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June 18, 2018

4/27/2018 7:23:00 AM
Scientists build huge genetic database for autism research
De novo mutations earn significant focus in genetics studies

Richard Moore
Investigative Reporter

While many scientists are gum-shoeing potential environmental hazards related to risks for autism in the general population, just as many are busy sleuthing around the genetic codes of thousands of people, hoping to better understand the role genetics plays in the development of autism spectrum disorders.

There are many theories but none are conclusive. Some believe autism is primarily an inherited genetic disorder; others believe environmental factors are the principal culprit, with little genetic influence; still others believe that peoples' genetic make-up can predispose them to a higher risk, with environmental factors triggering the onset of ASD.

The influence assigned to each factor forms a wide and far-ranging span, itself a spectrum of scientific inquiry. Just on the genetic side of the equation, scores of studies are underway.

To help provide clearer answers, one study called SPARK, sponsored by the Simons Foundation Autism Research Initiative, is attempting the largest autism study ever undertaken in the U.S.

Ongoing now for more than two years, researchers for SPARK (Simons Foundation Powering Autism Research for Knowledge) have been building personal profiles and collecting DNA samples from as many as 50,000 people with autism and their family members.

One goal of SPARK, the project's website states, is to enable a new level of research that was not possible previously by increasing the number of people available to participate in autism research.

"SPARK will enable advances in two major ways," its website states. "Having genetic samples from 50,000 families for scientists to analyze will enable far deeper insight into the genetic changes that contribute to autism. SPARK families will be available to receive invitations from researchers to participate in other studies, enabling research of all types to get off the ground more quickly."

In the Midwest, Rush University Medical Center in Chicago is a study hub, one of more than 20 sites around the country where data is being collected. Rush joined the study in 2016, but in the spring of 2018 they are still out swabbing cheeks and collecting DNA samples for the database.

Dr. Latha Soorya, an assistant professor of psychiatry, and Dr. Cesar Ochoa-Lubinoff, an assistant professor of pediatrics, are leading the effort at Rush, with help from the Autism Assessment, Research, Treatment and Services Center, developmental and behavioral pediatrics, pediatric neurology and the Rush Neurobehavioral Center.

In announcing the project in 2016, Soorya told Deb Song of Rush University news that more genetic research was critically needed to develop better treatments for autism. While there had been many advancements, Soorya told Song, there was not enough genetic research to develop personalized medicine approaches needed to advance treatment.

"Autism is diverse with many complexities, and currently we treat it as a single condition," Soorya said. "Researchers need a better understanding of how medical and behavioral characteristics are linked to autism spectrum disorder in order to treat all the variations and different presentations of the disease we see."

According to Rush, SPARK participants will provide a DNA sample obtained using a simple cheek or gum swab. Rush will collect samples at the Medical Center from consenting participants, including people who receive autism treatment or participate in other autism studies.

Meanwhile, over at Northwestern University, a network of researchers there is looking to pool their work to form another hub of research in the field of autism and genetics.

The university has recently launched a new Center for Autism and Neurodevelopment (CAN), what it calls a translational science hub that aims to investigate the neurobiology of autism and to facilitate the development of new treatments.

According to the university, the mission of the center is to catalyze scientific collaborations aimed at understanding the biological bases of autism and related neurodevelopmental disorders, and to translate those findings into new treatments.

Renewed interest in de novo mutations

While such databases are being enlarged and collaborative efforts take shape, a solid foundation of research has already provided some clues into the role genetics plays in ASD.

Many researchers believe genetic factors predispose some people to a higher risk for autism, and recent research has identified de novo genetic mutations as a potential culprit in as many as a third of all autism cases.

Two kinds of genetic mutational factors exist: inherited mutations, and de novo mutations, the latter of which are changes to the DNA that do not appear in the genetic makeup of either parent but emerge new in the child.

An increasing number of studies have linked de novo mutations and ASD diagnoses. In 2014, for example, in "The contribution of de novo coding mutations to autism spectrum disorder," researchers, including Dr. Michael Wigler of Cold Spring Harbor Laboratory and CSHL assistant professor Ivan Iossifov, found that de novo mutations that arise "spontaneously" and do not occur in either parent could account for approximately 30 percent of all ASDs.

And the researchers considered that a conservative estimate.

"By comparing affected to unaffected siblings, we estimate that 13 percent of de novo (DN) missense mutations and 42 percent of DN likely gene-disrupting (LGD) mutations contribute to 12 percent and 9 percent of diagnoses, respectively," the researchers stated. "Including copy number variants, coding DN mutations contribute to about 30 percent of all simplex and 45 percent of female diagnoses."

