Data do-over backs dominance of genetics in autism risk

BY CIARA CURTIN  /  19 OCTOBER 2017

A reanalysis of data from more than 2 million children in Sweden suggests inherited genetic factors account for 83 percent of autism risk1

A 2014 study using the same dataset pointed to an equal contribution from genetics and the environment, but experts in the field were critical of the findings, citing flaws in the study’s methods.

Then, to their surprise, the researchers came up with a heritability estimate of 85 percent using an overlapping dataset of nearly 800,000 Swedish children2. That result prompted them to revisit their earlier work.

In both studies, non-inherited genetic factors called de novo mutations are included in the 17 percent of autism risk dubbed ‘environmental.’ De novo mutations are thought to be important in autism.

“We have been working on this question using more updated data and, doing so, we then found heritability to be larger than we estimated earlier,” says lead researcher Sven Sandin, assistant professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York.

The new estimates align with findings from a 2010 study that placed the contribution of inherited genetic factors to autism risk at 80 percent3. That study also included de novo mutations in the ‘environmental’ category.

Sibling similarities:

In their 2014 study, Sandin and his team analyzed data from 2.6 million non-twin sibling pairs, 37,570 pairs of twins, and 877,812 half-sibling pairs, all born in Sweden between 1982 and 2006. Of these individuals, 14,516 have an autism diagnosis. The data came from Swedish national health registries.

The researchers looked for siblings who were ‘concordant’ for autism, meaning they both have the condition. They followed one sibling from each pair from birth until he or she was diagnosed or until the study ended in 2009, whichever came first. If that child was diagnosed, they looked to see whether the sibling had also received a diagnosis.

But this approach missed some children who received a diagnosis only after the sibling the researchers followed was diagnosed.

“Some concordant siblings would have been considered not concordant the first time” the researchers analyzed their data, says Qian (Kenny) Ye, associate professor of epidemiology and population health at Albert Einstein College of Medicine in New York, who was not involved in the study.

In the re-analysis, the researchers looked at data from both siblings until 2009. By that time, the youngest children were 4 — old enough to receive an autism diagnosis. If both members of the pair received an autism diagnosis at any point during the study, the researchers considered them concordant.

Double digits:

Using this approach, the researchers nearly doubled the number of concordant sibling pairs in their study. They also boosted their estimate of autism’s heritability from 50 percent to 83 percent. The results appeared in September in the Journal of the American Medical Association.

“I think it’s great that this group of researchers took the trouble, actually, to publicly acknowledge that their previous publication might have been suboptimal,” says Dorret Boomsma, professor of biological psychology at Vrije Universiteit in Amsterdam, who was not involved in the study.

In their other study, published in September in Biological Psychiatry, the researchers again drew on Swedish health registry data, but focused this time on the period between 1998 and 2007. This sample includes 776,212 children, 11,231 of whom have been diagnosed with autism. They also looked for autism diagnosed among the children’s relatives, including siblings and cousins.

They applied statistical models that account for the family relationships to estimate the heritability of autism. They calculated that genetics contributes 84.8 percent of autism risk.

“I think it has been repeated several times now and we are converging to this number,” Sandin says.

He and his colleagues are also using the Swedish registries to study recurrence of autism within a family — the likelihood that a sibling of a child with autism also has the condition

REFERENCES:

1. Sandin S. et al. JAMA 318, 1182-1184 (2017) PubMed
2. Yip B. et al. Biol. Psychiatry Epub ahead of print (2017) Full text
3. Lichtenstein P. et al. Am. J. Psychiatry 167, 1357-1363 (2010) PubMed

Pinpointing the origins of autism

CAPTION

This artwork shows a few of the connections in the brain of a typically developing 6-month infant who participated in the study. In the study, connections between all brain regions are generated, and the lengths and strengths of the connections are combined to determine the network efficiency of each region.

The origins of autism remain mysterious. What areas of the brain are involved, and when do the first signs appear? New findings published in Biological Psychiatrybrings us closer to understanding the pathology of autism, and the point at which it begins to take shape in the human brain. Such knowledge will allow earlier interventions in the future and better outcomes for autistic children.

Scientists used a type of magnetic resonance imaging (MRI), known as diffusion weighted imaging, to measure the brain connectivity in 260 infants at the ages of 6 and 12 months, who had either high or low risks of autism. The lengths and strengths of the connections between brain regions was used to estimate the network efficiency, a measure of how well each region is connected to other regions. A previous study with 24-month-old children found that network efficiency in autistic children was lower in regions of the brain involved in language and other behaviours related to autism. The goal of this new study was to establish how early these abnormalities occur.

