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Non-Genetic Factors Play Surprisingly Large Role In Determining Autism, Says Study By Group Including Stanford/Packard Researchers


STANFORD, Calif.
-- A new Stanford University School of Medicine study of twins suggests that non-genetic factors play an unexpectedly large role in determining autism risk, turning upside down recent assumptions about the cause of this common, disabling developmental disorder.

From prior studies of shared autism in twins, scientists had estimated that 90 percent of autism risk was attributable to genes and only 10 percent to non-genetic environmental factors. But the new study — the largest ever of twins in which at least one in each pair has autism — shows almost the opposite: It found that genes account for 38 percent of autism risk, with environmental factors explaining the remaining 62 percent.

"It took me a bit by surprise that the heritability of autism was so much lower than previous studies calculated," said Joachim Hallmayer, MD, the first author of the new paper, which appears July 4 in Archives of General Psychiatry. "Our work suggests that the role of environmental factors has been underestimated." Hallmayer is an associate professor of psychiatry and behavioral sciences at Stanford. The study's senior author is Neil Risch, PhD, professor of biostatistics at UC-San Francisco and director of the UCSF Institute for Human Genetics.

For years, studies of non-genetic autism risk factors focused on the idea that childhood vaccines might trigger autism, a theory that extensive research did not support. But it remains an open question how much time and resources to devote to other potential environmental risks and how they interact with genetic factors.

"Our research shows us that we need to be studying both genetic and environmental factors as well as how they interact with each other," Hallmayer said. "We need to explore areas of environmental risk that are shared by both twin individuals and impact the development of the child."

Although the study does not identify specific environmental factors, they could include any non-genetic factors that influence autism risk.

The children studied were 192 pairs of twins (384 individuals) identified from a California-wide registry of children who receive services for developmental disabilities. The large size of the study and the fact that the subjects were drawn from California's entire, highly diverse population means the study's results are more reliable and apply more broadly than those from prior studies, which examined small, homogeneous groups of children in Northern European countries, Hallmayer said.

The study included 54 pairs of identical twins and 138 pairs of fraternal twins. At least one child from each pair had been diagnosed with full-blown autism or a less severe form of autism spectrum disorder. The scientists conducted standardized evaluations to verify the children's diagnoses, a step that many prior studies had omitted. Children whose autism was known to be secondary to another disease were not included in the study.

To calculate the relative contributions of genes and environment to autism risk, the researchers then examined the difference in shared autism rates between identical and fraternal twins. Identical twins share all their genes, fraternal twins share half of theirs, and both types of twins share most elements of their environment from conception through childhood. As the scientists expected for a disease that is partly explained by genes, the identical twins were more likely to share an autism diagnosis than the fraternal twins. Identical twins did not always share their diagnosis, hinting that non-genetic factors contribute to autism. The surprise came, however, in the calculation of environmental contributions to autism risk.

"The dizygotic [fraternal] twins are more similar than you would expect if you take only genetic factors into account," Hallmayer said. The higher-than-expected degree of similarity between fraternal twins confirmed that something other than genes was at work — in other words, the twins' shared environments helped explain their shared diagnoses.

To precisely calculate the genetic and environmental contributions to autism risk, the scientists employed a mathematical model that used the rate of autism in the general population to estimate the rate at which fraternal twins would have been expected to share a diagnosis if autism were purely genetic. This figure was compared with the rates of shared autism observed in the twins in the study to arrive at the scientists' final projections. Demographic factors found in previous studies to be associated with autism, such as the ages of the twins' parents, years of parental education, ethnicity, difference in birth weight between twins and gestational age at birth did not impact the rate of shared diagnosis between twin individuals.

The finding that autism risk is strongly influenced by environmental factors should alert scientists to the need to study risk factors they haven't been considering, the researchers said. In recent years, autism research has been focusing more on genetics.

"Scientists need to look for environmental factors," said Linda Lotspeich, MD, a study author, a clinical professor of psychiatry and behavioral sciences at Stanford and a child and adolescent psychiatrist who treats children with autism at the Stanford Autism Center at Packard Children’s Hospital. "But that doesn't take away the fact that autism also has a genetic component and is still caused by unknown genes."

And what might the unknown environmental risk factors be?

"That's the multimillion dollar question," Hallmayer said. "I think a lot about it." Autism's manifestation in very young children points to something that happens in early life, potentially even during pregnancy, he said.

"Our findings suggest that events during pregnancy should be a focus for future research into the origins of autism," said Lisa Croen, PhD, a coauthor on the study.  Croen is a senior research scientist and director of the Autism Research Program at the Kaiser Permanente Division of Research.

In addition to Hallmayer and Lotspeich, the Stanford researchers who contributed to the project included Jennifer Phillips, PhD, clinical associate professor of psychiatry and behavioral sciences; and research assistants Sue Cleveland and Andrea Torres. The Stanford team collaborated on the study with scientists at the advocacy organization Autism Speaks; the California Department of Public Health; Kaiser Permanente Northern California; UC-Davis and UCSF.

The research was funded by grants from the National Institute of Mental Health and Autism Speaks.

More information about the Department of Psychiatry and Behavioral Sciences, which also supported this work, is available at http://psychiatry.stanford.edu/.

Authors

About Stanford Children’s Health and Lucile Packard Children’s Hospital Stanford
Stanford Children’s Health, with Lucile Packard Children’s Hospital Stanford at its core, is an internationally recognized leader in world-class, nurturing care and extraordinary outcomes in every pediatric and obstetric specialty from the routine to rare, for every child and pregnant woman. Together with our Stanford Medicine physicians, nurses, and staff, we deliver this innovative care and research through partnerships, collaborations, outreach, specialty clinics and primary care practices at more than 100 locations in the U.S. western region. As a non-profit, we are committed to supporting our community – from caring for uninsured or underinsured kids, homeless teens and pregnant moms, to helping re-establish school nurse positions in local schools. Learn more about our full range of preeminent programs and network of care at stanfordchildrens.org, and on our Healthier, Happy Lives blog. Join us on Facebook, Twitter, LinkedIn, and YouTube.


Lucile Packard Children’s Hospital Stanford
is the heart of Stanford Children’s Health, and is one of the nation’s top hospitals for the care of children and expectant mothers. For a decade, we have received the highest specialty rankings of any Northern California children’s hospital, according to U.S. News & World Report’s 2014-15 Best Children’s Hospitals survey, and are the only hospital in Northern California to receive the national 2013 Leapfrog Group Top Children’s Hospital award for quality and patient care safety. Discover more at stanfordchildrens.org.

About Stanford University School of Medicine
The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children’s Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.