Study finds association between genetics and sleep behavior

A recent study found an association between genetics and sleep behavior.

The Coriell Personalized Medicine Collaborative (CPMC), a research initiative exploring the utility of genetic information in the clinical setting, has published a study and identified six noteworthy genes that affect human sleep duration.

Available in Volume 168, Issue 8 of the American Journal of Medical Genetics: Neuropsychiatric Genetics, the paper, titled, "Using the Coriell Personalized Medicine Collaborative Data to Conduct a Genome-Wide Association Study of Sleep Duration," draws on data collected from Coriell study participants to establish its findings.

"The fundamental biological purpose of sleep is still not understood," says Dr. Michael Christman, President and CEO of Coriell Institute. "But by engaging a diverse participant population and accumulating rich datasets, the CPMC research study is pursuing the type of insights that will help us learn more about sleep duration and, ultimately, improve human health."

The focus of the CPMC paper was to identify the genes associated with sleep duration and validate the connection between sleep and several demographic and lifestyle factors, including age, gender, weight, ethnicity, exercise, smoking and alcohol. Analysis implicated genes involved in ATP metabolism, circadian rhythms, narcolepsy, sleep cycles in mice, and bear hibernation.

"Researchers widely acknowledge that receiving inadequate sleep is a serious problem and can potentially contribute to a variety of health complications, such as a weakened immune system or an increased risk for obesity and diabetes," says Dr. Laura Scheinfeldt, lead author on the paper and a research scientist at Coriell.

"Individuals who average six hours or less are more susceptible to adverse health issues, and we found that participants enrolled in the CPMC study vary greatly in the amount of sleep they receive," says Dr. Scheinfeldt. "Effectively, by learning more about an individual's sleep patterns and considering environmental and genetic risk factors, physicians may one day be able to identify risks before they occur and target health solutions."

Founded in 2007, the CPMC research study involves a network of physicians, scientists, genetic counselors, and upwards of 8,500 volunteer participants. The study has produced more than 20 publications examining a range of complex human conditions, including cardiovascular disease, breast and lung cancer, and type I and II diabetes.

The Coriell study is committed to advancing the precision medicine discussion by aligning with progressive institutions, including the United States Air Force Medical Service, and sharing noteworthy data.

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Gene mutations could cause up to half of autism cases

A study claims that nearly half of autism cases are caused by a combination of gene mutations.-
Im not surprised. We find our patients with new mutations every day. JR

A team led by researchers at Cold Spring Harbor Laboratory (CSHL) this week publishes in PNAS a new analysis of data on the genetics of autism spectrum disorder (ASD). One commonly held theory is that autism results from the chance combinations of commonly occurring gene mutations, which are otherwise harmless. But the authors' work provides support for a different theory.

They find, instead, further evidence to suggest that devastating "ultra-rare" mutations of genes that they classify as "vulnerable" play a causal role in roughly half of all ASD cases. The vulnerable genes to which they refer harbor what they call an LGD, or likely gene-disruption. These LGD mutations can occur "spontaneously" between generations, and when that happens they are found in the affected child but not found in either parent.

Although LGDs can impair the function of key genes, and in this way have a deleterious impact on health, this is not always the case. The study, whose first author is the quantitative biologist Ivan Iossifov, a CSHL assistant professor and on faculty at the New York Genome Center, finds that "autism genes" - i.e., those that, when mutated, may contribute to an ASD diagnosis - tend to have fewer mutations than most genes in the human gene pool.'

This seems paradoxical, but only on the surface. Iossifov explains that genes with devastating de novo LGD mutations, when they occur in a child and give rise to autism, usually don't remain in the gene pool for more than one generation before they are, in evolutionary terms, purged. This is because those born with severe autism rarely reproduce.

The team's data helps the research community prioritize which genes with LGDs are most likely to play a causal role in ASD. The team pares down a list of about 500 likely causal genes to slightly more than 200 best "candidate" autism genes.

The current study also sheds new light on the transmission to children of LGDs that are carried by parents who harbor them but whose health is nevertheless not severely affected. Such transmission events were observed and documented in the families used in the study, comprising the Simons Simplex Collection (SSC). When parents carry potentially devastating LGD mutations, these are more frequently found in the ASD-affected children than in their unaffected children, and most often come from the mother.

This result supports a theory first published in 2007 by senior author Michael Wigler, a CSHL professor, and Dr. Kenny Ye, a statistician at Albert Einstein College of Medicine. They predicted that unaffected mothers are "carriers" of devastating mutations that are preferentially transmitted to children affected with severe ASD. Females have an as yet unexplained factor that protects them from mutations which, when they occur in males, will be significantly more likely to cause ASD. It is well known that at least four times as many males as females have ASD.

Wigler's 2007 "unified theory" of sporadic autism causation predicted precisely this effect. "Devastating de novo mutations in autism genes should be under strong negative selection pressure," he explains. "And that is among the findings of the paper we're publishing today. Our analysis also revealed that a surprising proportion of rare devastating mutations transmitted by parents occurs in genes expressed in the embryonic brain." This finding tends to support theories suggesting that at least some of the gene mutations with the power to cause ASD occur in genes that are indispensable for normal brain development.

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Study: People with autism may be more susceptible to genetic sleep issues

A study indicates that people with autism might be more susceptible to carrying genetic mutations that changes their circadian clock.

People with autism are twice as likely to carry alterations in genes that regulate the circadian clock, or the body’s sleep-wake cycle, as those without the disorder. The findings, published 6 May in Brain and Development, may help to explain why most children with autism have troubled sleep¹.

Insufficient sleep is known to exacerbate the core symptoms of autism, such as social deficits and repetitive behaviors. The new findings suggest that the relationship between sleep and autism may have genetic roots.

“Sleep disturbance seems to be a main feature of autism,” says lead researcher Takanori Yamagata, professor of pediatric developmental medicine at Jichi Medical University in Shimotsuke, Japan. “My hypothesis is that some circadian genes may be related to some of the genetics of autism.”

To investigate this potential link, Yamagata and his team sequenced 18 genes known to govern the body’s day-night rhythms in 28 children and adults with autism, half of whom have sleep disorders, as well as 23 controls.

