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Summary of Advances Cover 2019

Summary of Advances

In Autism Spectrum Disorder Research


Question 3: What Causes ASD, and Can Disabling Aspects of ASD be Prevented or Preempted?

Association of Genetic and Environmental Factors with Autism in a 5-Country Cohort
Bai D, Yip BHK, Windham GC, Sourander A, Francis R, Yoffe R, Glasson E, Mahjani B, Suominen A, Leonard H, Gissler M, Buxbaum JD, Wong K, Schendel D, Kodesh A, Breshnahan M, Levine SZ, Parner ET, Hansen SN, Hultman C, Reichenberg A, Sandin S.JAMA Psychiatry. 2019 Jul 17. [PMID: 31314057]

The origins of ASD are not fully understood, but research has consistently supported a significant effect of both common and rare inherited genetic variations. Additionally, there is evidence that other, non-inherited traits may also influence the development of ASD. One type of non-inherited trait is maternal effects—the genetic influences originating from the mother independent of what is inherited by the child, such as gestational diabetes or complications resulting in pre-term birth. Another type of non-inherited trait is environmental exposure, which originates from either a shared environment (exposure that affects family members similarly) or a non-shared environment (exposure that uniquely affects an individual). Although both heritable and non-heritable traits have been associated with ASD, less is known about the potential for an additive effect of these traits on ASD risk.

The current study addressed this knowledge gap by estimating the cumulative influence of genetic variation, maternal effects, and environmental exposures on ASD risk. The researchers also aimed to determine the individual risk contribution associated with each of these factors and the consistency of risk estimates across different geographical locations.

The researchers examined five large, multigenerational datasets from children born between 1998 and 2011 across Denmark, Finland, Sweden, Israel, and Western Australia, collecting data from birth up to 16 years of age. To determine inherited and non-inherited influences of ASD risk, the researchers used health outcome data to estimate effects associated with degree of familial relation across three generations, including a given child, his/her full siblings, and his/her maternal parallel cousins (i.e. the children of the child’s mother’s sister). By comparing across these different relationships, the researchers were able to develop models to analyze the different components of risk and to identify any additive effect.

Of the 2,001,631 children included in the study, 22,156 (1.11%) were diagnosed with ASD. The researchers found that maternal effects had a minimal contribution, accounting for only 0.4 to 1.6% of ASD risk. Shared environmental effects on ASD risk ranged from 0 to 14.5%, while non-shared environmental effects ranged from 15 to 34%. Conversely, inherited genetic factors contributed approximately 80% of ASD risk, although this figure significantly varied by country (for example, 51% in Finland and 87% in Israel).

These findings indicate that the majority of ASD risk is attributable to inherited genetic factors, with a modest additional contribution from non-shared environmental effects. There was some variation in genetic risk across countries, indicating that there may be genetic differences between these population structures. Importantly, maternal effects accounted very minimally towards total ASD risk, indicating that maternal-targeted interventions may be less influential in reducing ASD risk.

Identification of Common Genetic Risk Variants for Autism Spectrum Disorder
Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, Pallesen J, Agerbo E, Andreassen OA, Anney R, Awashti S, Belliveau R, Bettella F, Buxbaum JD, Bybjerg-Grauholm J, Bækvad-Hansen M, Cerrato F, Chambert K, Christensen JH, Churchhouse C, Dellenvall K, Demontis D, De Rubeis S, Devlin B, Djurovic S, Dumont AL, Goldstein JI, Hansen CS, Hauberg ME, Hollegaard MV, Hope S, Howrigan DP, Huang H, Hultman CM, Klei L, Maller J, Martin J, Martin AR, Moran JL, Nyegaard M, Nærland T, Palmer DS, Palotie A, Pedersen CB, Pedersen MG, dPoterba T, Poulsen JB, Pourcain BS, Qvist P, Rehnström K, Reichenberg A, Reichert J, Robinson EB, Roeder K, Roussos P, Saemundsen E, Sandin S, Satterstrom FK, Davey Smith G, Stefansson H, Steinberg S, Stevens CR, Sullivan PF, Turley P, Walters GB, Xu X; Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium; BUPGEN; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; 23andMe Research Team, Stefansson K, Geschwind DH, Nordentoft M, Hougaard DM, Werge T, Mors O, Mortensen PB, Neale BM, Daly MJ, Børglum AD. Nat Genet. 2019 Mar;51(3):431-444. [PMID: 30804558]

