Environment-Wide Association Study (En WAS) of Prenatal and Perinatal Factors Associated With Autistic Traits: A Population-Based Study

Abstract

A combination of genetic and environmental factors contributes to the origins of autism spectrum disorder (ASD). While a number of studies have described specific environmental factors associating with emerging ASD, studies that compare and contrast multiple environmental factors in the same study are lacking. Thus, the goal of this study was to perform a prospective, data-driven environmental-wide association study of pre- and perinatal factors associated with the later development of autistic symptoms in childhood. The participants included 3891 6-year-old children from a birth cohort with pre- and perinatal data. Autistic symptoms were measured using the Social Responsiveness Scale in all children. Prior to any analyses, the sample was randomly split into a discovery set (2920) and a test set (921). Multiple linear regression analyses were performed for each of 920 variables, correcting for six of the most common covariates in epidemiological studies. We found 111 different pre- and perinatal factors associated with autistic traits during childhood. In secondary analyses where we controlled for parental psychopathology, 23 variables in the domains of family and interpersonal relationships were associated with the development of autistic symptoms during childhood. In conclusion, a data-driven approach was used to identify a number of pre- and perinatal risk factors associating with higher childhood autistic symptoms. These factors include measures of parental psychopathology and family and interpersonal relationships. These measures could potentially be used for the early identification of those at increased risk to develop ASD. LAY SUMMARY: A combination of genetic and environmental factors contributes to the development of autism spectrum disorder (ASD). Each environmental factor may affect the risk of ASD. In a study on 6-year-old children, a number of pre- and perinatal risk factors were identified that are associated with autistic symptoms in childhood. These factors include measures of parental psychopathology and family and interpersonal relationships. These variables could potentially serve as markers to identify those at increased risk to develop ASD or autistic symptoms. Autism Res 2020, 13: 1582-1600. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Keywords: autism spectrum disorder; autistic traits; environment-wide-association study; exposure; perinatal; prenatal.

Figure 1

Flow chart of the inclusion and exclusion of the study population.

Figure 2

Manhattan plot of false discovery rate (FDR)‐corrected minus log 10 p‐values of the iterative regression analysis. Each group of colored dots represents a domain. The green horizontal line marks the 0.05 uncorrected threshold. The red horizontal line marks the 0.05 FDR‐corrected threshold. The purple horizontal line marks the 0.05 Bonferroni‐corrected threshold.

Figure 3

Plot demonstrating the high covariance structure between the different variables used in the analyses. As there were too many variables to list all in the figure, the purpose is to show the high correlation between multiple variables in the EⁿWAS. Red indicates a positive correlation whereas blue indicates a negative correlation. The legend reflects the different covariates used in the study.

Figure 4

Manhattan plot of the false discovery rate (FDR)‐corrected minus log 10 p‐values of the adjusted iterative regression analysis. The analysis was adjusted for maternal age at birth, maternal education, maternal ethnicity, gender of the child, parity of the pregnancy, birth weight, gestational age at birth, and birth year. Each group of colored dots represents a domain. The green horizontal line marks the 0.05 uncorrected threshold. The red horizontal line marks the 0.05 FDR‐corrected threshold. The purple horizontal line marks the 0.05 Bonferroni‐corrected threshold.