studying the same delay discounting-related genetic traits in rodent models. They want to determine if changing those genes experimentally changes rodent behavior as expected. If it does, they will be able to use the animals to study how those delay discounting-related genes lead to those behaviors, at a molecular level.


  4. Study uses stem cells to explore the causes of autism

    November 17, 2017 by Ashley

    From the Elsevier press release:

    Using human induced pluripotent stem cells (iPSCs) to model autism spectrum disorder (ASD), researchers at the University of São Paulo, Brazil and University of California, San Diego have revealed for the first time that abnormalities in the supporting cells of the brain, called astrocytes, may contribute to the cause of the disorder. The findings, published in Biological Psychiatry, help explain what happens at a biological level to produce ASD behavior, and may help researchers identify new treatments for patients with the disorder.

    Astrocytes play an important role in the development and function of the nervous system. But until now, iPSC models of autism have neglected their contribution. The new study, led by Dr. Patricia Beltrão-Braga and Dr. Alysson Muotri, used iPSCs to generate neurons and astrocytes to model the interaction between these brain cells and better understand how the brain forms in the disorder.

    “This new use of pluripotent stem cells suggests that neurobiological approaches to autism based solely on abnormal neuronal development may fail to account for complex interplay of neurons and astrocytes that may be an underappreciated component of the biology of this disorder,” said Dr. John Krystal, Editor of Biological Psychiatry.

    Induced pluripotent stem cell technology allows researchers to reprogram human cells into any cell in the body. In the study, first authors Dr. Fabiele Russo and Beatriz Freitas and colleagues used cells from three patients diagnosed with ASD and three healthy individuals to generate neurons and astrocytes. Neurons derived from ASD patients had less complex structure than healthy neurons, but adding healthy astrocytes to the ASD neurons improved their poorly developed structure. In reverse, pairing ASD astrocytes with healthy neurons interfered with their development, making them look more like the neurons from ASD patients.

    “The article highlights for the first time the influence of astrocytes in ASD, revealing that astrocytes play a fundamental role in neuronal structure and function,” said Beltrão-Braga.

    The researchers further investigated how the astrocytes exert their influence, and pegged a substance that astrocytes produce called IL-6, already suggested as a player in ASD, as the culprit for the defects. Astrocytes from the patients with ASD appeared to be producing too much of the substance, and the findings suggest that reducing IL-6 could be a beneficial treatment for neurons in ASD.

    Importantly, ASD has been a challenging disease to model using iPSCs because of its complexity. Several genes have been linked to ASD, but their contributions remain unknown, and genetic differences between patients have made it difficult to understand the cause and develop treatments for the disorder. But in this study, the ASD subjects were selected because they shared similar behaviors, rather than similar genes. According to Beltrão-Braga, this means the findings could provide a new alternative strategy for treating ASD symptoms, independent of the patient’s genotype.


  5. Study links herbicide to Parkinson’s disease

    October 30, 2017 by Ashley

    From the Northwestern University press release:

    Northwestern Medicine scientists have used an innovative gene editing technique to identify the genes that may lead to Parkinson’s disease after exposure to paraquat, a commonly-used herbicide.

    This study, which utilized the CRISPR-Cas9 gene-editing tool, serves as a proof-of-concept for using genetic screens to investigate the biology of oxidative stress, according to senior author Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care at Northwestern University Feinberg School of Medicine.

    The study was published in Nature Chemical Biology and the first author was Colleen Reczek, PhD, a postdoctoral fellow in Chandel’s lab. Other authors included Chandel lab members Hyewon Kong, a student in the Walter S. and Lucienne Driskill Graduate Program in Life Sciences, and Inmaculada Martinez-Reyes, PhD, a postdoctoral fellow.

    The use of paraquat, which causes cell death via oxidative stress, is restricted in the United States and banned in the European Union, but the chemical is still used widely throughout Asia and the developing world, according to Chandel, also a professor of Cell and Molecular Biology. Ingestion of paraquat can lead to lung fibrosis or even death, but a 2011 study linked occupational use to an increased risk for Parkinson’s disease, renewing interest in its impact on humans.

    A major cause of Parkinson’s is the loss of function in dopamine neurons in a small brain region called the substantia nigra pars compacta, according to previous research. Those neurons are known to be highly vulnerable to oxidative stress, leading scientists to hypothesize paraquat was linked to Parkinson’s disease through this oxidative stress.