ASD is highly heritable, but the presentation of ASD is complex and varies significantly—ranging from individuals who have high support needs and intellectual disability to those who have high levels of academic and occupational functioning. ASD is a polygenic disorder, i.e. it is likely that combinations of several genetic variations contribute to the different forms of ASD. Researchers have identified both common and rare inherited genetic variations (differences in DNA sequence between individuals) that contribute to ASD risk. However, relatively small sample sizes in previous genome-wide association studies (GWAS) have limited our ability to identify the individually significant genetic variations that contribute to specific ASD traits.

Researchers conducted a GWAS meta-analysis to identify the common genetic variations that are strongly associated with ASD traits, using a significantly larger participant pool than previous efforts. They also evaluated the polygenic architecture of ASD subtypes in order to determine whether particular forms of ASD are more likely correlated with specific common variants or combinations of variants. Their population-based participant pool included 18,381 individuals with ASD and 27,969 age-matched control individuals born in Denmark between 1981 and 2005. The researchers processed and analyzed genotype data that had previously been validated from individuals with ASD in the iPSYCH registry, a nationwide effort to identify genetic and environmental causes of mental illness in Denmark. After processing the genotype data, 13,076 individuals with ASD and 22,664 controls were included in the meta-analysis.

The researchers identified five loci (specific areas of the chromosome) with genetic variations common to the risk of ASD. Using a second dataset, they further analyzed loci that were highly correlated with similarly complex phenotypes (observable characteristics) such as schizophrenia, major depression, and educational attainment. This led to the identification of an additional seven loci that were significantly associated with ASD.

When the researchers divided the ASD dataset into diagnostic subtypes, they found strong genetic correlations with specific traits. Cognitive traits such as educational attainment, as well as risk for adult psychiatric illness, were associated with the most significant genetic variation between ASD subtypes. Specifically, the researchers found individually significant genetic variations for higher educational attainment and intelligence only in individuals within the Asperger’s syndrome and childhood autism subtypes, which are typically associated with less severe impairments. Additionally, they found that individuals within the subtypes of atypical ASD or unspecified pervasive developmental disorders (PDD) had significantly higher genetic traits associated with neuroticism than other subtypes. Heritability was stronger and common genetic variations were more prominent in individuals with Asperger’s syndrome and childhood autism, while rare and de novo genetic variations (new genetic alterations, i.e., found in the child but not the parents) occurred more frequently in individuals with ASD and intellectual disability than other subtypes.

This study provides novel evidence of variations in polygenic architecture across subtypes of ASD. It builds on previous observations of differences among common and rare genetic variations. These insights provide a framework towards advancing the understanding of the biological foundation of ASD and its complexities.

Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study
Hviid A, Hansen JV, Frisch M, Melbye M. Ann Intern Med.. 2019 Apr 16;170(8):513-520. [PMID: 30831578]

Despite definitive research supporting the safety of vaccines, the now discredited link between the measles, mumps, and rubella (MMR) vaccine and the development of ASD remains a pervasive concern among many people. Previous safety studies have been conducted with scientific rigor and are widely accepted among health care practitioners. Nonetheless, critics assert that studies conducted on the MMR vaccine and ASD risk have not ruled out possible effects in specific subgroups of potentially at-risk children. They further argue that that specific links to the regressive form of autism, in which children are thought to show declines in abilities after receiving the MMR vaccine, have not been addressed.

This study aimed to determine if the MMR vaccine increased ASD risk among specific subgroups of children who may be at higher risk of developing ASD than the general population. Additionally, the researchers sought to evaluate ASD risk within specific periods of time following MMR vaccination in order to examine potential regression after vaccination. The study included data from 657,461 children born in Denmark between 1999 and 2010. Nearly all (95%) of the children included had received the MMR vaccine, with the average age of vaccination at just over 12 months. Of the total study population, 6,517 children were diagnosed with ASD, with an average age at diagnosis of 7 years old. ASD diagnoses were coded according to the International Classification of Diseases, 10th Revision. The following coding categories were used: autistic disorder, atypical autism, Asperger syndrome, other pervasive developmental disorders, and unspecified pervasive developmental disorder.