They identified a total of 68 mutations in 15 of these genes. About half of the mutations are ‘silent,’ which means they have no effect on the proteins the genes encode. But the other half are ‘missense’ mutations that disrupt the corresponding protein sequence. Nine of the mutations had never been reported before, Yamagata says.

People in the autism group have about twice as many mutations in circadian genes as do members of the control group, regardless of whether they have a sleep disorder.

Within the autism group, the researchers found seven missense mutations among individuals who have sleep disorders and the same number in those who sleep normally. By contrast, just one person in the control group carries a missense mutation in a circadian rhythm gene.

“We detected many mutations only in patients with autism, but almost nothing in the control group,” Yamagata says. “So I think these genes relate to some pathophysiology of autism.”

The researchers then used three types of computer algorithms to predict the impact of the missense mutations on the gene’s function. They found that 25 of the 33 missense mutations are likely to be benign, but 8 appear to be damaging.

One of the analyses found more damaging mutations in the individuals with autism who have sleep disorders than in those who sleep normally.

But the algorithms did not agree on which mutations are likely to be harmful. “Some of these virtual programs may reflect real damage, but they are not perfect,” Yamagata says.

The researchers are investigating whether these eight mutations in circadian genes interfere with brain development in mice. They’re starting with a mutation in a gene called TIMELESS that they found in a 9-year-old boy with autism who sleeps all day and stays awake all night. The boy’s mother, who also struggles with sleep but does not have autism, has the same mutation.

The results of these mouse studies may help elucidate the genetic relationship between sleep and autism.

“It is not yet clear exactly what the basis of this interaction is,” says Mustafa Sahin, associate professor of neurology at Harvard Medical School, who was not involved in the study. “It will be very interesting to further investigate the effects of these sequence variations.”

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Genes may be linked to autism and higher intelligence

What causes autism? A study claims that genes that may indicate an increased autism risk may also indicate a person has higher intelligence.JR

Genes believed to increase the risk of autism may also be linked with higher intelligence, a new study suggests.

Researchers analyzed the DNA of nearly 10,000 people in Scotland and also tested their thinking abilities. On average, those who had genes associated with autism scored slightly higher on the thinking (cognitive) tests.

Having autism-linked genes doesn't mean that people will develop the disorder, the researchers noted.

Similar evidence of an association between autism-linked genes and intelligence was found in previous testing of 921 teens in Australia, according to the study published March 10 in the journal Molecular Psychiatry.

"Our findings show that genetic variation which increases risk for autism is associated with better cognitive ability in non-autistic individuals," said study leader Toni-Kim Clarke, of the University of Edinburgh in Scotland.

"As we begin to understand how genetic variants associated with autism impact brain function, we may begin to further understand the nature of autistic intelligence," Clarke said in a university news release.

Another researcher went further. "This study suggests genes for autism may actually confer, on average, a small intellectual advantage in those who carry them, provided they are not affected by autism," Nick Martin, head of the Genetic Epidemiology Laboratory at the Queensland Institute for Medical Research in Australia, said in the news release.

While 70 percent of people with autism have intellectual disabilities, some people with the disorder have higher-than-average nonverbal intelligence, the study authors noted.

The study only revealed an association, and not a cause-and-effect link, between autism-related genes and intelligence.

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Study: Mutations causing autism are linked to brain development

A study shows that specific mutations that cause autism are linked to how the child's brain develops.

Scientists at the University of California, San Diego School of Medicine have found that mutations that cause autism in children are connected to a pathway that regulates brain development. The research, led by Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry, is published in the February 18 issue of Neuron.

The researchers studied a set of well-known autism mutations called copy number variants or CNVs. They investigated when and where the genes were expressed during brain development. "One surprising thing that we immediately observed was that different CNVs seemed to be turned on in different developmental periods," said Iakoucheva.

Specifically, the scientists noted that one CNV located in a region of the genome known as 16p11.2, contained genes active during the late mid-fetal period. Ultimately, they identified a network of genes that showed a similar pattern of activation including KCTD13 within 16p11.2 and CUL3, a gene from a different chromosome that is also mutated in children with autism.

"The most exciting moment for us was when we realized that the proteins encoded by these genes form a complex that regulates the levels of a third protein, RhoA," said Iakoucheva. Rho proteins play critical roles in neuronal migration and brain morphogenesis at early stages of brain development. "Suddenly, everything came together and made sense."

Further experiments confirmed that CUL3 mutations disrupt interaction with KCTD13, suggesting that 16p11.2 CNV and CUL3 may act via the same RhoA pathway. RhoA levels influence head and body size in zebrafish, a model organism used by geneticists to investigate gene functions. Children with 16p11.2 CNV also have enlarged or decreased head sizes and suffer from obesity or are underweight. "Our model fits perfectly with what we observe in the patients," said Guan Ning Lin, PhD, a fellow in Iakoucheva's laboratory and co-first author with Roser Corominas, PhD.

Interestingly, the RhoA pathway has recently been implicated in a rare form of autism called Timothy syndrome, which is caused by the mutation in a completely different gene. "The fact that three different types of mutations may act via the same pathway is remarkable," said Iakoucheva. "My hope is that we would be able to target it therapeutically."

Iakoucheva and colleagues are planning to test RhoA pathway inhibitors using a stem cell model of autism. "If we can discover the precise mechanism and develop targeted treatments for a handful of children, or even for a single child with autism, I would be happy," she said.

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Twin study shows there is a genetic component to insomnia

According to a study on twins, there is a genetic component to insomnia.

A new study of twins suggests that insomnia in childhood and adolescence is partially explained by genetic factors.

Results show that clinically significant insomnia was moderately heritable at all stages of the longitudinal study. Genetic factors contributed to 33 to 38 percent of the insomnia ratings at the first two stages of the study, when participants had an average age of 8 to 10 years. The heritability of insomnia was 14 to 24 percent at the third and fourth follow-up points, when the average age of participants was 14 to 15 years. The remaining source of variance in the insomnia ratings was the non-shared environment, with no influence of shared, family-wide factors. Further analysis found that genetic influences around age 8 contributed to insomnia at all subsequent stages of development, and that new genetic influences came into play around the age of 10 years.

