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Autism Awareness Month: Genes and Development in Autism Spectrum Disorder

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Understanding how the brain develops and functions remains among the most difficult of scientific challenges, as is the effort to understand the causes of conditions that alter its function. Among these is autism spectrum disorder (ASD). ASD is described as a spectrum because of the considerable variation in how individuals manifest both symptoms and severity. The core symptoms of ASD, including difficulty in social communication and restricted, often repetitive behaviors, are present in all those affected, but otherwise, there is wide variability in ASD. At the more severe end of the spectrum are individuals who need services as a result of co-occurring intellectual disability or minimal verbal ability, for example. At the other end are individuals with average or superior intellectual ability who can achieve considerable professional and personal success. And in between are the majority of children and adults living with a combination of social, intellectual, and behavioral challenges they and their families face on a daily basis.

Identifying the causes of ASD has proven to be a significant challenge. And while there are several available behavioral treatments that can benefit many if not all of those diagnosed with ASD, much remains to be done in terms of both making helpful treatments more widely available and discovering novel therapies that have the potential to dramatically enhance quality of life. In honor of Autism Awareness Month, I am writing two Director’s Messages about ASD in April. The first, below, explains what we know so far about what causes ASD, and what NIMH researchers are doing to clarify how these causes lead to symptoms. The second, to follow in a few weeks, will discuss currently available therapies for ASD, and NIMH research aimed at learning how to improve access to these therapies.

Genes and ASD

For some time, we have known that ASD is a heritable condition—that is, it runs in families. We know this from a variety of studies—including twin studies, which demonstrate that if one identical twin has ASD, the other twin almost always does also. Indeed, studies suggest that up to 90 percent of the variation in developing ASD is due to genetic factors.1 Nonetheless, as with all complex genetic conditions, environment also plays a role.

Early efforts to identify genetic factors associated with ASD were largely unsuccessful. As little as five years ago, only a handful of genes had been identified, all of which caused complex genetic syndromes, like Fragile X, Rett’s, and Down syndromes, of which ASD is one of several possible comorbid features.2 More recently, however, the situation has changed dramatically. We now know dozens of genes that contribute to ASD, with more being discovered seemingly every day. How many of these genes are there? The latest estimates suggest that hundreds of genes contribute to the likelihood of developing ASD.3

Gene mutations that raise the risk for ASD come in two basic types—common variants with small effects, and rare variants with large effects. Common variants are, well, common. Many people in the population carry these and most of them do not have ASD. However, each of these genetic variants raises the risk for developing ASD very slightly—often by as little as 5 percent, meaning that if you have any one of these variants, your risk of ASD is 1.05 times that of someone who doesn't carry it. We know from family and population studies that common variation explains a large portion of risk for ASD. Identifying the genes in which common variants play a role in ASD is difficult, however, and we have very few as yet. Ultimately, common variants can (and do, see below) give us clues about the biology underlying ASD. Even then, however, any single common variant can’t really predict with any great certainty whether an individual will develop ASD. Rare variants are bigger deals—they can confer significant risk on their own for ASD. For some of these variants, carriers are 30-50 times more likely to develop ASD than non-carriers.

Understanding how these genetic variants lead to ASD may help us understand particular features of risk. For example, we’ve known for a while that a child of older parents (mothers older than 35 or fathers older than 40) seem to be at higher risk for developing ASD.4 At least part of this increased risk appears to be due to the fact that new mutations—especially mutations that disrupt the function of genes—are found more often in the sperm of older men.5 Scientists have also found that girls with ASD have more frequent and more damaging mutations than boys, suggesting that girls are more resilient and boys more susceptible to ASD-related genetic variation, an insight that may help clarify why ASD is diagnosed much more often in boys. Finally, genetic factors that increase risk for ASD also influence normal differences in cognitive, social, and communication abilities in individuals in the general population, suggesting that these factors are important for normal development as well as for explaining ASD.

ASD begins in early neural development

Another way in which understanding the genetic basis of ASD helps us clarify its origins is by helping to specify when during development ASD first arises. NIMH-funded research has revealed that ASD risk genes are most likely to be activated in specific brain cells—pyramidal neurons in the cortex—during mid-fetal development.6, 7 A prenatal timeframe for the neurodevelopmental origins of ASD is also consistent with evidence from epidemiological studies suggesting links between prenatal infections and the later development of the disorder.8

If the developmental process that leads to ASD starts in the womb, one might expect that signs of the disorder would be discoverable even in early infancy. In fact, considerable evidence has emerged that subtle signs and symptoms of ASD are present as early as the first few months of life, long before the diagnosis is typically made. Subtle differences in behavior and motor skills can distinguish between children who will develop ASD and typically developing children.9, 10 These include delays in motor development that can be found as early as six months of age. Early social behavior can also be affected; researchers have reported a decline in attention to others’ eyes within the first two to six months of life in infants who go on to be diagnosed with ASD.11 In a separate study, ASD experts identified combinations of vocal communication behaviors at 18 months that could predict a later diagnosis of ASD.12

A recent NIH-funded brain imaging study supports and extends these behavioral findings. Using MRI scans to image brain growth over time in a high-risk group of siblings of children with ASD, researchers showed an increase in the growth of the cerebral cortex area between 6 and 12 months of age in infants who were diagnosed with ASD at 24 months. Researchers in the study were able to predict 88 percent of those infants who would later meet criteria for ASD at age two.13