The researchers defined ASD risk subgroups according to genetic susceptibility for ASD (i.e., sibling history of ASD) and an estimated summary index of combined environmental risk factors for ASD (including age of parents, smoking during pregnancy, method of delivery, preterm birth, birthweight, head circumference, and Apgar score). They used these definitions to estimate an “autism risk score” for each child in the dataset, and then used the scores to categorize children into four subgroups based on level of risk. They further characterized the subgroups according to sex, birth cohort, and prior vaccinations in the first year of life. They then compared children who received the MMR vaccination with those who did not—both by subgroup and also at age intervals of 1 to 3 years, 3 to 5 years, 5 to 7 years, 7 to 10 years, and more than 10 years of age.

The researchers identified several significant single risk factors for ASD: having an older or unknown father, an older mother, a poor Apgar score, low birthweight or preterm birth, a large head circumference, an assisted birth, and smoking during pregnancy. ASD risk was equal among children who had or had not received the MMR vaccine. Additionally, the MMR vaccine did not increase ASD risk among vulnerable subgroups, including children exposed to environmental risk factors, children with a sibling with ASD, and children who had received early childhood vaccinations prior to the MMR vaccine. ASD risk remained consistent at all assessed age periods following the MMR vaccine, indicating that no time period after receiving the vaccine is associated with higher risk of developing any form of ASD.

These results support findings from previous research, which maintain that the MMR vaccine does not increase ASD risk at any time after vaccination, nor for any subgroup of children—even those who have other risk factors for developing ASD. Use of subgroup analyses and time period analyses in the present study addresses many of the common criticisms that are launched against vaccine research. The researchers conclude that their study offers reassurance and provides reliable data on which clinicians and health authorities can base their decisions.

Air Pollution, Neighborhood Deprivation, and Autism Spectrum Disorder in the Study to Explore Early Development
McGuinn LA, Windham GC, Messer LC, Di Q, Schwartz J, Croen LA, Moody EJ, Rappold AG, Richardson DB, Neas LM, Gammon MD, Schieve LA, Daniels JL. Environmental Epidemiology. 2019 October;3(5):e067. []

Several environmental exposures during the prenatal and early postnatal periods have been implicated in the development of ASD. Specifically, some studies have identified maternal social stress and air pollution as environmental factors that may increase a child’s ASD risk. Environmental toxins and neighborhood stressors tend to co-occur in areas characterized by low socioeconomic status (SES), resulting in a phenomenon known as neighborhood deprivation. Epidemiologists use neighborhood deprivation as a measure of a geographic area’s social, economic, and health-related stressors—all of which may individually or collectively influence a child’s risk of developing ASD.

This study aimed to understand the cumulative role of neighborhood deprivation and air pollution exposure in ASD risk. Additionally, the researchers hypothesized that the chronic stress generally associated with neighborhood deprivation may lead to compromised immune systems, increasing neighborhood residents’ vulnerability to harmful environmental toxins.

Using data from the CDC’s ongoing Study to Explore Early Development (SEED), the researchers identified 674 children diagnosed with ASD who were born between 2003 and 2006, and 855 randomly sampled controls born within the same time period. Children who screened positive for ASD based on caregiver report were referred for comprehensive assessment. The researchers determined each child’s air pollution exposure level based on their home address at birth, residential proximity to major roadways (a measure of exposure to local pollutants), and exposure to potentially harmful particulate matter (mixed microscopic particles from both local and regionally transported pollutants). They also calculated each child’s neighborhood deprivation index (low, moderate, or high), determined by several neighborhood-level parameters such as household education level, household income, and housing conditions.

The researchers found that children with ASD were more likely to be male, born prematurely, and born to non-white, less-educated mothers. Children belonging to the “high deprivation” group were also more likely to be non-white and born to lower-income, less-educated mothers. Compared to moderate and low deprivation groups, mothers from the high deprivation group were more likely to have experienced particulate matter exposure and close proximity to major roadways during pregnancy. Children who lived near major roadways and were exposed to particulate matter during their first year of life were more likely to have an ASD diagnosis than those who were not. The association between major roadway proximity and ASD risk was strongest for the moderate deprivation group as compared to the high or low deprivation groups, suggesting that transported traffic particulates may be associated with different outcomes than region-specific particulates.

