Aging and gene expression -- possible links to autism and schizophrenia in offspring

Advanced paternal age has been associated with greater risk for psychiatric disorders, such as schizophrenia and autism. With an increase in paternal age, there is a greater frequency of certain types of mutations that contribute to these disorders in offspring. Mutations are changes in the genetic code. Recent research, however, looks beyond the genetic code to "epigenetic effects", which do not involve changes in the genes themselves, but rather in how they are expressed to determine one's characteristics. Such epigenetic changes in sperm, related to ageing, have been linked with psychiatric disorders in offspring. Maria Milekic, PhD, reported today, at the American College of Neuropsychopharmacology annual meeting in Hollywood Florida, that old mice have an epigenetic change ‒ a loss of DNA methylation at the locations where the genetic code starts being transcribed. DNA methylation is a biochemical process that plays an important regulatory role in development and disease. The work was done by a research team in the Department of Psychiatry at Columbia University. Offspring of old fathers showed the same deficit in DNA methylation, and they differed in their behavior from the offspring of the young fathers. They showed less exploratory activity and differed in the startle response and in habituation. Two groups, with 10 breeder mice per group, were tested. The breeders were either old (12 month) or young (3 month) males, each bred with two young (3 month) female mice. Then the behavior of the offspring was tested when they were 3 months old. DNA methylation also was tested in the young and old fathers' sperm, and brains of the offspring were tested for DNA methylation as well as gene expression. "We were interested in understanding the mechanism of the paternal age effect", said Dr. Milekic."The risk for schizophrenia increases 2-fold when a father is over 45 years of age, and the risk for autism increases 2-5-fold. It seemed unlikely that mutation alone could account for this. We therefore speculated that DNA methylation could provide an alternative mechanism." Not only did the offspring of the old fathers differ from their counterparts with young fathers in DNA methylation, they also showed significant differences in the expression of genes that have been implicated in autism spectrum disorders and that are known to regulate the development and function of the brain. These findings point to possible factors that can lead to autism spectrum disorders and schizophrenia, and ultimately may lead to more effective therapeutic interventions. With respect to studies in the immediate future, Dr. Milekic said,"We are trying to evaluate changes in different brain regions. Our studies before did not compare brain regions. Most of the genes that have altered expression are in the cerebellum. We are interested in how DNA methylation in the cerebellum is affected by paternal age." Social Worker CEUs ### The work was supported by grants from NIMH and the Simon Foundation to Jay Gingrich, MD, PhD, and a NARSAD Young Investigator Awa rd from the Brain and Behavior Research Foundation to Dr. Milekic.

For some women, genes may influence pressure to be thin

EAST LANSING, Mich. — Genetics may make some women more vulnerable to the pressure of being thin, a study led by Michigan State University researchers has found. From size-zero models to airbrushed film stars, thinness is portrayed as equaling beauty across Western culture, and it's an ideal often cited as a cause of eating disorder symptoms in young women. The researchers focused on the potential psychological impact of women buying into this perceived ideal of thinness, which they call thin-ideal internalization. Changes in self-perception and behavior, caused by this idealization, can lead to body dissatisfaction, a preoccupation with weight and other symptoms of eating disorders. "We're all bombarded daily with messages extoling the virtues of being thin, yet intriguingly only some women develop what we term thin-ideal internalization," said Jessica Suisman, lead author on the study and a researcher in MSU's Department of Psychology. "This suggests that genetic factors may make some women more susceptible to this pressure than others." To explore the role of genetic factors in whether women "buy in" to the pressure to be thin, the idealization of thinness was studied in sets of twins. More than 300 female twins from the MSU Twin Registry, ages 12-22, took part in the study. Suisman and colleagues measured how much participants wanted to look like people from movies, TV and magazines. Once the levels of thin idealization were assessed, identical twins who share 100 percent of their genes were compared with fraternal twins who share 50 percent. The results show that identical twins have closer levels of thin idealization than fraternal twins, which suggests a significant role for genetics. Further analysis shows that the heritability of thin idealization is 43 percent, meaning that almost half of the reason women differ in their idealization of thinness can be explained by differences in their genetic makeup. In addition to the role of genes, findings showed that influences of the environment are also important. The results showed that differences between twins' environments have a greater role in the development of thin ideal internalization than wider cultural attitudes, which women throughout Western societies are exposed to. "We were surprised to find that shared environmental factors, such as exposure to the same media, did not have as big an impact as expected," Suisman said. "Instead, non-shared factors that make co-twins different from each other had the greatest impact." Although the study did not look at specific environmental triggers, non-shared environmental influences typically include experiences that twins do not share with one another. This could include involvement by one twin in a weight-focused sport like dance, one twin being exposed to more media that promotes thinness than the other, or one of the twins having a friendship group that places importance on weight. "The take-home message," Suisman said, "is that the broad cultural risk factors that we thought were most influential in the development of thin-ideal internalization are not as important as genetic risk and environmental risk factors that are specific and unique to each twin." Kelly Klump, MSU professor of psychology and co-author on the study, said it is well established that a broad range of factors can contribute to the development of eating disorders LPC Continuing Education "This study reveals the need to take a similar approach to the ways in which women buy in to pressure to be thin, by considering how both genetic and environmental factors contribute to the development of thin-ideal internalization," Klump said. ### The study, funded by the National Institute of Mental Health, appears in the International Journal of Eating Disorders. Co-authors include Shannon O'Connor, Alexandra Burt and Cheryl Sisk from MSU; Steffanie Sperry and Kevin Thompson from the University of South Florida; Pamela Keel from Florida State University; Michael Neale from Virginia Commonwealth University; and Steven Boker from the University of Virginia.