Lead author John Lewis, a researcher at the Montreal Neurological Institute and Hospital of McGill University and the Ludmer Centre for Bioinformatics and Mental Health, found network inefficiencies had already been established in six-month-old infants who went on to be diagnosed with autism. Inefficiencies in the six-month-olds appeared in the auditory cortex. He also found the extent of the inefficiency at six months of age was positively related to the severity of autistic symptoms at 24 months. As the children aged, areas involved in processing of vision and touch, as well as a larger set of areas involved in sound and language, also showed such a relation between inefficiency and symptom severity.

Identifying the earliest signs of autism is important because it may allow for diagnosis before behavioural changes appear, leading to earlier intervention and better prospects for a positive outcome. By pinpointing the brain regions involved in processing sensory inputs as the earliest known locations of neural dysfunction related to autism, researchers narrow down the genetic factors and mechanisms that could be responsible for its development. The fact that neurological signs are already present at six months also eliminates some environmental factors as potential causes of the disorder.

"Our goal was to discover when and where in the brain the network inefficiencies first appeared," says Lewis. "The results indicate that there are differences in the brains of infants who go on to develop autism spectrum disorder even at six months of age, and that those early differences are found in areas involved in processing sensory inputs, not areas involved in higher cognitive functions. We hope that these findings will prove useful in understanding the causal mechanisms in autism spectrum disorder, and in developing effective interventions."

The research comes from the Infant Brain Imaging Study (IBIS), a collaborative effort by investigators at the Montreal Neurological Institute, and four clinical sites in the United States, coordinated to conduct a longitudinal brain imaging and behavioural study of infants at high risk for autism.

Autism Is Becoming More ‘Mainstream’

Written by Matthew Berger 

There are now more people with autism on-screen and in the workforce.

The two trends are related and, advocates hope, will open the door to even more progress.

“Sesame Street” debuted a character with autism in April after extensive collaboration with autism groups.

Filmmaker Rachel Israel wanted to make a movie about a neurological disorder that actually starred people with the condition. Her film “Keep the Change” won several awards at this year’s Tribeca Film Festival.

Autism encompasses a spectrum or symptoms, and many people on that spectrum are challenged by unemployment and lack of acceptance.

However, software giant SAP set a goal of hiring 650 people with autism, about 1 percent of its workforce.

It’s one of several technology companies that have been seeking employees with autism to apply their strong logic skills in the software industry.

Developments like these may signal a turning point from awareness to acceptance of people with autism.

And that may bring a large segment of society — and largely untapped labor force — off the sidelines and into prominent roles within society.

Finding employment

One in 68 U.S. children has autism — 1 in 42 boys — and that rate has steadily increased since researchers began tracking it in 2000.

But just 58 percent of people with autism were employed in 2015. That’s far lower than the overall employment rate, and also the overall rate for people with disabilities.

More people with autism in films and on TV — portrayed accurately — help fix that.

“There’s an unemployment rate that’s ridiculously high,” Matt Asner, vice president of development at the Autism Society of America, told Healthline.

He said people with autism are “model employees,” and that employers need to step up and hire them.

“But in order for that to happen, we need to educate employers on what autism is, and I think film and TV does a great job at that,” he said.

He added that he’s “really excited about what we’re seeing on-screen now.”

Asner points to shows like Netflix’s “Atypical,” which debuts later this week.

The show employs people with autism for both on-screen work and behind the scenes, although autism isn’t the main focus of the series.

Other shows, like ABC’s “The Good Doctor,” which debuts next month, will feature a lead character with autism and make the disorder a more central theme.

“The greatest thing that’s happening right now…is that we’re starting to see people talk about autism in a very respectful way. We’re seeing people weave it into the lives of the people on-screen instead of making a statement about it,” Asner said. “They’re dealing with autism the way it should be dealt with, just as a part of life.”

He cites the Scandinavian crime drama “The Bridge,” in which the heroine shows multiple signs of being on the spectrum, but it is never addressed and isn’t what the show is about.

“It wasn’t a driving part of the show, the characters didn’t talk about it — they talked about her,” he said.

A wide spectrum

That’s important because autism is different for everyone.

People with autism might all be on the same spectrum, but being on the spectrum can mean many different things.

