Now identified: High-confidence risk genes for autism spectrum disorder

About the School of Medicine Paper of the Month

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Senior Associate Dean for Research Mary Stenzel-Poore, Ph.D., Associate Dean for Clinical Science Eric Orwoll, M.D., and Assistant Dean for Basic Research Mary Heinricher, Ph.D.

November 26, 2014

November's featured paper is called "The contribution of de novo coding mutations to autism spectrum disorder," published in Nature. Brian O'Roak, Ph.D., assistant professor of molecular and medical genetics and member of the Institute on Development & Disability, is a lead author in collaboration with other research groups.

Autism spectrum disorder (ASD) is a developmental disability that affects the behavior, communication and social skills of affected individuals. The term “spectrum” is used to represent the wide range of symptoms and levels of impairment that children with ASD may exhibit: an autistic individual’s ability to learn and think can range from gifted to severely challenged. 

The CDC currently estimates that about 1 in 68 children has been diagnosed with ASD. Interestingly, most people who develop ASD have no reported family history of autism, suggesting that random gene mutations may affect a person's risk. 

"We've known for a long time that autism has a strong genetic component," said Brian O'Roak, Ph.D., assistant professor of molecular and medical genetics and member of the Institute on Development & Disability. "However, because there is not a single causative gene, identifying specific and high confidence risk genes has been difficult."  

o'roak lab group

Discovery of risk genes

Previous work by Dr. O'Roak and colleagues used cohorts of 200 to 300 families, each of which had at least one a child affected by ASD and one unaffected child. These families are ideally suited to help identify spontaneous mutations (also called de novo mutations) that likely contributed to autism in one child but do not affect other siblings.

"We hypothesized that in these 'sporadic' families, new mutations may be playing a significant role," said Dr. O'Roak.  "Unfortunately, we still lacked the ability to identify more high confidence genes without a larger sample size."

Dr. O'Roak is one of the lead authors in this month's featured paper. This multi-year study brought together three research groups to sequence and analyze the genomes of more than 2,500 families. With this unprecedented sample size, Dr. O'Roak and colleagues were able to identify 27 high confidence risk genes that appear to contribute to 25 percent of male autism diagnoses and just under half of all female diagnoses. Interestingly, the types of genes that were identified overlapped between boys and girls with lower IQ, but not with boys of higher IQ.  

Further analysis of the high confidence risk genes found that some mutations were enriched in specific populations. Genes that code for proteins that are either targets of the Fragile X protein or involved with DNA packaging appear to play a role in autism for all ASD children except higher IQ males.  De novo mutations in embryonically expressed genes appear to play a more significant role with female ASD children. 

"We've identified a whole set of novel genes and pathways that 10 years ago we would have never guessed were involved with autism," said Dr. O'Roak.  "Now autism researchers have a better understanding of the contribution of these mutations. But we estimate that there may be 400 more genes left to find," added Dr. O'Roak. 

Next steps

"I chose this paper because of its unprecedented insights into the genetic factors of autism," said Mary Heinricher, Ph.D., assistant dean for basic research.  "I am excited to see what Dr. O'Roak will do here at OHSU." 

Dr. O'Roak has been at OHSU since fall of 2013 and cites the strong community of neuroscience researchers as a major draw. "I was excited to come to OHSU and join Dr. Eric Fombonne, a world leader in autism epidemiology, along with other university leaders like Brian Rodgers and Jan van Santen," said Dr. O'Roak. "Together we plan to build a multidisciplinary, translational research program that will run the gamut from initial gene discovery to targeted therapeutics and clinical interventions for children with ASD and related disorders." 

Dr. O'Roak's laboratory is currently pursuing additional genetic and functional studies based on these findings. The lab has also started a new project, funded by the Simons Foundation, which looks at the role of a completely different class of mutations in autism. Emerging research suggests that some developmental disorders may be the result of genetic mutations that occur after fertilization (not present in the egg or sperm) but early in fetal development ─ so-called somatic mosaic mutations since they are only in a portion of cells.



Nature. 2014 Oct 29. doi: 10.1038/nature13908.
The contribution of de novo coding mutations to autism spectrum disorder.
Iossifov I1, O'Roak BJ2, Sanders SJ3, Ronemus M1, Krumm N4, Levy D1, Stessman HA4, Witherspoon KT4, Vives L4, Patterson KE4, Smith JD4, Paeper B4, Nickerson DA4, Dea J5, Dong S6, Gonzalez LE7, Mandell JD5, Mane SM8, Murtha MT7, Sullivan CA7, Walker MF5, Waqar Z7, Wei L9, Willsey AJ3, Yamrom B1, Lee YH1, Grabowska E10, Dalkic E11, Wang Z1, Marks S1, Andrews P1, Leotta A1, Kendall J1, Hakker I1, Rosenbaum J1, Ma B1, Rodgers L1, Troge J1, Narzisi G10, Yoon S1, Schatz MC1, Ye K12, McCombie WR1, Shendure J4, Eichler EE13, State MW14, Wigler M1.




Pictured above from left to right: Deidre Krupp, Dr. O'Roak, Sara Evans.