"Insomnia in youth is moderately related to genetic factors, but the specific genetic factors may change with age," said study author Philip Gehrman, PhD, assistant professor in the Department of Psychology at the University of Pennsylvania in Philadelphia. "We were most surprised by the fact that the genetic factors were not stable over time, so the influence of genes depends on the developmental stage of the child."

Study results are published in the January issue of the journal Sleep.

Insomnia involves difficulty initiating or maintaining sleep, or waking up earlier than desired, according to the American Academy of Sleep Medicine. Children with insomnia may resist going to bed on an appropriate schedule or have difficulty sleeping without intervention by a parent or caregiver. An insomnia disorder results in daytime symptoms such as fatigue, irritability or behavioral problems.

According to the authors, the results suggest that genes controlling the sleep-wake system play a role in childhood insomnia. Therefore, molecular genetic studies are needed to identify this genetic mechanism, which could facilitate the development of targeted treatments.

"These results are important because the causes of insomnia may be different in teens and children, so they may need different treatment approaches," said Gehrman.

The study group comprised 1,412 twin pairs who were between the ages of 8 and 18 years: 739 monozygotic pairs, 672 dizygotic pairs and one pair with unknown zygosity. Participants were followed up at three additional time points. Average ages at each of the four waves of the study were 8, 10, 14 and 15 years. Results were interpreted in terms of the progression across time, rather than differences between discrete age groups. Clinical ratings of insomnia symptoms were assessed by trained clinicians using the Child and Adolescent Psychiatric Assessment and rated according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition.

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Brain development in people with autism

This article discusses how brains develop in people with autism.

Geneticists at Heidelberg University Hospital's Department of Molecular Human Genetics have used a new mouse model to demonstrate the way a certain genetic mutation is linked to a type of autism in humans and affects brain development and behavior. In the brain of genetically altered mice, the protein FOXP1 is not synthesized, which is also the case for individuals with a certain form of autism. Consequently, after birth the brain structures degenerate that play a key role in perception. The mice also exhibited abnormal behavior that is typical of autism. The new mouse model now allows the molecular mechanisms in which FOXP1 plays a role to be explained and the associated changes in the brain to be better understood.

"While these kinds of results from basic research cannot be directly translated into treatment, they are still quite valuable for the affected individuals or in this case, for their parents and family. For many of them, it is important to be able to specifically put a name to the disorder and understand it. It can make dealing with it easier," said Professor Gudrun Rappold, Head of the Department of Molecular Human Genetics at Heidelberg University Hospital and senior author of the article. The results have now been published in a preliminary online version in the journal Molecular Psychiatry in cooperation with Miriam Schneider, Institute of Psychopharmacology at the Central Institute of Mental Health in Mannheim, and Dr. Corentin Le Magueresse, German Cancer Research Center (DKFZ) and Professor Hannah Monyer, Department of Clinical Neurobiology, Heidelberg University Hospital and DKFZ in Heidelberg.

Autism is a congenital perception and information-processing disorder in the brain that is frequently accompanied by intellectual disability and in rare cases, superior intelligence and special gifts such as photographic memory. The disorder is characterized by limited social interaction, repetitive behavior and language impairment. Furthermore, a wide range of other disturbances can occur. "Today, in addition to the defect in the FOXP1 gene, we are familiar with other genetic mutations that cause autism or increase the risk of this kind of disorder. However, we are only able to understand how they affect the molecular processes in the neurons, brain development and behavior for a few of these mutations," Rappold said.

This is also the case for FOXP1. Back in 2010, clear signs that structural flaws in this protein play a role in autism and mental disability had been discovered. But what role does it play in the healthy brain? What signal pathways is it involved in? Which other proteins does it interact with and exactly what damage is caused by its absence? The new mouse model has helped to shed light on these questions. The researchers discovered that the mice were born with a normally developed brain for the most part. During the course of the first weeks of life, the striatum, which is important for perception and behavior, degenerates. In a centrally located brain structure as well -- the hippocampus -- which is indispensable for developing long-term memory and recall, microscopically visible changes occur that can also impact signal processing. It could be proven, for example, that in the affected neurons the impulse conduction is changed through which signals are transmitted between neurons.

In addition to the striatum, the ventricles of the brain are degenerated; these are adjacent structures in the murine brain. "Enlarged ventricles were also detected in humans with a FOXP1 mutation," explained Dr. Claire Bacon, who works in the Molecular Human Genetics Department and is first author of the publication. The changes also trigger abnormal behavior that is comparable to the symptoms of autistic patients. The mice barely noticed their fellow mice and did not attempt to make contact to them. Further symptoms include stereotypical compulsive repetitive behaviors, hyperactivity and disturbed nestbuilding behavior.

The researchers now intend to study to what extent the communication of noise by FOXP1 mice (mice communicate via noises in the ultrasonic range) is impaired and whether there are also parallels to the disturbances in patients with FOXP1 mutation in this area as well. In addition, they plan to characterize the newly identified genes impacted by the FOXP1 in the brain and find out which signaling cascades and response paths are disrupted. In this way, they hope to find starting points for a specific treatment. "However, we first have to understand exactly how these changes occur before we can develop treatment concepts," Rappold stressed.

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Study: Genetic cause for childhood epilepsy

A recent study found a new genetic cause for childhood epilepsy.

A research team led by scientists at the Scripps Translational Science Institute (STSI) has used whole genome sequencing to identify a new genetic cause of a severe, rare and complex form of epilepsy that becomes evident in early childhood and can lead to early death.

The researchers found a mutation in the KCNB1 gene after mapping the DNA of a 10-year-old girl who suffers from epileptic encephalopathy. The findings were reported in the October edition of the peer-reviewed medical journal Annals of Neurology.

The KCNB1 gene encodes the Kv2.1 voltage-gated potassium channel, which regulates the flow of potassium ions through neurons, affecting how the cells communicate with one another. The voltage-gated potassium channel also regulates potassium flow in the kidney, which affects potassium excretion and fluid balance.

