Print“We show very clearly that inherited common variants comprise the bulk of the risk that sets up susceptibility to autism, says Joseph Buxbaum, of the Icahn School of Medicine at Mount Sinai in New York City and the study’s lead investigator. ”
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, according to a new study published in the July 20 edition of Nature Genetics.
The National Institutes of Health-funded study found that about 52.4 percent of autism was traced to common and rare inherited variations, with spontaneous mutations contributing a modest 2.6 percent of the total risk.
Researchers at the Population-Based Autism Genetics and Environment Study Consortium used data from Sweden's universal health registry to compare roughly 3,000 people with autism with matched controls. In the largest study of its kind to date, the team also showed that inheritability outweighs environmental risk.
“We show very clearly that inherited common variants comprise the bulk of the risk that sets up susceptibility to autism,” says Joseph Buxbaum, of the Icahn School of Medicine at Mount Sinai in New York City and the study’s lead investigator. “But while families can be genetically loaded for autism risk, it may take additional rare genetic factors to actually produce the disorder in a particular family member.”
Although autism is thought to be caused by the 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.
“Many people have been focusing on de novo mutations, such as the ones that can occur in the sperm of an older father,” Buxbaum says. “While we find these mutations are also key contributors, it is important to know that there is underlying risk in the family genetic architecture itself.”
Gauging the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect, has proven to be challenging. 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 lead to the 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. Sweden's universal health registry 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,” says Thomas Lehner, chief of the National Institute of Mental Health’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 autism spectrum disorder in a particular family member, Buxbaum says. “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.”
Other lead investigators on the study included Christina Hultman at the Karolinska Institute in Stockholm; Bernie Devlin at the University of Pittsburgh; Avraham Reichenberg at the Icahn School of Medicine at Mount Sinai; and Kathryn Roeder at Carnegie Mellon University in Pittsburgh.
July 17, 2014
http://www.burrillreport.com/article-genetic_risk_for_autism_mostly_from_common_gene_variants_.html