    “Paraquat generates a lot of oxidants. Naturally those dopaminergic neurons will be the most susceptible to damage,” Chandel said.

    However, the mechanism by which paraquat created oxidants was unknown — until now.

    Chandel and his collaborators conducted a CRISPR-Cas9 positive-selection screen, creating thousands of cells, each with one individual gene turned off.

    “We thought it was a metabolic protein that paraquat was activating to generate oxidants,” Chandel said. “So we localized our work to the 3,000 genes that encode for metabolic proteins, rather than the 18,000 to 20,000 genes human cells have in total.”

    They exposed that subset of cells to paraquat — the majority of cells died, but not all of them. Certain cells with knocked-out genes were resistant to paraquat, suggesting those genes may be responsible for the toxicity.

    Scientists identified three genes whose loss conferred resistance to paraquat: POR, ATP7A and SLC45A4. POR, a protein in the endoplasmic reticulum, was fingered as the main source of oxidation that caused the damage. Pinpointing these genes could help identify people who are especially vulnerable to paraquat, Chandel said.

    “Certain people with genetic mutations could have high levels of this gene. They would be very susceptible to paraquat poisoning while working on a farm, for example,” he said.

    However, the most impactful takeaway from the paper may be as a proof-of-concept for investigative biology of oxidative stress, according to Chandel.

    POR had been previously implicated in oxidant generation, but the majority of evidence had pointed to systems in the mitochondria, according to the study, and no definitive answer had emerged until this study was conducted.

    “Now, we can go in and test how agents of oxidant stress work,” Chandel said. “The beauty of the paper is in the power of these unbiased genetic screens we can now use with CRISPR technology.”

    Investigating oxidant stress could pay dividends in the future, according to Chandel, including in the development of drugs designed to generate oxidative stress in cancer cells, killing them while leaving healthy cells alone. While some drugs currently exist, not enough is known about their pathways to create a functioning compound, Chandel said.

    “The biology of oxidative stress is still a mystery,” he said. “CRISPR positive-selection screens could be a way to figure it out.”


  6. Mysterious DNA modification seen in stress response

    October 25, 2017 by Ashley

    From the Emory Health Sciences press release:

    With advances in genomics, scientists are discovering additional components of the DNA alphabet in animals. Do these unusual chemical modifications of DNA have a special meaning, or are they just signs that cellular machines are making mistakes?

    Geneticists at Emory University School of Medicine led by Peng Jin, PhD have been studying a modification of DNA that is not well understood in animals: methylation of the DNA letter A (adenine). They’ve found that it appears more in the brain under conditions of stress, and may have a role in neuropsychiatric disorders.

    The results are scheduled for publication in Nature Communications.

    Methylation on the DNA letter C (cytosine) generally shuts genes off and is an important part of epigenetic regulation, a way for cells to change how the DNA code is read without altering the DNA letters themselves. Methylation describes a mark consisting of an extra carbon atom and three hydrogens: -CH3.

    What if methylation appears on adenine? In bacteria, N6-methyladenine is part of how they defend themselves against invasion by phages (viruses that infect bacteria). The same modification was recently identified as present in the DNA of insects and mammals, but this epigenetic flourish has been awaiting a full explanation of its function.

    Just to start, having that extra -CH3 jutting out of the DNA could get in the way of proteins that bind DNA and direct gene activity. For C-methylation, scientists know a lot about the enzymes that grab it, add it or erase it. For A-methylation, less is known.

    “We found that 6-methyl A is dynamic, which could suggest a functional role,” Jin says. “That said, the enzymes that recognize, add and erase this type of DNA methylation are still mysterious.”

    It does appear that the enzymes that add methyl groups to A when it is part of RNA are not involved, he adds.

    First author Bing Yao, PhD, assistant professor of human genetics, recently established his own laboratory at Emory to examine these and other emerging parts of the DNA alphabet. Jin is vice chair of research in the Department of Human Genetics.

    In the Nature Communications paper, Yao, Jin and their colleagues looked at the prefrontal cortex region of the brain in mice that were subjected to stress, in standard models for the study of depression (forced swim test and tail suspension test).