The link between the KCNB1 mutation and epileptic encephalopathy has opened new treatment options for the young patient, said Robert Bjork, MD, her physician and a member of the Scripps Memorial Hospital La Jolla staff.

Earlier this year, "her prognosis was grim and appeared hopeless when she was experiencing many convulsive seizures, could barely eat or drink, and had 'drop attacks' where she would abruptly drop to the floor up to 25 times a day," he said.

Given continued close medical monitoring, an expanded medical treatment team, a uniquely designed home-school program and avoidance of dehydration, Dr. Bjork is optimistic that she can be kept out of harm's way and her status will improve over time.

Case part of IDIOM Study

The research was part of STSI's IDIOM Study, an ongoing project that uses whole genome sequencing to help determine the causes and treatments of idiopathic diseases -- those serious, rare and perplexing health conditions that defy a diagnosis and standard treatment.

"We are continuing to learn the impressive power of whole genome sequencing for making a difficult -- and heretofore impossible -- diagnosis," said Eric Topol, MD, who is the director of STSI and chief academic officer of Scripps Health.

STSI is a National Institutes of Health sponsored consortium led by Scripps Health in collaboration with The Scripps Research Institute (TSRI). Through this innovative partnership, Scripps is leading the effort to translate genetic and wireless medical technologies into high-quality, cost-effective treatments and diagnostics for patients.

To validate their findings, STSI researchers teamed with colleagues at Northwestern University Feinberg School of Medicine in Chicago, who had previously looked at similar KCNB1 mutations. The Northwestern colleagues were listed as co-authors of the journal report, along with contributors from the University of California, San Diego; Kennedy Krieger Institute; Johns Hopkins University; and Vanderbilt University.

Potential benefits of discovery

The benefits of discovering the role of KCNB1 mutations in epileptic encephalopathy reach far beyond the STSI research case, said Ali Torkamani, director of genome informatics at STSI and an assistant professor of integrative, structural and computational biology at TSRI.

"These findings can serve as a model on how to treat this particular form of epilepsy in other patients," he said. "The KCNB1 mutations also might have a role as a diagnostic biomarker for this condition, and they could help to direct the discovery and testing of new drugs to treat epilepsy."

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Mouse models help find new genetic links to autism

New genetic links to autism have been found using mouse models.

With the help of mouse models, induced pluripotent stem cells (iPSCs) and the "tooth fairy," researchers at the University of California, San Diego School of Medicine have implicated a new gene in idiopathic or non-syndromic autism. The gene is associated with Rett syndrome, a syndromic form of autism, suggesting that different types of autism spectrum disorder (ASD) may share similar molecular pathways.

"I see this research as an example of what can be done for cases of non-syndromic autism, which lack a definitive group of identifying symptoms or characteristics," said principal investigator Alysson Muotri, PhD, associate professor in the UC San Diego departments of Pediatrics and Cellular and Molecular Medicine. "One can take advantage of genomics to map all mutant genes in the patient and then use their own iPSCs to measure the impact of these mutations in relevant cell types. Moreover, the study of brain cells derived from these iPSCs can reveal potential therapeutic drugs tailored to the individual. It is the rise of personalized medicine for mental/neurological disorders."

But to effectively exploit iPSCs as a diagnostic tool, Muotri said researchers "need to compare neurons derived from hundreds or thousands of other autistic individuals." Enter the "Tooth Fairy Project," in which parents are encouraged TO register for a "Fairy Tooth Kit," which involves sending researchers like Muotri a discarded baby tooth from their autistic child. Scientists extract dental pulp cells from the tooth and differentiate them into iPSC-derived neurons for study.

"There is an interesting story behind every single tooth that arrives in the lab," said Muotri.

The latest findings, in fact, are the result of Muotri's first tooth fairy donor. He and colleagues identified a de novo or new disruption in one of the two copies of the TRPC6 gene in iPSC-derived neurons of a non-syndromic autistic child. They confirmed with mouse models that mutations in TRPC6 resulted in altered neuronal development, morphology and function. They also noted that the damaging effects of reduced TRPC6 could be rectified with a treatment of hyperforin, a TRPC6-specific agonist that acts by stimulating the functional TRPC6 in neurons, suggesting a potential drug therapy for some ASD patients.

The researchers also found that MeCP2 levels affect TRPC6 expression. Mutations in the gene MeCP2, which encodes for a protein vital to the normal function of nerve cells, cause Rett syndrome, revealing common pathways among ASD.

"Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model," Muotri said. "This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells."

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Many genes are involved in autism

Two large-scale genetic studies show that many genes are involved in autism.

Two major genetic studies of autism, led in part by UC San Francisco scientists and involving more than 50 laboratories worldwide, have newly implicated dozens of genes in the disorder. The research shows that rare mutations in these genes affect communication networks in the brain and compromise fundamental biological mechanisms that govern whether, when, and how genes are activated overall.

The two new studies, published in the advance online edition of Nature on October 29, 2014, tied mutations in more than 100 genes to autism. Sixty of these genes met a “high-confidence” threshold indicating that there is a greater than 90 percent chance that mutations in those genes contribute to autism risk.

The majority of the mutations identified in the new studies are de novo (Latin for “afresh”) mutations, meaning they are not present in unaffected parents’ genomes but arise spontaneously in a single sperm or egg cell just prior to conception of a child.

The genes implicated in the new studies fall into three broad classes: they are involved in the formation and function of synapses, which are sites of nerve-cell communication in the brain; they regulate, via a process called transcription, how the instructions in other genes are relayed to the protein-making machinery in cells; and they affect how DNA is wound up and packed into cells in a structure known as chromatin. Because modifications of chromatin structure are known to lead to changes in how genes are expressed, mutations that alter chromatin, like those that affect transcription, would be expected to affect the activity of many genes.

One of the new Nature studies made use of data from the Simons Simplex Collection (SSC), a permanent repository of DNA samples from nearly 3,000 families created by the Simons Foundation Autism Research Initiative. Each SSC family has one child affected with autism, parents unaffected by the disorder and, in a large proportion, unaffected siblings. The second study was conducted under the auspices of the Autism Sequencing Consortium (ASC), an initiative supported by the National Institute of Mental Health that allows scientists from around the world to collaborate on large genomic studies that couldn’t be done by individual labs.

