Summary of Advances
In Autism Spectrum Disorder Research
Most genetic risk for autism resides with common variation
Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, Buxbaum JD. Nat Genet. 2014 Aug;46(8):881-5. [PMID: 25038753]
Genetic risk for autism comes from alterations to genes that may be inherited or that may occur spontaneously during fetal development. Many past genetic studies of ASD have focused on the possible roles of rarely occurring inherited mutations and spontaneous genetic mutations. However, common genetic variations—inherited genetic differences in the genetic code that are found in many people with and without autism—are also thought to be an important component of autism risk. This study was designed to estimate the relative contributions of spontaneously occurring mutations, rare inherited mutations, and common genetic variations to the risk of ASD. The researchers analyzed data from Sweden’s Population-Based Autism Genetics and Environment Study (PAGES). They looked at nearly 532,000 common genetic variants from 466 individuals with autism and 2,580 individuals who were not known to have autism. They found that common genetic variations accounted for roughly half (49%) of autism heritability in the population. Although each common genetic variant has a relatively small impact on autism risk by itself, taken together, the researchers estimate that common variations present the largest type of heritable risk for autism. In contrast, they found that spontaneous genetic alterations as well as rare inherited alterations each accounted for only about 3% of autism risk. Although spontaneous genetic changes contributed relatively little to autism risk overall, such mutations can exert a disproportionately large influence on an individual’s likelihood of exhibiting autism. For example, researchers estimated that of the 14% of autistic individuals with a certain kind of spontaneous mutation contributing to autism risk, the vast majority (approximately 80%) would not have been affected had they not been carrying that particular mutation. The researchers also looked at the relative contribution of non-genetic (environmental) factors on autism risk. Past studies have provided vastly different estimates of the importance of genetic versus other factors, with estimates of the genetic role ranging from 38% to nearly 100%. This study’s researchers estimated autism heritability at around 60% (with the majority of risk associated with common genetic variations), and found that other factors account for the remaining 40% of autism risk.
Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay
Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I. Pediatrics. 2014 May;133(5):e1241-8. [PMID: 24733881]
Serotonin is a chemical neurotransmitter that plays an important role in relaying signals from one neuron in the brain to another, and is involved in regulation of mood, appetite, sleep and other important brain functions. It is hypothesized by scientists that serotonin may also play a role in early brain development. Serotonin has been implicated in autism in part because about one third of children with ASD have higher blood levels of this neurotransmitter. The most commonly prescribed medications used to treat depression are drugs that interfere with the normal uptake of serotonin back into nerve cells following release; medications in this class are known as selective serotonin reuptake inhibitors (SSRIs). Using SSRI medication during pregnancy may raise a mother’s blood levels of serotonin, which may, in turn, affect serotonin levels in the developing fetus. About one in 25 pregnant women take SSRIs. Previous findings on risk of ASD in children whose mothers take antidepressants during pregnancy are mixed. This population-based case-control study tests for a relationship between mothers’ prenatal use of SSRIs and the odds of ASD and developmental disorders (DD) in their children. Cases were drawn from the Childhood Autism Risks from Genetics and Environment (CHARGE) study, which enrolled children with ASD or DD from the general population. Children in the CHARGE study were 2 to 5 years of age at the time of enrollment, born in California to a parent who speaks English or Spanish, and lived with at least one biological parent. The researchers compared these children to a group of children that matched in terms of age, gender, and location, but who had not been diagnosed with ASD or DD. A total of 966 mother-child pairs were studied: 492 ASD, 154 DD, and 320 typical development (TD). Mothers were interviewed by telephone to learn about their SSRI use 3 months before pregnancy and during each trimester, and their medical records were also reviewed. Other information collected included maternal substance use history, use of St John’s wort and other supplements that affect serotonin, history of mood or anxiety disorders or other psychiatric conditions, birthplace of the mother, and more.