Genetic Switch Involved in Depression

The activity of a single gene sets in motion some of the brain changes seen in depression, according to a new study. The finding suggests a promising target for potential therapies. People with major depressive disorder, or major depression, have feelings of sadness, loss, anger or frustration that interfere with daily life for weeks or longer. The symptoms of depression also include memory loss and trouble thinking. Past studies have found that people with major depression have brains that are physically different from those of non-depressed people. The depressed brain has a smaller prefrontal cortex, a region at the front of the brain that handles emotion and complicated thought. The area also has fewer and smaller neurons (nerve cells) in the depressed brain. To gain insight into the neural mechanisms at work, a group led by Dr. Ronald Duman of Yale University began with data collected in a previous study. They had done a comparison of postmortem brains from 15 depressed people and 15 non-depressed people who were matched in age, ethnicity and gender. Using DNA microarray chips to analyze the activity of 20,000 genes, the researchers had found numerous genes that were expressed (turned on and off) differently in the brains of depressed people. For the new study, the team focused specifically on genes related to synapses, the place where signals pass from one neuron to another. The work was funded in part by NIH’s National Institute of Mental Health (NIMH) and National Center for Research Resources (NCRR). The findings were published in the September 2012 issue of Nature Medicine. Analysis revealed that about 30% of the genes with significantly lower expression in the depressed brains related to some aspect of synapse function. Further experiments found significantly reduced expression for 5 particular genes in the prefrontal cortex of depressed people. The scientists searched for transcription factors—proteins that bind to the DNA of other genes to turn them on or off—that were capable of regulating the 5 genes. They found one called GATA1 that is expressed significantly more in the brains of people with major depressive disorder. Expression of the Gata1 gene in the prefrontal cortex was also higher in a rat model of depression. Raising expression of Gata1 in cultured rat neurons decreased the expression of synapse-related genes. It also decreased the number of connections between neurons, supporting the idea that higher Gata1 expression can lead to the changes seen in depressed brains. The researchers next tested the gene in rats and found that putting extra copies of Gata1 into their brains made them behave as if they were depressed MHC Ceus “We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated,” Duman explains. These findings may point toward a new target for treatment. “We hope that by enhancing synaptic connections, either with novel medications or behavioral interventions, we can develop more effective antidepressant therapies,” says Duman. — by Helen Fields Related Links: Depression: http://www.nimh.nih.gov/health/topics/depression/index.shtml More Young Neurons Equals Better Brain Function: http://www.nih.gov/researchmatters/april2011/ 04112011brainfunction.htm Brain Basics: Know Your Brain: http://www.ninds.nih.gov/disorders/brain_basics/know_your_brain.htm Reference: Nat Med. 2012 Aug 12. [Epub ahead of print] PMID: 22885997.

