A new paper in Nature Genetics finds that nearly 60 percent of the risk of developing autism is genetic and most of that risk is caused by inherited variant genes that are common in the population and present in individuals without the disorder.

Although autism is thought to be caused by an interplay of genetic and other factors, there has been no consensus on their relative contributions and the nature of its genetic architecture. Recently, evidence has been mounting that genomes of people with autism are prone to harboring de novo mutations - rare, spontaneous mutations that exert strong effects and can largely account for particular cases of the disorder.

Specifically, the current 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.

"We show very clearly that inherited common variants comprise the bulk of the risk that sets up susceptibility to autism," says Joseph D. Buxbaum, PhD, the study's lead investigator and Director of the Seaver Autism Center for Research and Treatment and Professor of Psychiatry, Neuroscience and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. "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."

Buxbaum and colleagues of the Population-Based Autism Genetics and Environment Study (PAGES) Consortium conducted a rigorous analysis of DNA sequence variations from an ongoing, comprehensive study of autism in Sweden. 

"Many people have been focusing on de novo mutations, such as the ones that can occur in the sperm of an older father," explains Dr. Buxbaum. "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 variations in the genetic code shared by most people, individually much subtler in effect, has proven to be even more challenging. Limitations in sample size and composition have made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited and rare, spontaneous de novo variation. Differences in methods and statistical models have also resulted in estimates of autism 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. The PAGES study was made possible by Sweden's universal health registry, which allowed investigators to compare very large samples (n~3000 in the current study) of people with autism with matched controls. Researchers also employed 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 family-based study in the Swedish population, which took into account data from twins, cousins and factors such as age of the father at birth and parents' psychiatric history.

"This is a different kind of analysis than employed in previous studies," says Thomas Lehner, PhD, Chief of the National Institute of Mental Health's (NIMH) Genomics Research Branch. "Data from genome-wide association studies was used to identify a genetic model instead of focusing on just pinpointing genetic risk factors. The researchers were able to pick from all 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 in 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, a de novo mutation could be a critical determinant that leads to the manifestation of autism spectrum disorder in a particular family member," says Dr. Buxbaum. "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."