More recent research in 2015, led by Iossifov, suggests that devastating "ultra-rare" mutations of genes play a causal role in roughly half of all ASD cases. Those mutations can occur "spontaneously" between generations, the researchers reported, and when that happens they are found in the affected child but not found in either parent.


A newly released 2017 study links de novo mutations in particular to general cognitive and motor skills impairment.

"Diminished motor skills appear to be an almost universal property of children with autism," said Wigler, one of three researchers conducting the new study, in a statement from Cold Springs Harbor Laboratory.

Wigler said the data studied suggests the genetic factors causing ASD broadly diminish the brain's cognitive functions. Past research at CSHL and elsewhere has revealed the presence of damaging de novo mutations correlates with lower non-verbal IQ, the statement reported, and the more severe the mutations, the more pronounced the impact.

The researchers also found that diminished motor skills, like lower IQ, also correlate significantly with de novo mutations in ASD, and is an even more sensitive indicator of the damage of a de novo mutation than is IQ.

According to the researchers, the defining core behavioral components of ASD - impaired social skills and communication - do not correlate with either the presence or severity of de novo mutations.

"In other words, a child with autism who has a severe de novo mutation is no more likely to have severely impaired social skills than is a child with autism for whom no such mutation was found, and who presumably has inherited his causal factors," CSHL states in its release.

So the researchers think children who have autism as a consequence of inherited factors have less general cognitive damage than those with severe de novo mutations, and Wigler said that was puzzling.

This study was based on DNA sequence and deep phenotypic data from the Simons Simplex Collection, a set of 2,760 families that have a single child affected by ASD, CSHL stated.

Causes of de novo mutations

Scientists have also been researching the potential causes of de novo mutations.

Some researchers have linked the mutations with parental age, particularly of the father. A 2016 study reviewed the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.

"Approximately 80 percent of all de novo germline point mutations arise on the paternal allele, and advanced paternal age at conception has been established as the major factor linked to the increase in the number of de novo mutations in the offspring, both at the population level and within the same family," the researchers reported from their review in "New insights into the generation and role of de novo mutations in health and disease," published in Genome Biology.

In addition, the researchers found, de novo mutations in children of young fathers show a different signature and localize to later-replicating regions of the genome compared with those of children of older fathers, suggesting that additional factors contribute to de novo mutations with age.

Each additional year in paternal age at conception adds one to three de novo mutations to the genome of the offspring, the review stated.

But many studies point to other environmental factors besides parental age as possible causes of de novo mutations.

A still widely cited 2010 study, "Environmental Risk Factors for Autism: Do They Help Cause De Novo Genetic Mutations That Contribute to the Disorder?" by Harvard's Dr. Dennis Kinney acknowledged that advanced parental age at the time of conception is associated with increased risk for both autism and de novo mutations, but his team set out to investigate the hypothesis that other environmental factors associated with increased risk for autism might also be mutagenic and contribute to autism by causing de novo mutations.

In a review of the literature, his team identified nine environmental factors for which increased pre-conceptual exposure appears to be associated with increased risk for autism. Five of the factors - mercury, cadmium, nickel, trichloroethylene, and vinyl chloride - are established mutagens, the researchers reported, while another four, including residence in regions that are urbanized, located at higher latitudes, or experience high levels of precipitation, are associated with decreased sun exposure and increased risk for vitamin D deficiency.

"Vitamin D plays important roles in repairing DNA damage and protecting against oxidative stress - a key cause of DNA damage," Kinney and his team reported. "Factors associated with vitamin D deficiency will thus contribute to higher mutation rates and impaired repair of DNA."

The likelihood of de novo mutations playing a strong role in autism prevalence rates explains many heretofore puzzling facts about the disorder, the researchers stated.

As the study observed, autism is surprisingly common for a disorder that is so disabling and is associated with such low rates of marriage and fertility, yet is estimated to have an extremely high heritability - over 90 percent based on twin concordance rates.

"De novo mutations could help explain this puzzle if a constant influx of such new mutations into a population helps offset the continual elimination of autism susceptibility genes from the population because of low average fertility rates in individuals with autism," Kinney and his colleagues wrote. "If de novo mutations play a significant role in a disorder, it will also tend to produce a much higher concordance rate in monozygotic than dizygotic twins, because the same de novo mutation will typically be inherited by both members of a monozygotic twin pair, but only very rarely by both members of a dizygotic twin pair."

And that's the pattern found in twin concordance rates in autism, Kinney wrote.

