Common gene variants account for most genetic risk for autism

The bulk of risk, or liability, for autism spectrum disorders was traced to inherited variations in the genetic code shared by many people. 

These and other (unaccounted) factors dwarfed contributions from rare inherited, non-additive and spontaneous (de novo) genetic factors 

Credit: Population-Based Autism Genetics and Environment Study

Most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the National Institutes of Health (NIH) have found.

Heritability also outweighed other risk factors in this largest study of its kind to date. About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.

"Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture," explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City.

"Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together."

Buxbaum, and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.

"Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now detect common as well as rare genetic variation associated with risk," said Thomas R. Insel, M.D., director of the NIH's National Institute of Mental Health (NIMH).

"Knowing the nature of the genetic risk will reveal clues to the molecular roots of the disorder. Common variation may be more important than we thought."

Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive.

Recently, evidence has been mounting that genomes of people with autism are prone to harboring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.

More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect.

Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.

Differences in methods and statistical models also resulted in sometimes wildly discrepant estimates of autism's heritability, ranging from 17 to 50 percent.

Meanwhile, recent genome-wide studies of schizophrenia have achieved large enough sample sizes to reveal involvement of well over 100 common gene variants in that disorder.

These promise improved understanding of the underlying biology, and even development of risk-scores, which could help predict who might benefit from early interventions to nip psychotic episodes in the bud.

With their new study, autism genetics is beginning to catch up, say the researchers. It was made possible by Sweden's universal health registry, which allowed investigators to compare a very large sample of about 3,000 people with autism with matched controls.

Researchers also brought to bear new statistical methods that allowed them to more reliably sort out the heritability of the disorder.

In addition, they were able to compare their results with a parallel study in 1.6 million Swedish families, which took into account data from twins and cousins, and factors like age of the father at birth and parents' psychiatric history.

A best-fit statistical model took form, based mostly on combined effects of multiple genes and non-shared environmental factors.

"This is a different kind of analysis than employed in previous studies," explained Thomas Lehner, Ph.D., chief of NIMH's Genomics Research Branch.

"Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry."

Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications of genetic material and spontaneous mutations.

Even though such rare spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches makes them important clues to understanding the molecular underpinnings of the disorder, say the researchers.

"Within a given family, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member," said Buxbaum.

"The family may have common variation that puts it at risk, but if there is also a de novo [spontaneous} mutation on top of that, it could push an individual over the edge."

"So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder."

More information: Gaughler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CH, Devlin B, Roeder K, Buxbaum JD. Most genetic risk for autism resides with common variation. Nature Genetics, July 20, 2014. dx.doi.org/10.1038/ng.3039

Landmark NIMH ADHD study backed drugs over therapy at a cost

Many children with attention-deficit hyperactivity disorder (ADHD) may have missed out on valuable counseling because of a widely touted study that concluded stimulants such as Ritalin or Adderall were more effective for treating the disorder than medication plus behavioral therapies, experts say.

That 20-year-old study, funded with $11 million from the U.S. National Institute of Mental Health, concluded that the medications outperformed a combination of stimulants plus skills-training therapy or therapy alone as a long-term treatment.

But now experts, who include some of the study's authors, think that relying on such a narrow avenue of treatment may deprive children, their families and their teachers of effective strategies for coping with ADHD.

"I hope it didn't do irreparable damage," study co-author Dr. Lily Hechtman, of McGill University in Montreal, stated. "The people who pay the price in the end [are] the kids. That's the biggest tragedy in all of this."

Professionals worry that the findings have overshadowed the long-term benefits of school- and family-based skills programs.

The original findings also gave pharmaceutical companies a significant marketing tool—now more than two-thirds of American kids with ADHD take medication for the condition.

And insurers have also used the study to deny coverage of psychosocial therapy, which costs more than daily medication but may deliver longer-lasting benefits.

An insured family might pay $200 a year for stimulants, while individual or family therapy can be time-consuming and expensive, reaching $1,000 or more.

About 8 percent of U.S. children are diagnosed with ADHD before the age of 18, according to the U.S. Centers for Disease Control and Prevention.

People with the condition may have trouble paying attention, often act without thinking and may be hyperactive, making school work and the acquisition of essential skills extremely difficult.

Drugs that improve attention make it easier for the children to learn, but when the drug wears off or if the users stop taking the drugs, benefits are less apparent.

Some experts today cite limitations of the original study, which looked at classic ADHD symptoms such as forgetfulness and restlessness over academic achievement and family and peer interactions.

This gave medication an edge over therapy from the get-go, several people involved with the study reported.

"When you asked families what they really liked, they liked combined treatment," said Dr. Peter Jensen, formerly head of child psychiatry at the National Institute of Mental Health (NIMH) who oversaw the study for the institute.

"They didn't not like medicine, but they valued skill training. What doctors think are the best outcomes and what families think are the best outcomes aren't always the same thing."

For the study, the NIMH enlisted more than a dozen experts to determine the best ADHD treatment.

Close to 600 children with ADHD, aged 7 to 9, received one of four treatments for more than a year: medication alone, behavioural therapy alone, a combination of both treatments, or nothing in addition to their current treatment.

The study authors concluded in a 1999 paper that medication was superior to behavioural treatment.

But when the children in the study were followed into adulthood, the study results looked less conclusive.

Use of any treatment "does not predict functioning six to eight years later," a follow-up paper from the study determined, the Times reported.