autism and genetics

Posted on August 22, 2019August 22, 2019 Autism

Study identifies 69 genes that increase the risk for autism

UCLA-led team compares DNA of children with the disorder to that of their siblings and parents

A UCLA-led research team has identified dozens of genes, including 16 new genes, that increase the risk of autism spectrum disorder. The findings, published in the journal Cell, were based on a study of families with at least two children with autism.

Researchers from UCLA, Stanford University and three other institutions used a technique called whole genome sequencing to map the DNA of 2,300 people from nearly 500 families. They found 69 genes that increase the risk for autism spectrum disorder; 16 of those genes were not previously suspected to be associated with a risk for autism.

Researchers also identified several hundred genes they suspect may increase the risk of autism based on their proximity to genes previously identified to carry an increased risk. The study analyses further revealed several new biological pathways not previously identified in studies of autism.

The findings shed light on how genetic variants or mutations — the differences that make each person’s genome unique — are passed from parents to children affected with autism, said the study’s co-lead author Elizabeth Ruzzo, a UCLA postdoctoral scholar. Former UCLA postdoctoral scholar Laura Pérez-Cano is the study’s other co-lead author.

“When we look at parents of autistic children and compare them to individuals without autism, we find that those parents carry significantly more, rare and highly damaging gene variants,” Ruzzo said. “Interestingly, these variants are frequently passed from the parents to all of the affected children but none of the unaffected children, which tells us that they are significantly increasing the risk of autism.”

Of the children in the study, 960 have autism and 217 children do not. That enabled researchers to analyze the genetic differences between children with and without autism across different families.

“Studying families with multiple children affected with autism increased our ability to detect inherited mutations in autism spectrum disorder,” said Dr. Daniel Geschwind, senior, corresponding author of the study and the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology and Psychiatry at the David Geffen School of Medicine of UCLA.

“We show a substantial difference between the types of mutations that occur in different types of families, such as those that have more than one affected child versus those having only one child with ASD,” said Geschwind, who also was the study’s co-principal investigator and director of the UCLA Center for Autism Research and Treatment and director of the Institute of Precision Health at UCLA.

The research also found that the 16 genes newly determined to be associated with an increased risk for autism form a network with previously identified ASD risk genes. The way they interact with one another further heightens the risk, said the study’s co-senior author and co-principal investigator Dennis Wall, a Stanford University School of Medicine associate professor of pediatrics and of biomedical data science.

“They associate with each other more tightly than we’d expect by chance,” he said. “These genes are talking to each other, and those interactions appear to be an important link to autism spectrum disorder.”

The nearly 600 genes researchers suspect as carrying an increased risk of autism were identified through “guilt by association,” or through their interactions with other genes that already have been shown to carry an increased autism risk, Ruzzo said.

“And although not all of those genes will be found to increase the risk for autism, our analysis indicates that future studies will provide support for many of these genes,” she said.

The families studied are part of the Autism Genetic Resource Exchange (AGRE), which was originally developed nearly two decades ago by researchers and the National Institutes of Health in collaboration with Cure Autism Now, which is now a program of Autism Speaks.

Autism is a spectrum of neurological disorders characterized by difficulties with communication and social interaction. Geschwind has been working to identify the genetic causes and biological mechanisms of the disorder for more than a decade, and led the original development of the AGRE resource that was used in this study in the late 1990s. In 2018, he and colleagues at UCLA received their second, five-year grant from the NIH to expand autism research by studying genetic causes of autism in African American families.

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Posted on July 20, 2019July 23, 2019 Autism

3q29 deletion survey: distinct social profile, high ASD risk Chromosomal deletion connected to both schizophrenia + autism

A survey of 93 people with 3q29 deletion syndrome reveals a distinct pattern of social disability and anxiety, even without a diagnosis of autism spectrum disorder.

The results were published online in Molecular Autism on July 16.

Geneticists at Emory University School of Medicine teamed up with clinicians at Children’s Healthcare of Atlanta’s Marcus Autism Center to evaluate the largest cohort of people with 3q29 deletion ever assembled. Because 3q29 deletion syndrome is relatively rare (1/30,000 people), most physicians who have seen a case have only seen one. Study participants were recruited through a registry website, and they or their parents completed questionnaires about social, communication and behavioral issues. The average age was 10, but adults up to age 41 were included.

In 3q29 deletion syndrome, a stretch of DNA containing several genes is missing from one of a child’s chromosomes. 3q29 deletion — usually spontaneous, not inherited — is one of the strongest genetic risk factors for schizophrenia, increasing the risk at least 20 fold. It also increases the likelihood of autism spectrum disorder at a similar level, the survey indicates: 24 fold for males and more than 40 fold for females.

Most people with 3q29 deletion did not have autism spectrum disorder (ASD) diagnoses (29 percent did), but overall they did have higher scores for social disability and anxiety. While not all participants were the same, their average profile was distinct from the general picture of autism spectrum disorder, in that people with 3q29 deletion tended to have high scores for restricted interests and repetitive behaviors, but only mild impairment in social motivation.