“Before these studies, only 11 autism genes had been identified with high confidence, and we have now more than quadrupled that number,” said Stephan Sanders, PhD, assistant professor of psychiatry at UCSF, co-first author on the SSC study, and co-author on the ASC study. Based on recent trends, Sanders estimates that gene discovery will continue at a quickening pace, with as many as 1,000 genes ultimately associated with autism risk.

“There has been a lot of concern that 1,000 genes means 1,000 different treatments, but I think the news is much brighter than that,” said Matthew W. State, MD, PhD, chair and Oberndorf Family Distinguished Professor in Psychiatry at UCSF. State was co-leader of the Nature study focusing on the SSC and a senior participant in the study organized by the ASC, of which he is a co-founder. ”There is already strong evidence that these mutations converge on a much smaller number key biological functions. We now need to focus on these points of convergence to begin to develop novel treatments.”

Autism, which is marked by deficits in social interaction and language development, as well as by repetitive behaviors and restricted interests, is known to have a strong genetic component. But until a few years ago, genomic research had failed to decisively associate individual genes with the disorder.

The two new studies highlight the factors that have radically changed that picture, State said. One is the advent of next-generation sequencing (NGS), which allows researchers to read each of the “letters” in the DNA code at unprecedented speed. Another is the establishment of the SSC; a 2007 study had suggested that de novo mutations would play a significant role in autism risk, and the SSC was specifically designed to help test that idea by allowing for close comparisons between children with autism and their unaffected parents and siblings. Lastly, collaborative initiatives such as the ASC are enabling teams of researchers around the world to work closely together, pooling their resources to create large datasets with sufficient statistical power to draw valid conclusions.

The large research teams behind each of the two new studies used a form of NGS known as “whole-exome” sequencing, a letter-by-letter analysis of just the portion of the genome that encodes proteins.

In November 2013, a study led by A. Jeremy Willsey, a graduate student in State’s lab, showed that the functional roles of the nine high-confidence autism risk genes that had then been discovered all converged on a single cell type in a particular place in the brain at a particular time during fetal development. Willsey is a co-author on both of the new Nature studies, which State believes will further accelerate our understanding of how the myriad of genes involved in autism affect basic biological pathways in the brain.

“These genes carry really large effects,” State said. “That we now have a bounty of dozens of genes, and a clear path forward to find perhaps hundreds more, provides an incredible foundation for understanding the biology of autism and finding new treatments.”

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Language and attention gene variations in those with ADHD

A study shows that in those with ADHD, gene variations are seen specifically in language and attention.

Are deficits in attention limited to those with attention-deficit/hyperactivity disorder (ADHD) or is there a spectrum of attention function in the general population? The answer to this question has implications for psychiatric diagnoses and perhaps for society, broadly.

A new study published in the current issue of Biological Psychiatry, by researchers at Cardiff University School of Medicine and the University of Bristol, suggests that there is a spectrum of attention, hyperactivity/impulsiveness and language function in society, with varying degrees of these impairments associated with clusters of genes linked with the risk for ADHD.

Viewing these functions as dimensions or spectrums contrasts with a traditional view of ADHD as a disease category.

To answer this question, researchers led by senior author Dr. Anita Thapar used genetic data from patients with ADHD as well as data from the Avon Longitudinal Study of Parents and Children (ALSPAC). The ALSPAC is based in England and is a large, ongoing study of parents and children followed since birth in the early '90s.

They created polygenic risk scores -- a 'composite' score of genetic effects that forms an index of genetic risk -- of ADHD for 8,229 ALSPAC participants.

They found that polygenic risk for ADHD was positively associated with higher levels of traits of hyperactivity/impulsiveness and attention at ages 7 and 10 in the general population. It was also negatively associated with pragmatic language abilities, e.g., the ability to appropriately use language in social settings.

"Our research finds that a set of genetic risks identified from UK patients with a clinical diagnosis of childhood ADHD also predicted higher levels of developmental difficulties in children from a UK population cohort, the ALSPAC," said Thapar.

First author Joanna Martin added, "Our results provide support at a genetic level for the suggestion that ADHD diagnosis represents the extreme of a spectrum of difficulties. The results are also important as they suggest that the same sets of genetic risks contribute to different aspects of child development which are characteristic features of neurodevelopmental disorders such as ADHD and autism spectrum disorder."

"It may be the case that at some point polygenic risk scores may, in conjunction with other clinical information, help to identify children who will struggle in school and other demanding contexts due to attention difficulties," said Dr. John Krystal, Editor of Biological Psychiatry. "The objective of this type of early identification would be to provide children who are at risk for difficulties with support so that problems at school may be prevented."

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Mutations and severe childhood epilepsies

An international study pinpoints a specific gene mutation that causes severe types of childhood epilepsies.

An international research team has identified gene mutations causing severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” said pediatric neurologist Dennis Dlugos, M.D., director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and a study co-author. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

Multiple researchers from the U.S. and Europe performed the research, the largest collaborative study to date focused on the genetic roots of severe epilepsies. The scientists reported their results online today in the American Journal of Human Genetics (epub ahead of print).

Two international research consortia collaborated on the study—the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the European EuroEPINOMICS consortium. The genetic analysis was performed at the NINDS-funded Epi4K Sequencing, Biostatistics, and Bioinformatics Core at Duke University, led by Drs. David Goldstein, Erin Heinzen and Andrew Allen.

The current study added to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies. The researchers sequenced the exomes (those portions of DNA that code for proteins) of 356 patients with severe childhood epilepsies, as well as their parents. The scientists looked for “de novo” mutations—those that arose in affected children, but not in their parents. In all, they identified 429 such de novo mutations.

In 12 percent of the children, these mutations were considered to unequivocally cause the child’s epilepsy. In addition to several known genes for childhood epilepsies, the study team found strong evidence for additional novel genes, many of which are involved in the function of the synapse.

