What are the greatest risk factors for autism? Are they genetic or environmental? If genetic, does the risk come from inherited mutations or from ones that arise spontaneously? From rare genetic variations or common ones? In the largest study of its kind to probe these elusive questions, an international team of scientists determined genes play a crucial role in the development of autism spectrum disorder (ASD), and that most of the risk comes from common inherited genetic variations, each of which have little influence alone but are powerful en masse.
"Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact when taken together," says Brain & Behavior Research Foundation Scientific Council member Joseph D. Buxbaum, Ph.D., Professor of Psychiatry, Neuroscience, Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, New York, first author of the study paper published online July 20th in Nature Genetics.
Drawn from the Population-Based Autism Genetics and Environment Study (PAGES) Consortium and led by Kathryn Roeder, Ph.D., of Carnegie Mellon University, the research team applied sophisticated new statistical methods to analyze data from approximately 3,000 samples from patients with ASD and compare them to samples from typical control subjects. The large sample was made available by the Swedish universal health registry. The research team included 2006 NARSAD Independent Investigator Grantee Pamela Sklar, M.D., Ph.D., and 2004 NARSAD Young Investigator Grantee Abraham Reichenberg, Ph.D., of the Icahn School of Medicine at Mount Sinai.
While, the researchers report, more than half of the risk for developing ASD appears to come from common inherited gene variations—and only 2.6 percent from spontaneously arising mutations, what scientists call ‘de novo’ mutations—the rarer mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member. "The family may have a common variation that puts it at risk, but if there is also a de novo mutation on top of that, it could push an individual over the edge,” explains Dr. Buxbaum. “So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder.”
Thomas R. Insel, M.D., Director of the National Institute of Mental Health, states: "Thanks to the boost in statistical power that comes with ample sample size, autism geneticists can now see the forest for the trees.” He adds: “Knowing the nature of the genetic risk will help focus the search for clues to the molecular roots of the disorder."