Agent Reduces Autism-like Behaviors in Mice

Press Release • April 25, 2012

Agent Reduces Autism-like Behaviors in Mice Boosts Sociability, Quells Repetitiveness – NIH Study National Institutes of Health researchers have reversed behaviors in mice resembling two of the three core symptoms of autism spectrum disorders (ASD). An experimental compound, called GRN-529, increased social interactions and lessened repetitive self-grooming behavior in a strain of mice that normally display such autism-like behaviors, the researchers say. GRN-529 is a member of a class of agents that inhibit activity of a subtype of receptor protein on brain cells for the chemical messenger glutamate, which are being tested in patients with an autism-related syndrome. Although mouse brain findings often don’t translate to humans, the fact that these compounds are already in clinical trials for an overlapping condition strengthens the case for relevance, according to the researchers. “Our findings suggest a strategy for developing a single treatment that could target multiple diagnostic symptoms,” explained Jacqueline Crawley, Ph.D., of the NIH’s National Institute of Mental Health (NIMH). “Many cases of autism are caused by mutations in genes that control an ongoing process – the formation and maturation of synapses, the connections between neurons. If defects in these connections are not hard-wired, the core symptoms of autism may be treatable with medications.” Crawley, Jill Silverman, Ph.D., and colleagues at NIMH and Pfizer Worldwide Research and Development, Groton, CT, report on their discovery April 25th, 2012 in the journal Science Translational Medicine. "These new results in mice support NIMH-funded research in humans to create treatments for the core symptoms of autism,” said NIMH director Thomas R. Insel, M.D. “While autism has been often considered only as a disability in need of rehabilitation, we can now address autism as a disorder responding to biomedical treatments." social worker ceus Crawley’s team followed-up on clues from earlier findings hinting that inhibitors of the receptor, called mGluR5, might reduce ASD symptoms. This class of agents – compounds similar to GRN-529, used in the mouse study – are in clinical trials for patients with the most common form of inherited intellectual and developmental disabilities, Fragile X syndrome, about one third of whom also meet criteria for ASDs. To test their hunch, the researchers examined effects of GRN-529 in a naturally occurring inbred strain of mice that normally display autism-relevant behaviors. Like children with ASDs, these BTBR mice interact and communicate relatively less with each other and engage in repetitive behaviors – most typically, spending an inordinate amount of time grooming themselves. Crawley’s team found that BTBR mice injected with GRN-529 showed reduced levels of repetitive self-grooming and spent more time around – and sniffing nose-to-nose with – a strange mouse. Moreover, GRN-529 almost completely stopped repetitive jumping in another strain of mice. “These inbred strains of mice are similar, behaviorally, to individuals with autism for whom the responsible genetic factors are unknown, which accounts for about three fourths of people with the disorders,” noted Crawley. “Given the high costs – monetary and emotional – to families, schools, and health care systems, we are hopeful that this line of studies may help meet the need for medications that treat core symptoms.” Reference: Silverman JL, Smith DG, Rizzo SJS, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley, JN. Negative allosteric modulation of the MGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. April 25, 2012, Science Translational Medicine.

Spontaneous Gene Glitches Linked to Autism Risk with Older Dads

Non-Inherited Mutations Spotlight Role of Environment – NIH-Supported Study, Consortium ceus for nurses

Researchers have turned up a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders. Moreover, the number of such transmitted genetic glitches increased with paternal age. The discovery may help to explain earlier evidence linking autism risk to older fathers.

The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs. One of the studies determined that having such glitches boosts a child’s risk of developing autism five to 20 fold.

Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. They reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not. While the changes identified don’t account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum.

“These results confirm that it’s not necessarily the size of a genetic anomaly that confers risk, but its location – specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it’s this kind of knowledge that will yield potential targets for new treatments,” explained Thomas, R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

Multi-site research teams led by Mark Daly, Ph.D., of the Harvard/MIT Broad Institute, Cambridge, Mass., Matthew State, M.D., Ph.D., of Yale University, New Haven, Conn., and Evan Eichler, Ph.D., of the University of Washington, Seattle, report on their findings online April 4, 2012 in the journal Nature.

The study by Daly and colleagues was supported by NIMH – including funding under the American Recovery and Reinvestment Act. The State and Eichler studies were primarily supported by the Simons Foundation Autism Research Initiative. The studies also acknowledge the NIH’s National Human Genome Research Institute, National Heart Lung and Blood Institute, and National Institute on Child Health and Human Development and other NIH components.

All three teams sequenced the protein coding parts of genes in parents and an affected child – mostly in families with only one member touched by autism. One study also included comparisons with healthy siblings. Although these protein-coding areas represent only about 1.5 percent of the genome, they harbor 85 percent of disease-causing mutations. This strategy optimized the odds for detecting the few spontaneous errors in genetic transmission that confer autism risk from the “background noise” generated by the many more benign mutations.

Like larger deletions and duplications of genetic material previously implicated in autism and schizophrenia, the tiny point mutations identified in the current studies are typically not inherited in the conventional sense – they are not part of parents’ DNA, but become part of the child’s DNA. Most people have many such glitches and suffer no ill effects from them. But evidence is building that such mutations can increase risk for autism if they occur in pathways that disrupt brain development.

State’s team found that 14 percent of people with autism studied had suspect mutations – five times the normal rate. Eichler and colleagues traced 39 percent of such mutations likely to confer risk to a biological pathway known to be important for communications in the brain.

Although Daly and colleagues found evidence for only a modest role of the chance mutations in autism, those pinpointed were biologically related to each other and to genes previously implicated in autism.

The Eichler team turned up clues to how environmental factors might influence genetics. The high turnover in a male’s sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process. These can be passed-on to the offspring’s DNA, even though they are not present in the father’s DNA. This risk may worsen with aging. The researchers discovered a four-fold marked paternal bias in the origins of 51 spontaneous mutations in coding areas of genes that was positively correlated with increasing age of the father. So such spontaneous mutations could account for findings of an earlier study that found fathers of boys with autism were six times – and of girls 17 times – more likely to be in their 40’s than their 20’s.

“We now have a path forward to capture a great part of the genetic variability in autism – even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness,” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium. “These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence.”

References

Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. April 5, 2012. Nature.

O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. April 5, 2012.

Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin CF, Stevens C, Wang LS, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shair K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 5, 2012.

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