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the U.S. Up to one third of all epilepsies are resistant to treatment with antiepileptic medication and may be associated with other disabilities such as intellectual impairment and autism. Severe epilepsies are particularly devastating in children. In many patients with severe epilepsies, no cause for the seizures can be identified, but there is increasing evidence that genetic factors may play a causal role.

The research teams used a method called family-based exome sequencing, which looks at the part of the human genome that carries the blueprints for proteins. When comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify the de novo changes that arose in the genomes of the affected children. While de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes are necessarily disease-causing.

“Everybody has one or two de novo mutations and it is our task to find those changes that cause disease,” said co-author Ingo Helbig, M.D., now at The Children’s Hospital of Philadelphia. “We pulled out those genes that have more mutations in patients with epilepsy than you would expect by chance. These genes will hopefully tell us a bit more about the underlying disease mechanisms and how we can address them with new treatments.” As a member of the European EuroEPINOMICS consortium, Helbig was a co-initiator of the transatlantic collaboration that conducted the study. Helbig is also a member of the Genetics Commission of the International League Against Epilepsy (ILAE).

The most surprising finding in the study by the international research group is a gene called DNM1, which was found to be mutated in five patients. The gene carries the code for dynamin-1, a structural protein that plays a role in shuttling small vesicles between the body of the neuron and the synapse. These vesicles are structures that contain neurotransmitters, chemical signals crucial to communication between nerve cells. When the researchers looked on a network level, they found that many of the genes that were found to be mutated in patients had a clear connection with the function of the synapse.

This research finding, says Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he added.

A spokesperson for Citizens United for Research in Epilepsy (CURE), a non-profit organization dedicated to finding a cure for epilepsy and increasing awareness of the disease, applauded this study. Dr. Tracy Dixon-Salazar, Associate Research Director at CURE and mother of a child with severe genetic epilepsy, added, “It is exciting to see the big consortia put the genomic data of almost 400 patients together. This clearly highlights that by working together we can find new genes faster, helping us to explain what causes this often devastating disease in children.”

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Why does autism occur?

This article explains the factors that influence autism development, such as genetics, brain imaging, and cognition, and describes how they play into autism development.

An analysis of autism research covering genetics, brain imaging, and cognition led by Laurent Mottron of the University of Montreal has overhauled our understanding of why autism potentially occurs, develops and results in a diversity of symptoms. The team of senior academics involved in the project calls it the "Trigger-Threshold-Target'' model.

Brain plasticity refers to the brain's ability to respond and remodel itself, and this model is based on the idea that autism is a genetically induced plastic reaction. The trigger is multiple brain plasticity-enhancing genetic mutations that may or may not combine with a lowered genetic threshold for brain plasticity to produce either intellectual disability alone, autism, or autism without intellectual disability. The model confirms that the autistic brain develops with enhanced processing of certain types of information, which results in the brain searching for materials that possess the qualities it prefers and neglecting materials that don't. "One of the consequences of our new model will be to focus early childhood intervention on developing the particular strengths of the child's brain, rather than exclusively trying to correct missing behaviors, a practice that may be a waste of a once in a lifetime opportunity," Mottron said.

Mottron and his colleagues developed the model by examining the effect of mutations involved in autism together with the brain activity of autistic people as they undertake perceptual tasks. "Geneticists, using animals implanted with the mutations involved in autism, have found that most of them enhance synaptic plasticity -- the capacity of brain cells to create connections when new information is encountered. In parallel, our group and others have established that autism represents an altered balance between the processing of social and non-social information, i.e. the interest, performance and brain activity, in favor of non-social information," Mottron explained. "The Trigger-Threshold-Target model builds a bridge between these two series of facts, using the neuro cognitive effects of sensory deprivation to resolve the missing link between them."

The various superiorities that subgroups of autistic people present in perception or in language indicates that an autistic infant's brain adapts to the information it is given in a strikingly similar way to sensory-deprived people. A blind infant's brain compensate the lack of visual input by developing enhanced auditory processing abilities for example, and a deaf infant readapts to process visual inputs in a more refined fashion. Similarly, cognitive and brain imaging studies of autistic people work reveal enhanced activity, connectivity and structural modifications in the perceptive areas of the brain. Differences in the domain of information "targeted'' by these plastic processes are associated with the particular pattern of strengths and weaknesses of each autistic individual. "Speech and social impairment in some autistic toddlers may not be the result of a primary brain dysfunction of the mechanisms related to these abilities, but the result of their early neglect," Mottron said. "Our model suggests that the autistic superior perceptual processing compete with speech learning because neural resources are oriented towards the perceptual dimensions of language, neglecting its linguistic dimensions. Alternatively, for other subgroups of autistic people, known as Asperger, it's speech that's overdeveloped. In both cases, the overdeveloped function outcompetes social cognition for brain resources, resulting in a late development of social skills."

The model provides insight into the presence or absence of intellectual disability, which when causative mutation alter the function of brain cell networking. Rather than simply triggering a normal but enhanced plastic reaction, these mutations cause neurons to connect in a way that does not exist in non-autistic people. When brain cell networking functions normally, only the allocation of brain resources is changed.

As is the case with all children, environment and stimulation have an effect on the development and organization of an autistic child's brain. "Most early intervention programs adopt a restorative approach by working on aspects like social interest. However this focus may monopolize resources in favor of material that the child process with more difficulties, Mottron said. "We believe that early intervention for autistic children should take inspiration from the experience of congenitally deaf children, whose early exposure to sign language has a hugely positive effect on their language abilities. Interventions should therefore focus on identifying and harnessing the autistic child's strengths, like written language." By indicating that autistic ''restricted interests'' result from cerebral plasticity, this model suggest that they have an adaptive value and should therefore be the focus of intervention strategies for autism.

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Common genes form genetic risk for autism

Common genes were found to comprise of a person's genetic risk for autism.

Using new statistical tools, Carnegie Mellon University's Kathryn Roeder has led an international team of researchers to discover that most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches.