The researchers found that, taken as a whole, children exposed to SSRIs in the womb were no more likely than unexposed children to have ASD or DD. However, when classified by sex, boys whose mothers used SSRIs were nearly three times more likely to have ASD than were TD children. (There were too few exposed girls to analyze.) The strongest relationship was seen in boys with ASD exposed to SSRIs in the first trimester. SSRI use also was correlated with DD, with the strongest relationship seen in boys exposed in the second and third trimesters. In previous studies of SSRI use and ASD or DD, it has been difficult to determine whether SSRI use or the underlying depression, anxiety, or other mood disorder may be increasing the risk of certain developmental outcomes. To help address this question, the researchers in this study restricted their analysis of SSRI use to those mothers who reported a history of anxiety or mood disorder at any time prior to birth. A pattern of results similar to those in previous studies (correlating SSRI use with ASD/DD) was found, suggesting that the observed association of ASD and DD with maternal SSRI use in this study was not confounded by maternal mental health. The strength of this study in comparison to others on the same topic is that the study captured actual use of medication and not just whether medication was dispensed, but the interview-based approach has the limitation of recall bias (that participants may not have accurately recalled/reported their earlier activities). The researchers note that due to the overall low prevalence of SSRI use during pregnancy and other factors that may have a stronger influence on the development of ASD, SSRI use among pregnant women will likely not drive increasing rates of ASD. They also caution that untreated depression during pregnancy carries known risks for both mother and child and conclude that the benefits and risks of using SSRIs to treat depression during pregnancy must be carefully considered.
The contribution of de novo coding mutations to autism spectrum disorder
Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha M, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, McCombie WR, Shendure J, Eichler EE, State MW, Wigler M. Nature. 2014 Nov 13;515(7526):216-21. [PMID: 25363768]
Because ASD tends to run in families, much research has focused on inherited genetic mutations that increase the risk of autism. However, less is known about how or to what extent spontaneously occurring mutations (known as de novo mutations) increase ASD risk, compared to the contributions of inherited mutations. To begin to address this question, the researchers in this study analyzed the DNA of more than 2,500 children with ASD, 1,900 of their siblings without autism, and their parents. Based on their analysis, the researchers estimate that de novo mutations accounted for about 30% of the ASD diagnoses in low-risk families (having only one child with ASD). At the same time, de novo mutations were found to account for about 45% of ASD in females. Some de novo genetic mutations— specifically, Likely Gene Disrupting (LGD) mutations—are relatively rare yet were found to be more harmful; the researchers estimate that, when these kinds of mutations do occur, a large percentage of them (roughly 43%) contribute to ASD. Siblings with and without ASD had similar rates of de novo mutations, but the children with ASD had significantly higher rates of LGD mutations compared with their unaffected siblings.
The researchers then looked more closely at the LGD mutations across their study population of children with ASD and identified 391 different LGD mutations affecting a total of 353 genes. Of these, 27 genes were affected by more than one de novo mutation (known as a recurrent mutation). The LGD mutations in ASD tended to affect genes thought to be important in early neurological development, including genes involved in the modification of chromatin (part of a cell that packages DNA and determines whether genes are “turned on” or “turned off”), genes important for brain plasticity, and genes active in stages of embryonic development.
Among individuals with ASD attributable to de novo mutations, the researchers observed key differences between two groups: (1) high-IQ males (those with a nonverbal IQ >90); and (2) females of all IQ levels and low-IQ males. For instance, both females and low-IQ males shared a number of the same genes targeted by LGD mutations, while the genes found to be affected in the high-IQ males did not overlap. In addition, the affected genes in females and low-IQ males also overlapped significantly with genes targeted by mutations associated with schizophrenia and intellectual disability; genes of high-IQ males did not, suggesting there may be different molecular pathways involved in the high-IQ group. Recurrent mutations may be associated with the more severe symptoms seen in females and low-IQ males. For example, in this study, males with recurrent LGD mutations had on average a 20-point lower IQ than unaffected individuals. By examining these rare yet particularly harmful mutations and gaining a better understanding of the genes affected in ASD, the researchers are hopeful that their observations will lead to a deeper knowledge of the underlying biology of autism and perhaps enable the future development of treatments with widespread promise for those with ASD.