“The kids are motivated to have peer relationships, and desperately want them, yet aside from social motivation, they often lack other skills with which to form those relationships,” says senior author Jennifer Mulle, PhD, assistant professor of human genetics at Emory University School of Medicine.

“One of our recommendations is that all individuals with 3q29 deletion should receive a thorough ASD evaluation as standard of care, so that they can have access to social services and therapeutic programs.” Mulle says. “Because their intellectual disability is generally mild, cognitive behavioral therapy to teach social skills may be an effective intervention.”

Another distinctive aspect of 3q29 deletion syndrome is its relatively greater effects on ASD risk in females compared with males. In the general ASD population, males outnumber females 4 to 1; this ratio is reduced to 2 to 1 for ASD diagnoses in the 3q29 group.

The first author of the paper is Genetics and Molecular Biology graduate student Rebecca Pollak. She worked with associate scientist Melissa Murphy, PhD at Emory and Celine Saulnier, PhD and Cheryl Klaiman, PhD at Marcus Autism Center. Emory geneticists Michael Epstein, PhD and Michael Zwick, PhD also contributed to the paper.

Mulle sees investigating 3q29 deletion syndrome – and other genetic variations connected with schizophrenia and autism — as a way of unraveling the biological complexity of both conditions.

The Emory team is beginning to investigate individual genes found within the 3q29 deletion, aiming to understand molecular mechanisms. Working with cell biology chair Gary Bassell, scientists plan to create a human neuronal model of 3q29 deletion, using induced pluripotent stem cell lines. They are also investigating the patterns of gene activity in blood samples from 3q29 donors.

In April, Mulle and her colleagues from the Department of Human Genetics, including Tamara Caspary, PhD, David Weinshenker, PhD and Steve Warren, PhD published a mouse model of 3q29 deletion in Molecular Psychiatry. The mice display social and cognitive impairments that correspond to some symptoms of related neuropsychiatric disorders.

Posted on April 13, 2019April 14, 2019 Autism

Sinclair Cares: New autism study looks to genes for answers

Five-year-old Kiernan, 6-year-old Malachai and 19-year-old Skyler are siblings.

Skylar and Kiernan are confirmed to have autism. Their brother Malachai is in the process of being diagnosed, and is likely also on the spectrum.

Most people with autism spectrum disorder (ASD) have social, communication, and other challenges.

“It’s kind of a bombshell,” said their mother, Kami Denison, about the diagnoses. “You know, it blindsides you the first time you hear that. It’s, ‘What did I do wrong?'”

“You always wonder why something like that happens to you,” said the kids’ father, Lance.

These are common questions, but most scientists agree, autism isn’t caused by a parent’s choices. The biggest risk factor is in their genes.

Full article here

Posted on February 28, 2019February 28, 2019 Autism

First common risk genes discovered for autism

A study headed by researchers from the Danish project iPSYCH and the Broad Institute, USA, has found the first common genetic risk variants for autism and uncovered genetic differences in clinical subgroups of autism. The discovery means that we will in future be able to determine the genes which separate the diagnostic groups, make more precise diagnoses, and provide better counselling for the individual person suffering from autism disorders.

Autism is not a new phenomenon as we have historical records describing individuals with symptoms that today are associated with the group of disorders that today is known as autism. It was not until 1938 that the first person was given that diagnosis though. Ever since then researchers have tried to explain where the disorder stems from. There have been many suggestions, but one factor has long been established – that genes play a very important role.

A large-scale international collaboration headed by the Danish iPSYCH project and Broad Institute together with several international groups organized in the Psychiatric Genomics Consortium has now identified the first common genetic risk variants for autism and for the first time found the genetic differences between different types of autism.

These genes increase risk

“When we look at autism, there is a heredity factor of up to eighty percent, so genes have a great deal of impact overall. Nevertheless, despite many years of work, identifying precisely which genes are involved has been very challenging,” says Professor Mark Daly from Broad Institute and Institute for Molecular Medicine Finland who is one of the leading scientists of the study.

In the study, researchers have compared the genome of 20,415 people with autism and 174,280 healthy control subjects, and in this way they have been able to determine five different genetic variants which increase the risk of autism. The results have recently been published in the scientific journal Nature Genetics.

“It is known that there are very rare genetic variants that carry a high risk for autism, but they do not explain many cases. However, according to our estimates, there are common variants that do that when enough of them act together. In this study we have examined all the approximately nine million frequent variants that can be found in the genome of the people who are included in our study. These are genetic variants which are common in the population at large and where the individual variant’s contribution to the risk is very small,” explains Associate Professor Jakob Grove from Aarhus University. He is the lead author of the study and a member of the iPSYCH research project.

Findings provide new insights

The genetic findings provide an entirely new insight into the biological processes involved in the development of autism.

“By comparing the genetic risk variants with the genes’ expression and the 3D structure of the genome in the developing brain, we can show that the identified risk genes are important for the development of the brain and in particular the development of the cerebral cortex,” explains Professor Anders Børglum from Aarhus University, who is research head at iPSYCH and directed the study together with Dr. Daly.