Published in the July 20 issue of the journal Nature Genetics, the study found that about 52 percent of autism was traced to common genes and rarely inherited variations, with spontaneous mutations contributing a modest 2.6 percent of the total risk. The research team -- from the Population-Based-Autism Genetics and Environment Study (PAGES) Consortium -- used data from Sweden's universal health registry to compare roughly 3,000 subjects, including autistic individuals and a control group. The largest study of its kind to date, the team also showed that inheritability outweighs environmental risk.

"From this study, we can see that genetics plays a major role in the development of autism compared to environmental risk factors, making autism more like height than we thought -- many small risk factors add up, each pushing a person further out on the spectrum," said Roeder, professor of statistics and computational biology at Carnegie Mellon and a leading expert on statistical genomics and the genetic basis of complex disease. "These findings could not have happened without statistics, and now we must build off of what we learned and use statistical approaches to determine where to put future resources, and decide what is the most beneficial direction to pursue to further pinpoint what causes autism."

Although autism is thought to be caused by an interplay of genetic and other factors, including environmental forces, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive, until now. With this new study, the researchers believe that autism genetics is beginning to catch up.

Led by Roeder, the researchers used new statistical methods -- such as machine learning techniques and dimension reduction tools -- that allowed them to more reliably sort out the inheritability of the disorder. In addition, they were able to compare their results with a parallel family-based study in the Swedish population, which took into account data from twins, cousins, and factors like age of the father at birth and parents' psychiatric history. A best-fit statistical model took form, based mostly on additive genetic and non-shared environmental effects.

"Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now see the forest for the trees," said Thomas R. Insel, director of the National Institute of Mental Health (NIMH). "Knowing the nature of the genetic risk will help focus the search for clues to the molecular roots of the disorder."

Thomas Lehner, chief of the NIMH's Genomics Research Branch, agreed and added, "This is a different kind of analysis than employed in previous studies. Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry."

Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications of genetic material and spontaneous mutations. The researchers said even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches make them important clues to understanding the molecular underpinnings of the disorder.

"Within a given family, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member," said Joseph Buxbaum, the study's first author and professor of psychiatry, neuroscience, genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai (ISMMS). "The family may have common variation that puts it at risk, but if there is also a 'de novo' mutation on top of that, it could push an individual over the edge. So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder."

Current studies have not been large enough to reveal the many common genetic variants that increase the risk of autism. On their own, none of these common variants will have sufficient impact to cause autism.

"Our group in Pittsburgh is working to develop a model that predicts the genetic risk for a family based on a myriad of small effects. Such a score could provide clinical benefit to families," Roeder said.

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The CHD8 mutation was found to be a genetic link to Autism

A study found that the CHD8 mutation is a genetic link to autism.

In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. The results are being published in Cell magazine July 3, 2014: "Disruptive CHD8 Mutations Define a Subtype of Autism in Early Development."

"We finally got a clear cut case of an autism specific gene," said Raphael Bernier, the lead author, and UW associate professor in the Department of Psychiatry and Behavioral Sciences and the clinical director of the Autism Center at Seattle Children's.

Bernier said people with a mutation in the CHD8 gene have a very "strong likelihood" that they will have autism marked by gastrointestinal disorders, a larger head and wide set eyes.

In their study of 6,176 children with autism spectrum disorder, researchers found 15 had a CHD8 mutation and all these cases had similar characteristics in appearance and issues with sleep disturbance and gastrointestinal problems.

Bernier and his team interviewed all 15 cases with CHD8 mutations.

To confirm the findings, researchers worked with scientists at Duke University who do zebra fish modeling. The researchers disrupted the CHD8 gene in the fish and the fish developed large heads and wide set eyes. They then fed the fish fluorescent pellets and found that the fish had problems discarding food waste and were constipated.

Bernier said this is the first time researchers have shown a definitive cause of autism to a genetic mutation. Previously identified genetic events like Fragile X, which account for a greater number of autism cases, are associated with other impairments, such as intellectual disability, more than autism. Although less than half a percent of all kids will have this kind of autism related to the CHD8 mutation, Bernier said there are lots of implications from this study.

"This will be a game changer in the way scientists are researching autism," he said.

The results could lead the way to a "genetics-first approach" that could uncover hundreds more genetic mutations and lead to genetic testing. Genetic testing could be offered to families as a way of guiding them on what to expect and how to care for their child. Currently, autism is diagnosed based on behavior, said Bernier.

In the short term, Bernier said, clinicians can pay attention to the small population with this CHD8 mutation and provide targeted treatment.

Researchers say autism has currently been linked to different types of genetic events. The most commonly researched genetic events associated with autism are chromosomal re-arrangements, called "copy number variations," in which a chunk of chromosome is copied or deleted. But no one rearrangement affects more than 1 percent of all autism cases. While these copy number events are associated with autism, they do not have a definitive link, or as they say among researchers, a "strong penetrance."

Then there are genetic mutations in which a gene has been disrupted and is not creating the kind of protein it should create. The CHD8 gene mutation is the first gene mutation to show a very strong penetrance linked to a certain subtype of autism.

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Study: Century-old anti-parasitic medication may reverse symptoms of autism... in mice...temporarily

A study looks into a century-old sleep medication and found that it reversed the symptoms of autism in mice.

In a further test of a novel theory that suggests autism is the consequence of abnormal cell communication, researchers at the University of California, San Diego School of Medicine report that an almost century-old drug approved for treating sleeping sickness also restores normal cellular signaling in a mouse model of autism, reversing symptoms of the neurological disorder in animals that were the human biological age equivalent of 30 years old.

The findings, published in the June 17, 2014 online issue of Translational Psychiatry, follow up on similar research published last year by senior author Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology, and colleagues.

Naviaux said the findings fit neatly with the idea that autism is caused by a multitude of interconnected factors: "Twenty percent of the known factors associated with autism are genetic, but most are not. It's wrong to think of genes and the environment as separate and independent factors. Genes and environmental factors interact. The net result of this interaction is metabolism."

Naviaux, who is co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego, said one of the universal symptoms of autism is metabolic disturbances. "Cells have a halo of metabolites (small molecules involved in metabolism, the set of chemical processes that maintain life) and nucleotides surrounding them. These create a sort of chemical glow that broadcasts the state of health of the cell."