    Under these conditions, the abundance of N6-methyladenine in the brain cells’ DNA rose four-fold, the scientists found. The DNA modification was detected with two sensitive techniques: liquid chromatography/mass spectrometry and binding to an antibody against N6-methyladenine. The peak abundance is about 25 parts per million, which isn’t that high — but it appears to be confined to certain regions of the genome.

    The methyl-A modification tended to appear more in regions that were between genes and was mostly excluded from the parts of the genome that encode proteins. The loss of methyl-A correlates with genes that are upregulated with stress, suggesting that something removes it around active genes. There does seem to be some “cross talk” between A and C methylation, Jin adds.

    Genes bearing stress-induced 6mA changes overlapped with those associated with neuropsychiatric disorders; a relationship that needs more investigation. The scientists speculate that aberrant 6mA in response to stress could contribute to neuropsychiatric diseases by ectopically recruiting DNA binding proteins.

    The research was supported in part by the National Institute of Neurological Disorders and Stroke (NS051630, NS097206) and the National Institute of Mental Health (MH102690).


  7. Study suggests signaling pathway may be key to why autism is more common in boys

    October 17, 2017 by Ashley

    From the University of Iowa Health Care press release:

    Researchers aiming to understand why autism spectrum disorders (ASD) are more common in boys have discovered differences in a brain signaling pathway involved in reward learning and motivation that make male mice more vulnerable to an autism-causing genetic glitch.

    “One intriguing aspect of autism is that it predominantly affects males; four boys are affected for every one girl,” says senior study author Ted Abel, PhD, director of the Iowa Neuroscience Institute at the University of Iowa Carver College of Medicine. “We don’t understand what it is about this disorder that predisposes boys as compared to girls to develop autism.”

    This male bias is also seen in other neurodevelopmental disorders, like attention deficit hyperactivity disorder (ADHD) and specific language impairments.

    Nearly one in every 200 cases of autism is caused by the deletion of a section of DNA on a particular chromosome. This type of disorder is also known as a copy number variation (CNV). The mouse model of autism used by the research team is missing the same stretch of DNA.

    The researchers tested the mice for abnormalities in reward-learning behavior — learning to associate actions with rewarding outcomes. This type of learning is mediated by a part of the brain called the striatum and is disrupted in people with autism and other neurodevelopmental disorders.

    The study, published online Oct. 17 in Molecular Psychiatry, shows that only male mice with the autism-associated genetic deletion have abnormal reward-learning behavior. Female mice with the same genetic deletion are not affected. Moreover, these sex-specific behavioral differences are accompanied by sex differences in molecular signaling pathways in the striatum brain region.

    Problems with reward learning could explain why individuals with autism don’t interact socially — because they don’t find it rewarding in the same way. It could explain why people with autism have restricted interests — because they find only very selective things rewarding — and it could explain the differences in language acquisition — because the neural circuitry involved in reward learning is the same circuitry that mediates both language learning and production,” says Abel, who also is the Roy J. Carver Chair in Neuroscience and UI professor of molecular physiology and biophysics.

    Female protective effect

    One of the genes contained in the missing section of DNA is an important signaling protein called ERK1. Activity of this protein affects the function of the striatum — the part of the brain that’s involved in reward learning and motivation. The researchers found that male mice carrying this genetic deletion have increased activation of ERK1 in the striatum coupled with decreased amounts of another protein that reduces ERK1 activity. In contrast, the female mice carrying the genetic deletion do not have overactivated ERK1. In addition, despite the genetic deletion, the female deletion mice have higher levels of ERK1 than the male deletion mice. All of these molecular differences mean that ERK1 signaling is particularly sensitive to disruption in male mice.

    “This is some of the first evidence in a mouse model of autism of a ‘female protective effect,’ from the behavioral to the molecular level,” says Nicola Grissom, first author of the study who is now an assistant professor of psychology at the University of Minnesota. “These findings shed valuable new light on the science of neurodevelopmental disorders, many of which are more common in boys. However, they also address the broader question of how sex and gender influence the neurobiology of how we learn and behave, which may be involved in the different levels of risk between women and men for developing many other neuropsychiatric conditions, as well.”

    The study also found that male mice carrying this genetic alteration linked to autism have increased expression of a receptor for dopamine; the D2 receptor. The level of D2 expression did not increase in the female autism mice. Abel notes that risperidone, one of very few drugs that is approved by the Food and Drug Administration to treat ASD symptoms, targets D2 dopamine receptors.