These findings indicate that neighborhood deprivation and air pollution exposure during the first year of life are associated with the development of ASD. Importantly, these factors likely interact reciprocally to increase overall ASD risk. That is, families who live in deprived neighborhoods are more likely exposed to early environmental factors that increase ASD risk and tend to have limited access to health care services and other resources that may improve ASD-related outcomes. Communities experiencing deprivation and other chronic environmental stressors may benefit from targeted interventions to reduce the effects of early ASD risk factors.

Association of Maternal Prenatal Vitamin Use with Risk for Autism Spectrum Disorder Recurrence in Young Siblings
Schmidt RJ, Iosif AM, Guerrero Angel E, Ozonoff S. JAMA Psychiatry. 2019 Apr 1;76(4):391-398. [PMID: 30810722]

The development of ASD is thought to be influenced in part by the prenatal environment, including gestational nutrition. Recent research suggests that the use of prenatal vitamins with folic acid very early in pregnancy may be associated with lower risk of developing ASD. However, mothers who have access to these prenatal vitamins and are aware of their health benefits also may have generally healthier lifestyles than those who do not. It is therefore uncertain whether reduced ASD risk can be attributed specifically to prenatal vitamin use rather than other factors such as overall maternal health. Researchers can address this uncertainty by studying families who already have a child affected by ASD, as most siblings share similar environmental, gestational, and genetic factors. With these factors held constant, research studies can provide more accurate conclusions about the association between prenatal vitamin use and ASD risk.

This study investigated the relationship between maternal prenatal vitamin use and ASD development in high-risk children (i.e. those with a sibling who has ASD). The researchers aimed to determine if early prenatal vitamin use may be a protective factor for families with ASD-affected children, whose future children are approximately 12 times more likely to also have ASD than children with no sibling history of ASD.

Using existing data from the Markers of Autism Risk in Babies: Learning Early Signs (MARBLES) study, researchers recruited children from families who sought ASD services from the California Department of Developmental Services between 2006 and 2015. Children were classified as ASD, typically developing (TD), or nontypically developing (non-TD) based on results from the Autism Diagnostic Observation Schedule (ADOS) and the Mullen Scales of Early Learning (MSEL). The researchers interviewed mothers by telephone to obtain data about their prenatal vitamin use, using brand names to determine folic acid and iron intake. They also collected data related to maternal health including demographic, lifestyle, medical, and environmental information.

The study sample included 241 younger siblings of children with ASD. According to the ADOS and MSEL results, about 23% of the younger siblings met criteria for ASD, 52% were TD, and 25% were non-TD. Although most (231) of the mothers took prenatal vitamins at some point during pregnancy, only 87 (36%) followed clinical recommendations to take prenatal vitamins during the six months prior to pregnancy. In general, mothers who took any prenatal vitamins were more likely to have higher educational attainment, own a home, have health insurance, and intentionally plan their pregnancies. About 14% of mothers in the study also reported taking other vitamin supplements during the first month of pregnancy.

After adjusting for factors of overall maternal health, the researchers determined that ASD prevalence was 17% among children whose mothers took prenatal vitamins during the first month of pregnancy as compared to 33% among children whose mothers did not. Additionally, ASD symptoms tended to be less severe among children who were exposed to prenatal vitamins during the first month of gestation. The influence of prenatal vitamin use on ASD risk did not vary by race, ethnicity, or maternal age; however, girls were more likely than boys to have a reduced risk of ASD associated with prenatal vitamin use. There was no association between prenatal vitamin use and a designation of TD versus non-TD.

Children whose mothers who took more than 600 micrograms of folic acid were at lower risk of developing ASD but had equal risk of a non-TD diagnosis. Additionally, children whose mothers consumed higher amounts of iron during the first month of pregnancy, as compared to the bottom one-third of mothers who consumed lower amounts of iron, also had reduced risk of ASD.

The results of this study indicate that maternal prenatal vitamin use during the first month of pregnancy may reduce ASD risk among children who are at high risk as a result of sibling history of ASD. Importantly, these findings suggest that controlling for gestational exposures may have a protective effect, even among subgroups of children who are at elevated genetic risk for ASD. Because prenatal vitamins contain several nutritional components, further research is necessary to specifically determine which nutrients are associated with reduced risk of ASD.

Question 3

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