The familial risk of autism
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. JAMA. 2014 May 7;311(17):1770-7. [PMID: 24794370]
ASD is considered the most heritable of all developmental disorders, which has led to much research on the genetic factors that contribute to the development of autism. Although these studies have produced evidence about alterations to genes associated with ASD, they have not been able to measure the individual risk of ASD. This study addresses that knowledge gap. In Sweden, all children are assessed for development disorders at age 4, and diagnostic information is reported to the National Patient Register. The Register contains virtually complete national coverage of psychiatric disorders from 1973. This study aimed to calculate the individual risk of an autism diagnosis by analyzing data on all births in Sweden from 1982 through 2006. The study looked at data from more than two million families, including approximately 20,000 children with ASD. To date, it is the largest long-term study of the risk of ASD in families. Specifically, the study aimed to estimate relative recurrence risk (RRR), which is the risk that a sibling of a child who has autism will also have an autism diagnosis compared with a sibling of a child who does not have autism. The study measured RRR for fraternal and identical twins, full siblings, half siblings, and cousins of full siblings of children with ASD. The researchers also accounted for the psychiatric history of parents prior to the child’s birth, the ages of parents at birth of the child, the birth year, and the child’s sex. Results showed that RRR increased with closer familial relationships. Compared with a full sibling of a child without ASD, a full sibling of a child diagnosed with ASD was more than 10 times more likely to also have a diagnosis. Similarly, a maternal half sibling was more than three times more likely, a paternal half sibling was nearly three times more likely, and a cousin was twice as likely to have ASD. There was no significant difference in risk between boys or girls with a sibling with ASD based on the sex of that sibling (a boy with a sister with ASD is at similar risk for ASD as a girl with a brother with ASD and vice versa). For individuals without a sibling with ASD, the chance of having an ASD diagnosis by age 20 was 1% (one out of 100). In comparison, a cousin of an individual with ASD has a 3% chance of being diagnosed with ASD before age 20, a paternal half sibling: 7%, a maternal half-sibling: 9%, full siblings and fraternal twins: 13%, and identical twins: 59%. The study also assessed the importance of environmental and genetic factors and estimated that genetics accounted for 50% of the risk for ASD.
Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies
Taylor LE, Swerdfeger AL, Eslick GD. Vaccine. 2014 Jun 17;32(29):3623-9. [PMID: 24814559]
Though several research studies conducted in recent years have suggested that there is not a link between vaccines and autism, this issue continues to be a concern for some members of the autism community and the general public. This study was conducted to review existing research in finer detail to try to determine whether the body of scientific literature to date supports a link between vaccines and autism. The study used a meta-analysis approach, which is a method of pooling research data across studies and evaluating outcomes, to examine the relationship between two variables, which in this case are ASD and vaccines. Multiple biomedical research databases were searched for studies that looked at any of the proposed causes associated with vaccination (measles, mumps, and rubella [MMR]; mercury; or thimerosal), and included development of conditions on the autistic spectrum as an outcome. The researchers identified 10 studies as meeting the inclusion criteria: five case-control studies (a type of observational study that compares two groups of study subjects) involving just over 1.2 million children, and five cohort studies (a type of observational study that follows the same group of subjects over a long period of time) involving close to 10,000 children. None of the 10 studies reported a positive link between ASD and MMR, mercury, or thimerosal. When researchers pooled the data from the five cohort studies, they found that exposure to vaccine or vaccine components had no effect on the risk of developing autism, either when all data were pooled or when separated by type of exposure. The researchers found the same result with the five case-control studies; MMR, thimerosal, and mercury exposure did not increase the risk of developing ASD either overall or individually. This meta-analysis found overall that across multiple studies using rigorous methodology, which when pooled included over 1.2 million children, there was no evidence for a link between vaccines or vaccine components and the development of any ASD outcome.