autism risk study
July 21, 2014

Common Variants Responsible For Most Genetic Risk Of Autism

redOrbit Staff & Wire Reports - Your Universe Online

The majority of the genetic risks for developing autism can be traced to common versions of genes, not rare variants or spontaneous mutations, according to the results of a National Institutes of Health-funded study that appeared in Sunday’s edition of the journal Nature Genetics.

In total, approximately 52 percent of the risk for autism was traced to common or rare inherited variation, while spontaneous mutations comprised just 2.6 percent of the overall risk, a team of researchers led by Dr. Joseph Buxbaum of the Icahn School of Medicine at Mount Sinai (ISMMS) in New York reported in the paper.

In addition, heritability was also found to outpace other risk factors. The study is said to be the largest of its kind, and the Population-Based-Autism Genetics and Environment Study (PAGES) Consortium researchers behind the paper claim that their findings indicate that inheritability outweighs environmental risk.

Dr. Buxbaum and his colleagues conducted a rigorous analysis of DNA sequence variations from an ongoing, comprehensive study of autism in Sweden. Health registry data from 3,000 patients, some of whom were autistic individuals and some belonging to a control group, was analyzed for the purposes of the study.

“We show very clearly that inherited common variants comprise the bulk of the risk that sets up susceptibility to autism,” explained Dr. Buxbaum, is an ISMMS professor as well as the director of the Seaver Autism Center for Research and Treatment. “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.”

“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,” added Dr. Thomas R. Insel, 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.”

While autism is believed to be caused by the interplay of genetic and other factors, scientists have never been able to reach a consensus on the relative contributions of those factors, the researchers said. Recent research has uncovered mounting evidence that the genomes of autistic men and women are likely to contain de novo mutations – rare, spontaneous mutations with strong effects that are largely to blame for certain cases of the ailment.

“Many people have been focusing on de novo mutations, such as the ones that can occur in the sperm of an older father. 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,” Dr. Buxbaum said.

“Within a given family, a de novo mutation could be a critical determinant that leads to the manifestation of autism spectrum disorder in a particular family member,” he added. “If the family has a common variation that puts it at risk, an added de novo mutation could push an individual over the edge and result in that person developing the disorder.”

Determining the impact on autism risk in genetic variations shared by most individuals - which have a much subtler impact - has proven to be difficult due to limits in sample size and composition. However, thanks to Sweden’s health registry, the authors of this new study were able to compare large groups of autistic people with matched controls, as well as use new statistical techniques of sorting out the heritability of the disorder.

“This is a different kind of analysis than employed in previous studies,” said Dr. Thomas Lehner, chief of the Genomics Research Branch of the NIH's National Institute of Mental Health (NIMH). “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.”

Image 2 (below): 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