    “We think we are on the right track,” Abel says. “We have begun to identify what may be an underlying reason why neurodevelopmental disorders predominantly affect boys, and that involves the function of the striatum and reward learning. This has implications for how we think about the underlying behavioral differences in autism and implications for how we develop both behavioral or pharmacological therapies to improve the lives of those with autism.”

    The new findings are part of a bigger study where Abel and his colleagues are investigating many different mouse models of autism, in which different autism-linked genes have been disrupted. The researchers are seeking commonalities among the different models. One emerging theme, supported by the new study, is that a deficit in reward learning may be a common feature of ASD, and males are specifically deficient in this type of behavior.

    Abel notes that funding from the Simons Foundation was critical to the success of the project.

    “None of this would have happened without the support of the Simons Foundation Autism Research Initiative (SFARI). The impact they have had on autism research has been tremendous,” he says.


  8. 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.


  9. Study suggests possible genetic component to divorce running in families

    October 9, 2017 by Ashley

    From the Virginia Commonwealth University press release:

    Children of divorced parents are more likely to get divorced when compared to those who grew up in two-parent families — and genetic factors are the primary explanation, according to a new study by researchers at Virginia Commonwealth University and Lund University in Sweden.

    “Genetics, the Rearing Environment, and the Intergenerational Transmission of Divorce: A Swedish National Adoption Study,” which will be published in a forthcoming issue of the journal Psychological Science, analyzed Swedish population registries and found that people who were adopted resembled their biological — but not adoptive — parents and siblings in their histories of divorce.

    “We were trying to answer the basic question: Why does divorce run in families?” said the study’s first author, Jessica Salvatore, Ph.D., assistant professor in the Department of Psychology in the College of Humanities and Sciences at VCU. “Across a series of designs using Swedish national registry data, we found consistent evidence that genetic factors primarily explained the intergenerational transmission of divorce.”

    In addition to Salvatore, the study was conducted with Kenneth S. Kendler, M.D., professor of psychiatry and human and molecular genetics in the Department of Psychiatry at VCU’s School of Medicine, along with Swedish colleagues Sara Larsson Lönn, Ph.D.; Jan Sundquist, M.D., Ph.D.; and Kristina Sundquist, M.D., Ph.D., of the Center for Primary Health Care Research at Lund University.

    The study’s findings are notable because they diverge from the predominant narrative in divorce literature, which suggests that the offspring of divorced parents are more likely to get divorced themselves because they see their parents struggling to manage conflict or lacking the necessary commitment, and they grow up to internalize that behavior and replicate it in their own relationships.

    “I see this as a quite significant finding. Nearly all the prior literature emphasized that divorce was transmitted across generations psychologically,” Kendler said. “Our results contradict that, suggesting that genetic factors are more important.”

    By recognizing the role that genetics plays in the intergenerational transmission of divorce, therapists may be able to better identify more appropriate targets when helping distressed couples, Salvatore said.

    “At present, the bulk of evidence on why divorce runs in families points to the idea that growing up with divorced parents weakens your commitment to and the interpersonal skills needed for marriage,” she said. “So, if a distressed couple shows up in a therapist’s office and finds, as part of learning about the partners’ family histories, that one partner comes from a divorced family, then the therapist may make boosting commitment or strengthening interpersonal skills a focus of their clinical efforts.”

    “However, these previous studies haven’t adequately controlled for or examined something else in addition to the environment that divorcing parents transmit to their children: genes,” she said. “And our study is, at present, the largest to do this. And what we find is strong, consistent evidence that genetic factors account for the intergenerational transmission of divorce. For this reason, focusing on increasing commitment or strengthening interpersonal skills may not be a particularly good use of time for a therapist working with a distressed couple.”

    The study’s findings suggest that it might be useful for therapists to target some of the more basic personality traits that previous research has suggested are genetically linked to divorce, such as high levels of negative emotionality and low levels of constraint, to mitigate their negative impact on close relationships.

    “For example, other research shows that people who are highly neurotic tend to perceive their partners as behaving more negatively than they objectively are [as rated by independent observers],” Salvatore said. “So, addressing these underlying, personality-driven cognitive distortions through cognitive-behavioral approaches may be a better strategy than trying to foster commitment.”


  10. 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.