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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Similarities and differences between migraines and epilepsy

This article discusses similarities and differences between migraines and epilepsy.

Migraine and epilepsy have several things in common: they often co-occur and share similar symptoms, each is generally undertreated, one is often misdiagnosed as the other,1 and various medications are effective in treating both disorders.2 Recent research may help elucidate the relationship between the two and shed light on more appropriate diagnosis and treatment options.

“Patients with migraine are more likely to have epilepsy, and patients with epilepsy are more likely to experience migraine,” Pavel Klein, MD, director of the Mid-Atlantic Epilepsy and Sleep Center, told Neurology Advisor. In fact, people with seizure disorders are twice as likely to experience migraines which can often lead to misdiagnosis.3

There are commonalities between the two disorders “in clinical symptomatology, particularly with regard to visual and other sensory disturbances, pain, and alterations of consciousness.”3 For instance, if a patient has a migraine that causes focal neurological symptoms — numbness in the arm or face, for example — it can appear to be a seizure. It is also known that stress can trigger seizures, and in a less common scenario, “in someone with very severe migraine, it is possible that the stress of the pain could trigger a seizure,” Klein explained.

The potential reasons for the close relationship between the two disorders are just as varied. “There could be common substrates that cause both headaches and seizures,” said Klein. For example, a condition called benign epilepsy of childhood is commonly associated with migraine and is often misdiagnosed as such,3 while another possibility is that migraine could lead to mild forms of brain damage that increase the risk of epilepsy. Studies have found that MRI of some patients with migraine show small areas of abnormal lesions or scarring.4,5 Researchers are not yet sure of the cause, but it is possible that the scarring is a result of a stroke that is otherwise asymptomatic, and the “scarring leads to reorganization of the local network that could lead to seizures,” said Klein.

What Role Do Genetics Play?

Research published in Epilepsia in 2013 was the first to investigate the role of genetics in the co-occurrence of migraine and epilepsy.5 After testing 730 participants with epilepsy, researchers divided them into two non-overlapping groups — one with migraine with aura and one with migraine without aura — and interviewed participants about their family history of seizure disorders. The results showed that a history of migraine with aura was “significantly increased in enrolled participants with two or more additional affected first-degree relatives,” supporting the researchers' hypothesis of a shared genetic susceptibility to migraine and epilepsy.

“The hope of scientists, caregivers, and families with epilepsy is that genetics will offer a novel and wider understanding of the causes and the pathophysiology of epilepsy,” study co-author Melodie R. Winawer, MD, MS, an associate professor of neurology at Columbia University, told Neurology Advisor.

Approximately two thirds of epilepsy cases have no known cause, and genetic factors may play a critical role in that subset of cases. A ground-breaking aspect of these findings is in regards to reconceptualizing disease boundaries.

“A disorder does not stand alone but can be seen as part of a network of intersecting disorders — in fact, there have been intersecting bidirectional relationships identified for epilepsy, migraine, anxiety, depression, suicidality, and psychosis,” she said. “As we start to understand that some of these disorders are occurring in a network or a cluster rather than standing by themselves, I think it is going to completely transform treatment strategies” and potentially affect preventive efforts.

Ultimately, the knowledge of a shared pathophysiology could lead to the development of new treatment options, as well as recognition of accompanying disorders beyond seizures that can severely impact a patient's quality of life.

After all, failing to treat co-occuring disorders is a disservice to patients, said Winawer. Treatment of any condition — including migraine and epilepsy — should consider potential comorbidities that could worsen or improve depending on the chosen treatment. “We really need to understand epilepsy in its context,” said Winawer. “There is a huge move in the last few years to do that and I think this work is part of that larger question.” 

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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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The pediatric neuro-genetics revolution is here....But ...what can the exome not do?

Does your child have an unknown? The exome is here to stay! 

But...here is what the exome cant do....  JR

10 Things Exome Sequencing Can’t Do–but Why It’s Still Powerful

By Ricki Lewis | May 16, 2012 |  4

The views expressed are those of the author and are not necessarily those of Scientific American.

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Sequencing of the exome – the protein-encoding parts of all the genes – is beginning to dominate the genetics journals as well as headlines, thanks to its ability to diagnose the formerly undiagnosable.

The 2011 Pulitzer Prize in Explanatory Reportinghonored the Milwaukee-Wisconsin Journal Sentinel’s coverage of a 4-year-old whose intestinal disorder was finally diagnosed after sequencing his exome. Once investigators assigned a gene to his symptoms, a bone marrow transplant saved his life. And a just-published study compared the exomes of 12 children with combinations of developmental delay, intellectual disability, and birth defects at the Duke University genetics clinic to reference exomes, revealing 7 mutations, 2 in genes not known to be associated with disease.