The researchers have also found a significant overlap between the genetic background for autism and other mental disorders such as schizophrenia and depression – though also with positive cognitive characteristics such as educational attainment and IQ.

“The positive correlation with educational attainment might seem paradoxical because some autistic people have reduced cognitive function and on average, fewer people with an autism diagnosis end up with a higher education. The correlation is seen in several previous studies, and in our data we can confirm that in general, this correlation between the genes for autism and genes that predispose for longer education does exist,” says Jakob Grove and continues:

“However, we can demonstrate that this does not apply to all subsets of autism. We see that people with Asperger’s syndrome or infantile autism on average have more of the genes that are beneficial for taking an education, while this is not the case for people with so-called atypical autism or unspecified autism disorders.”

Better treatment on the horizon

Autism refers to a very mixed group with different autism disorders. Some have very pervasive developmental disorders with mental retardation, while others may be cognitively well-functioning with a normal or high IQ.

“Thanks to a new and highly sensitive method that we’ve developed, we can for the first time establish genetic differences between the various diagnostic subgroups. This indicates that larger studies in the future will be able to pinpoint genes that separate the diagnostic groups and enable more precise diagnosis and advice for the individual person suffering from an autism disorder. We also hope that the genes we identify can provide an opportunity for developing actual treatment or prevention of the condition, which is something that we unfortunately cannot offer at present,” says Anders Børglum.

About iPSYCH

The national research project iPSYCH – which is financed by the Lundbeck Foundation – was established back in 2012 with the purpose of carrying out research into and finding the causes of five of the most serious mental disorders: schizophrenia, bipolar disorder (formerly manic depression), autism, ADHD and depression. iPSYCH’s purpose was – and still is – to lay the foundations for better treatment and prevention of mental disorders by mapping the factors that play a role for these diseases. By examining genetic and risk factors in more than 80,000 Danes both with and without mental disorders, iPSYCH sheds light on the complex interaction between heredity factors and the environment, which for some people result in them developing a mental disorder. The project examines the diseases from various angles, ranging from genes and cells to population studies, prenatal life to adult patient and from cause to symptom. iPSYCH is a national collaborative project between Aarhus University, the University of Copenhagen, the Central Denmark Region and the Capital Region of Denmark, as well as SSI, the Danish State Serum Institute.

Today iPSYCH is one of the world’s largest studies of genetic and environmental causes of mental disorders and it now comprises more than 150 researchers within psychiatry, genetics and register-based research.

Background for the results

Type of study: Researchers scan the entire genome of a large number of people with autism and a large number of healthy control subjects. When a genetic variation is significantly more frequent in people with autism than in the healthy control group, it is possible to conclude that the variant increases the risk of suffering from the disorder. In the iPSYCH project, researchers have collected genetic information on 13,076 autists and 22,644 control subjects. The results where combined with the results from an additional 5,305 people with autism and 5,305 control subjects from an international multi-centre study under the auspices of The Psychiatric Genomics Consortium, and a follow-up was also carried out on 2,119 people with autism and 142,379 control persons from, among other places, deCODE in Iceland.

Posted on February 16, 2019February 16, 2019 Autism

New study shows hidden genes may underlie autism severity

DNA and autism

Scientists at the University of Colorado Anschutz Medical Campus have implicated a largely hidden part of the human genome in the severity of autism symptoms, a discovery that could lead to new insights into the disorder and eventually to clinical therapies for the condition.

The researchers found the critical genes are part of the human genome that is so complex and difficult to study that it has been unexamined by conventional genome analysis methods.

In this case, the region encodes most copies of the Olduvai (formerly DUF1220) protein domain, a highly duplicated (~300 copies in the human genome) and highly variable gene coding family that has been implicated in both human brain evolution and cognitive disease.

The researchers, led by James Sikela, PhD, a professor in the Department of Biochemistry and Molecular Genetics at the CU School of Medicine, analyzed the genomes of individuals with autism and showed that, as the number of copies of Olduvai increased, the severity of autism symptoms became worse.

While the Sikela lab has shown this same trend previously, the discovery has not been pursued by other researchers due to the complexity of the Olduvai family.

“It took us several years to develop accurate methods for studying these sequences, so we fully understand why other groups have not joined in.” Sikela said. “We hope that by showing that the link with autism severity holds up in three independent studies, we will prompt other autism researchers to examine this complex family.”

In order to provide more evidence that the association with autism severity is real, the Sikela lab used an independent population and developed a different, higher resolution measurement technique. This new method also allowed them to zero in on which members of the large Olduvai family may be driving the link with autism.

Though autism is thought to have a significant genetic component, conventional genetic studies have come up short in efforts to explain this contribution, Sikela said.

“The current study adds further support to the possibility that this lack of success may be because the key contributors to autism involve difficult-to-measure, highly duplicated and highly variable sequences, such as those encoding the Olduvai family, and, as a result, have never been directly measured in other studies of autism,” Sikela said.

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