Heavy metals and other pollutants

The researchers explored the role that heavy metals and other pollutants might play in higher autism rates and they did find evidence of a strong correlation.

One study, for example, identified several pollutants associated with increased prevalence of autism spectrum disorders by comparing U.S. Environmental Protection Agency data on pollutant exposure with demographic data on 284 children with ASD and 657 controls in the San Francisco Bay Area, the researchers wrote.

"Children from areas exposed to higher concentrations of three heavy metals and two chlorinated solvents had significantly higher rates of ASD than children residing in areas with low exposure," Kinney wrote. "The substances for which higher exposure was most strongly correlated with increased ASD risk were mercury, cadmium, nickel, trichloroethylene, and vinyl chloride."

Kinney said a complementary ecological study investigated autism prevalence as a function of proximity to industrial and power plant sources of environmental mercury in 1,040 Texas school districts and found higher rates of autism.

"After controlling for socioeconomic factors and urbanicity, Palmer et al. found that autism prevalence increased 2.6 percent for every 1,000 pounds of mercury released in the vicinity of the geographical center of a given district, and 3.7 percent with nearby power plant emissions," the researchers wrote.

Kinney and his team said ecological studies had also identified several other environmental factors, for which exposure early in development was associated with increased risk for autism.

"Exposure to these factors appears to have included the period before conception," the researchers wrote. "A recent meta-analysis of prevalence studies around the world found that significantly increased risk for autism is associated with urban vs. rural residence (odds ratio - OR - of 2.44). Several studies have also reported that a significantly higher autism prevalence is associated with residence in geographic regions at higher latitudes."

For example, Kinney wrote, two studies conducted by the Centers for Disease Control found that when prevalence rates of ASD were compared across different U.S. states that had used the same ascertainment procedures, the autism prevalence was significantly higher in New Jersey than in any of the nine other, more southern states.

In a second comparison, the researchers stated, involving four states that used a different ascertainment procedure from the first set of states, autism prevalence was significantly lower in Alabama than in any of three other, more northern states.

"Higher prevalence has also been found to be significantly associated with infants' and toddlers' residence in counties with high levels of precipitation; this was found to hold in each of three different states, even after controlling for income and ethnicity," the researchers found.

One study even found a significantly higher prevalence in counties with increased access to cable television, and that study's authors suggested that their data are consistent with early childhood television watching as a contributor to autism risk.

"However, their data are also consistent with autism risk being associated with more time spent inside watching television by parents - and thus with decreased exposure to sunlight before the children were conceived," Kinney and colleagues wrote.

Higher and higher

The researchers also reviewed several reports that in geographic regions at higher latitudes, such as Sweden and Minnesota, there is an extremely high incidence of autism among children of dark-skinned immigrants from African countries such as Somalia.

"In Minnesota, for example, the Department of Health recently released a study estimating the prevalence of autism among Somali children to be between 2 and 7 times greater than the prevalence among non-Somali children," the researchers wrote. "Although these studies of immigrants involved modest sample sizes, the increases in autism risk are so large that they merit attention."

In the Kinney study, many of the risk factors were consistent with an etiologic role for vitamin D deficiency in autism.

"The action of UV rays in sunlight on the skin is the most powerful natural source of vitamin D, and factors that reduce the amount and intensity of sunlight to which skin is exposed significantly increase the risk of vitamin D deficiency," the researchers wrote. "Vitamin D deficiency is common in populations at higher latitudes, especially those with darker skin, because more darkly pigmented skin reduces penetration of UV rays to the skin layers that synthesize vitamin D. Higher rates of precipitation are associated with less sunshine."

Precipitation, like television watching, also encourages people to spend more time inside, reducing their exposure to sunlight and increasing their risk of vitamin deficiency, the researchers found.

"Vitamin D plays an important role in dozens of different biochemical processes, in addition to its well-known role in bone metabolism," the researchers wrote. "As (researchers have) pointed out, prenatal vitamin D deficiency can disrupt normal brain development. A complementary effect of vitamin D deficiency in families, however, will be to increase de novo mutations in offspring."

Finally some new research shows that children with autism possess rare mutations in DNA segments known as "junk DNA," or noncoding regions that now are seen as more important than before, and the children seem to inherit these mutations from their fathers.

Some experts are skeptical of those findings, however, because most mutations are inherited from the mother, and in any case the variants account for only a small number of people with autism, as few as .39 percent.

Richard Moore is the author of The New Bossism of the American Left and can be reached at www.rmmoore1.com.

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