In the best-case scenario, mutations revealed by exome sequencing suggest a treatment, as it did for the 4-year-old. But that may be unusual. “We can’t treat most of the Mendelian diseases we know about, so we won’t be able in the near and medium term to treat most of the cases that are diagnosed by sequencing,“ says David Goldstein, PhD, director of the center for human genome variation at Duke and an author of the study. The new National Center for Advancing Translational Sciencesmay add to existing treatments and new drug discovery by providing access to compounds from three major pharmaceutical companies. One study’s reject could be another’s cure.

But for certain types of genetic disorders, exome sequencing won’t help. Understanding what, exactly, an exome is reveals why.

A little less than 2% of the 3.2 billion bases of a human genome encode protein. Most genes consist of sections that are transcribed (into RNA) and translated into protein — these are exons – and sections that are transcribed but are then snipped out before the protein forms – these are introns. The exome, including only exons, is to the genome what a Wikipedia entry about a book is to the actual book. It’s part of the story, albeit an important part.

Admission: Back in the Precambrian period when I was in high school, I read the CliffsNotes version of John Steinbeck’s “The Grapes of Wrath.” I read the actual book many years later, and what a difference! The meager plot summary I read in high school missed the nuances, the connections, the feel and the utter devastation of the final scene.

Analyzing an exome to understand a disease is, in some cases, like reading the CliffsNotes version of a classic book.

The 10 Exceptions

Understanding the limitations of exome sequencing is important because it’s already here. “Be one of the first to get your personal exome sequence,” proclaims 23andMe, about its pilot Exome80x project, offered direct-to-consumer, “for research and educational use only.”'

The first CLIA-certified test, Clinical Diagnostic ExomeTM, became available fromAmbry Genetics earlier this year. A news release announcing the diagnosis of three tough cases calls the technology “essentially a human genome project for an individual patient.” Said CEO Charles Dunlop, “Some of these families have been trying to figure out what was ailing their children for years, and we solved the riddle in weeks.”

But exome sequencing won’t help every family, and here’s my list of reasons why. The technology won’t detect:

1. Genes in all exons. A few exons, such as those buried in stretches of repeats out towards the chromosome tips, aren’t part of exome sequencing chips.

2. Mutations in the handful of genes that reside in mitochondria, rather than in the nucleus.

3. “Structural variants,” such as translocations and inversions, that move or flip DNA but don’t alter the base sequence (detectable other ways).

4. Triplet repeat disorders, such as Huntington’s disease and fragile X syndrome. Their mutations don’t change the DNA base sequence – they expand what’s already there.

5. Other copy number variants will remain beneath the radar, for they too don’t change the sequence, but can increase disease risk.

6. Genes in introns. A mutation that jettisons a base in an intron can have dire consequences: inserting intron sequences into the protein, or obliterating the careful stitching together of exons, dropping gene sections. For example, a mutation in the apoE4 gene, associated with Alzheimer’s disease risk, puts part of an intron into the protein.

7. “Uniparental disomy.” Two mutations from one parent, rather than one from each, appear the same in an exome screen: the kid has two mutations. But whether mutations come from only mom, only dad, or one from each has different consequences for risk to future siblings. In fact, a case of UPD reported in 1988 led to discovery of the cystic fibrosis gene.

8. Control sequences. Much of the human genome tells the exome what to do, like a gigantic instruction manual for a tiny but vital device. For example, mutations in microRNAs cause cancer by silencing various genes, but the DNA that encodes about half of the 1,000 or so microRNAs is intronic – and therefore not on exome chips.

9. Gene-gene (epistatic) interactions. One gene affecting the expression of another can explain why siblings with the same single-gene disease suffer to a different extent. For example, a child with severe spinal muscular atrophy, in which an abnormal protein shortens axons of motor neurons, may have a brother who also inherits SMA but has a milder case thanks to a variant of a second gene that extends axons. Computational tools will need to sort out networks of interacting genes revealed in exome sequencing.

10. Epigenetic changes. Environmental factors can place shielding methyl groups directly onto DNA, blocking expression of certain genes. Starvation during the “Dutch Hunger Winter” of 1945, for example, is associated with schizophrenia in those who were fetuses at the time, due to methylation of certain genes. Exome sequencing picks up DNA sequences – not gene expression.

3 Great Uses for Exome Sequencing

Exome sequencing is of great value in two obvious situations: (a) finding a mutation in a known gene behind an “atypical presentation,” such as Nicholas Volker, the saved Pulitzer boy; and (b), identifying mutations in novel genes, like 2 of the 7 children in the Duke University clinic.

Another application is subtle: exome sequencing reveals incomplete penetrance, a phenomenon in which a person gets lucky. He or she has mutations that should cause a particular trait or illness, but they don’t.

Exome sequencing of parent-child trios can reveal when an apparently healthy parent actually has the same mutation as the sick child, but for some reason escaped the genetic fate. A genetic counselor would use this information in predicting risk for siblings. If mom or dad contributes a mutation, the next kid faces a much higher risk than if the affected child has a new mutation. But there’s a bigger picture. Figuring out how the parent stays healthy can reveal new drug targets, and perhaps even lead to repurposing an existing treatment.

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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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