Collectively, the genetic, behavioral and neuroimaging findings clarify that the period of risk for ASD is earlier than the age when symptoms may first be noticed by families and caregivers. Attempts to understand how ASD arises—and particularly any environmental exposures that may moderate genetic risk—should be directed at the prenatal and very early postnatal period. The findings also suggest that early detection of ASD might be feasible, in order to link affected children with appropriate interventions as soon as possible. Indeed, straightforward screening of children in primary care settings can identify individuals who are at high risk for developing ASD, enabling early intervention,14 which we know from numerous studies improves long-term outcomes.15

Causes are also opportunities

Current research is focused on the two-fold goal of identifying additional causal factors, as well as exploiting those we already know about to understand the biology of ASD. Identifying additional causal factors requires that investigators examine large datasets with sophisticated “big data” techniques. To facilitate such efforts, NIMH supports several databases and consortia, including the National Database for Autism Research  (NDAR), the Autism Brain Imaging Data Exchange  (ABIDE), the Biomarkers Consortium , and the NeuroBioBank/Autism BrainNet partnership.

On the biological mechanism front, NIMH supports research using a range of advanced technologies to understand the impact of risk factors on the brain. For example, scientists are using a technique by which they can use skin cells from patients to create neurons and grow them in a dish. Using these neurons, they can explore how genetic variants associated with ASD alter neuronal function.16, 17, 18 Other researchers are engineering mice to carry ASD risk genes to test the behavioral effects of these mutations, and to search for treatments that reverse these effects.19 While findings from animals need to be interpreted with caution, they can provide clues as to possible treatments. 

In terms of research time frames, genetic research is in the category of work that will pay off in the long-term. These insights will help provide the basis for mitigating the factors that cause impairment in ASD early in childhood, when behavioral interventions are more likely to be beneficial. Research is also underway aimed at providing benefits in the short term: new ways of identifying and treating children early, and providing services as they mature. That will be the subject of the next message.


References

1 Tick B et al. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J. Child Psychol Psychiatry. 2016 57(5):585-95. PMID: 26709141  

2 Miles JH. Autism spectrum disorders—a genetics review. Genetics in Medicine. 2011 Apr;13(4):278-94. PMID: 21358411 

3 De Rubeis S et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014 515(7526):209-15. PMID: 25363760   Paper estimates more than 1,000 ASD risk genes. (2014 NIMH science update)

4 Durkin MS et al. Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol. 2008 168(11):1268-76. PMID: 18945690 . But see Gratten J et al. Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations. Nat Genet. 2016 Jul;48(7):718-24. PMID: 27213288 

5 Sanders SJ et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012 Apr 4;485(7397):237-41. PMID: 22495306 

6 Parikshak NN et al. Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature. 2016 Dec 15;540(7633):423-427. PMID: 27919067 

7 Willsey AJ et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell. 2013 Nov 21;155(5):997-1007. PMID: 24267886 

8 Careaga M, Murai T, Bauman MD. Maternal immune activation and autism spectrum disorder: from rodents to nonhuman and human primates. Biol. Psychiatry. 2017 Mar 1;81(5):391-401. PMID: 28137374 

9 Zwaigenbaum L. Early identification of autism spectrum disorder: recommendations for practice and research. Pediatrics. 2015 Oct;136 Suppl 1:S10-40. PMID: 26430168 

10 Varcin KJ and Jeste SS. The emergence of autism spectrum disorder: insights gained from studies of brain and behaviour in high-risk infants. Curr. Opin. Psychiatry. 2017 Mar;30(2):85-91. PMID: 28009726. 

11 Jones W, Klin A. Attention to eyes is present but in decline in 2-6-month-old infants later diagnosed with autism. Nature. 2013 Dec 19;504(7480):427-31. PMID: 24196715  (2013 NIMH press release)

12 Swanson MR et al. Naturalistic Language Recordings Reveal "Hypervocal" Infants at High Familial Risk for Autism. Child Dev. Epub 2017 Mar 10. PMID: 28295208 

13 Hazlett HC et al. Early brain development in infants at high risk for autism spectrum disorder. Nature. 2017 Feb 15;542(7641):348-351. PMDD: 28202961  

14 Zwaigenbaum L et al. Early screening of autism spectrum disorder: recommendations for practice and research. Pediatrics. 2015 Oct;136 Suppl 1:S41-59. PMID: 26430169 

15 Zwaigenbaum L et al. Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research. Pediatrics. 2015 Oct;136 Suppl 1:S60-81. PMID: 26430170 

16 Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell. 2010 Nov 12;143(4):527-39. PMID: 21074045  

17 Pasca SP et al. Using iPS cell-derived neurons to uncover cellular phenotypes associated with Timothy Syndrome. Nature Medicine. 2011 17(12):1657-62. PMID: 22120178  (2011 NIMH press release)

18 Sztainberg Y and Zoghbi HY. Lessons learned from studying syndromic autism spectrum disorders. Nat Neurosci. 2016 Oct 26;19(11):1408-1417. PMID: 27786181 

19 Wells MF et al. Thalamic reticular impairment underlies attention deficit in Ptchd1Y/- mice.  Nature. 2016 Mar 23. doi: 10.1038/nature17427. PMID: 27007844   (2016 NIMH science update)