Hollywood appears to be getting better at depicting forms of autism in more head-on ways, too. Films like 2011’s “Fly Away,” last year’s “A Boy Called Po,” and the Special Olympics documentary “Swim Team” released earlier this year, were well-received by both critics and mental health groups.

When it may start to make a difference in hiring is an open question, but the first step is getting society as a whole to become aware of people with autism.

“In order to reach acceptance we need awareness,” Asner said.

“The issue with autism is that you can’t readily see it — it’s not visible,” he added. “Certainly there are traits that make it more visible...but basically it’s just a person with different abilities.” 

With the help of 50,000 families, a landmark study aims to unlock the genetics of autism

By Diane Atwood

When she was two, Kaylee Lurvey could say Mamma, Daddy and a toddler version of her kitty’s name — Buball for Snowball.

But by the time she was three, Kaylee was no longer using words. She was diagnosed with autism and a rare condition known as 10Q deletion syndrome.

Kaylee is now 11 years old and while she has come a long way, her parents are still looking for answers as to why she developed these conditions. Take autism: “There are so many what if things and so many ideas that say hey, there’s this increased risk,” says Kaylee’s mother Candice. “We hear a lot of that but there are no real concrete answers.”

Candice is the kind of woman who jumps in with both feet in her search for answers and to help other families touched by autism. That’s why she and her husband put on an annual community event to raise money for autism research (in the past seven years they’ve raised $10,400). Why she doesn’t hesitate to spend time on the phone with another parent who has a child with autism. And why she decided to participate in SPARK.

SPARK is a landmark online autism research project launched in 2016. The project is sponsored by the Simons Foundation Autism Research Initiative. The goal is to enroll 50,000 people with autism over a three-year period along with their biological parents. One individual and two parents are referred to as a trio.

The Lurvey family is a trio. They gained their status by enrolling online (took about 15 – 20 minutes) and then each contributing a DNA sample. Once they had enrolled, SPARK sent them three collection kits. Candice and her husband simply spit into the provided tubes and mailed them back. It was a bit trickier to get Kaylee’s sample, but Candice prevailed!

“It took longer because Kaylee would swallow her saliva before she would let me in,” she said. “I had to make a little game out of it. She likes a high pitched voice. I’d say hey, how’s it going and she’d get all excited and laugh and giggle and that’s when I stuck the syringe in real quick and got the spit.”

It may have been a game getting Kaylee’s saliva sample, but dealing with autism is absolutely no fun. Autism is an umbrella term for a group of complex developmental or autism spectrum disorders. An estimated one in 68 children in the U.S. is on the autism spectrum. 

“The autism spectrum captures people who have challenges in two core areas,” explained child psychiatrist Dr. Matthew Siegel. “One is in social communication challenges and the second is in restricted repetitive behaviors and interests. It’s called the spectrum because in one or both of those areas there’s a wide range of symptoms. For instance, with communication, it goes all the way from someone who does not speak at all to someone who is hyper-verbal but has difficulties with some of the subtleties of social communication.”

Dr. Siegel works for Maine Behavioral Healthcare and the Maine Medical Center Research Institute. SPARK tapped the two organizations to recruit participants from Maine, New Hampshire, and Vermont — 250 trios annually for the next three years. Dr. Siegel is the principal investigator for the region.

Because autism represents such a wide spectrum of disorders, it is challenging to study possible causes and treatments. Being able to study the DNA or genes of 50,000 people and their biological parents nationwide is why the SPARK study is considered so important.

“We know that a significant portion of autism can be attributed to changes in a person’s DNA,” said Dr. Siegel. “However, we are still in the early stages of identifying specific changes in a person’s genetic code that we can relate to autism or to certain features of autism. In order to become much more knowledgeable and specific about all of the changes that can be part of autism at the genetic level, we need very large DNA samples from people. The genesis of the SPARK study is to collect 50,000 samples from people with autism — of any age, anywhere on the spectrum, any severity, and any gender. If we obtain their genetic code or sequence as it’s called we can start analyzing what kinds of changes are associated with or line up with certain features of autism.”

So far, 50 genes with a connection to autism have been identified, but there could be an additional 300. Once identified, the next step would be to gather information on the people who have changes in those genes. “Say this person with autism has a change on chromosome 22,” explained Dr. Siegel. “We then need to look across all samples and see if there is anyone else who has the same exact change. Then we look at the characteristics of those two people or those 10 or 20 or 50 people who have that specific change. And then we can start to identify whether this is a particular form of autism. That’s what moves us forward toward getting more specific about understanding autism and potentially, developing treatments.”