Cells threatened or damaged by microbes, such as viruses or bacteria, or by physical forces or by chemicals, such as pollutants, react defensively, a part of the normal immune response, Naviaux said. Their membranes stiffen. Internal metabolic processes are altered, most notably mitochondria -- the cells' critical "power plants." And communications between cells are dramatically reduced. This is the "cell danger response," said Naviaux, and if it persists, the result can be lasting, diverse impairment. If it occurs during childhood, for example, neurodevelopment is delayed.

"Cells behave like countries at war," said Naviaux. "When a threat begins, they harden their borders. They don't trust their neighbors. But without constant communication with the outside, cells begin to function differently. In the case of neurons, it might be by making fewer or too many connections. One way to look at this related to autism is this: When cells stop talking to each other, children stop talking."

Naviaux and colleagues have focused on a cellular signaling system linked to both mitochondrial function and to the cell's innate immune function. Specifically, they have zeroed in on the role of nucleotides like adenosine triphosphate (ATP) and other signaling mitokines -- molecules generated by distressed mitochondria. These mitokines have separate metabolic functions outside of the cell where they bind to and regulate receptors present on every cell of the body. Nineteen types of so-called purinergic receptors are known to be stimulated by these extracellular nucleotides, and the receptors are known to control a broad range of biological characteristics with relevance to autism, such as impaired language and social skills.

In their latest work, Naviaux again tested the effect of suramin, a well-known inhibitor of purinergic signaling that was first synthesized in 1916 and is used to treat trypanosomiasis or African sleeping sickness, a parasitic disease. They found that suramin blocked the extracellular signaling pathway used by ATP and other mitokines in a mouse model of autism spectrum disorder (ASD), ending the cell danger response and related inflammation. Cells subsequently began behaving normally and autism-like behaviors and metabolism in the mice were corrected.

However, the biological and behavioral benefits of suramin were not permanent, nor preventive. A single dose remained effective in the mice for about five weeks, and then washed out. Moreover, suramin cannot be taken long-term since it can result in anemia and adrenal gland dysfunction.

Still, Naviaux said these and earlier findings are sufficiently encouraging to soon launch a small phase 1 clinical trial with children who have ASD. He expects the trial to begin later this year.

"Obviously correcting abnormalities in a mouse is a long way from a cure in humans, but we think this approach -- antipurinergic therapy -- is a new and fresh way to think about and address the challenge of autism.

"Our work doesn't contradict what others have discovered or done. It's another perspective. Our idea is that this kind of treatment -- eliminating a basic, underlying metabolic dysfunction -- removes a hurdle that might make other non-drug behavioral and developmental therapies of autism more effective. The discovery that a single dose of medicine can fundamentally reset metabolism for weeks means that newer and safer drugs might not need to be given chronically. Members of this new class of medicines might need to be given only intermittently during sensitive developmental windows to unblock metabolism and permit improved development in response to many kinds of behavioral and occupational therapies, and to natural play."

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Study: Genes link circadian clock to eating schedule

A study found that specific genes link a person's circadian clock to their eating schedule.

For most people, the urge to eat a meal or snack comes at a few, predictable times during the waking part of the day. But for those with a rare syndrome, hunger comes at unwanted hours, interrupts sleep and causes overeating.

Now, Salk scientists have discovered a pair of genes that normally keeps eating schedules in sync with daily sleep rhythms, and, when mutated, may play a role in so-called night eating syndrome. In mice with mutations in one of the genes, eating patterns are shifted, leading to unusual mealtimes and weight gain. The results were published in this month's Cell Reports.

"We really never expected that we would be able to decouple the sleep-wake cycle and the eating cycle, especially with a simple mutation," says senior study author Satchidananda Panda, an associate professor in Salk's Regulatory Biology Laboratory. "It opens up a whole lot of future questions about how these cycles are regulated."

More than a decade ago, researchers discovered that individuals with an inherited sleep disorder often carry a particular mutation in a protein called PER2. The mutation is in an area of the protein that can be phosphorylated -- the ability to bond with a phosphate chemical that changes the protein's function. Humans have three PER, or period, genes, all thought to play a role in the daily circadian clock and all containing the same phosphorylation spot.

The Salk scientists joined forces with a Chinese team led by Ying Xu of Nanjing University to test whether mutations in the equivalent area of PER1 would have the same effect as those in PER2 that caused the sleep disorder. So they bred mice to lack the mouse period genes, and added in a human PER1 or PER2 with a mutation in the phosphorylation site. As expected, mice with a mutated PER2 had sleep defects, dozing off earlier than usual. The same wasn't true for PER1 mutations though.

"In the mice without PER1, there was no obvious defect in their sleep-wake cycles," says Panda. "Instead, when we looked at their metabolism, we suddenly saw drastic changes."

Mice with the PER1 phosphorylation defects ate earlier than other mice -- causing them to wake up and snack before their sleep cycle was over -- and ate more food throughout their normal waking period. When the researchers looked at the molecular details of the PER1 protein, they found that the mutated PER1 led to lower protein levels during the sleeping period, higher levels during the waking period, and a faster degradation of protein whenever it was produced by cells.

Panda and his colleagues hypothesize that normally, PER1 and PER2 are kept synchronized since they have identical phosphorylation sites -- they are turned on and off at the same times, keeping sleep and eating cycles aligned. But a mutation in one of the genes could break this link, and cause off-cycle eating or sleeping.

"For a long time, people discounted night eating syndrome as not real," says Panda. "These results in mice suggest that it could actually be a genetic basis for the syndrome." The researchers haven't yet tested, however, whether any humans with night eating syndrome have mutations in PER1.

When Panda and Xu's team restricted access to food, providing it only at the mice's normal meal times, they found that even with a genetic mutation in PER1, mice could maintain a normal weight. Over a 10-week follow-up, these mice -- with a PER1 mutation but timed access to food -- showed no differences to control animals. This tells the researchers that the weight gain caused by PER1 is entirely caused by meal mistiming, not other metabolic defects.

Next, they hope to study exactly how PER1 controls appetite and eating behavior -- whether its molecular actions work through the liver, fat cells, brain or other organs.

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