Perinatal Autism Genetics and Epigenetics Study

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disabilities, adversely affecting an increasing number of families worldwide. Although its etiology is strongly linked to genetic factors, perinatal experience, including prenatal stress and post-natal social experience, may also contribute to deficits in social communication in ASD, potentially via epigenetic mechanisms. For example, the oxytocin receptor gene (OXTR) is epigenetically altered by early social experience, plays a crucial role in mammalian social and cognitive development, and is associated with both genetic and epigenetic risk for ASD. However, the relationship between perinatal experience and epigenetic change in ASD is unclear. Our central hypothesis is that prenatal stress and early social experience predicts epigenetic changes in specific genes, which are associated with social communication deficits in ASD. To achieve our overall goal of discovering modifiable pathways for intervention in children at risk for ASD, we will recruit over 7,200 pregnant women to use a smartphone tool called BabySteps, to collect prospective data from the 3rd trimester of pregnancy until 30 months post-delivery. Between ages 18 to 27 months, BabySteps will be used to screen for symptoms of ASD or developmental delay (DD) in the offspring, which will trigger a full diagnostic assessment online or in person at the Center for Disabilities and Development. Children with a range of social communication deficits (including those diagnosed with ASD or non-ASD DD [n=200]) will be compared with typically developing children (TD; n=200) who are matched on race, sex, and socioeconomic status. We will examine 1) differences in DNA methylation (DNAm), and change over time, in specific ASD-associated loci and OXTR loci, and 2) differences in biologic age acceleration using epigenetic clock algorithms, as a function of age, perinatal experience, and social communication outcomes. We will compare DNAm from buccal swabs to samples collected around the time of diagnosis. We will calculate polygenic risk scores for social communication, repetitive behavior, and ASD, and assess the relative polygenic and epigenetic risk. The relationship between perinatal experience, DNAm, and social communication outcomes will be evaluated using 4 complementary measures: 1) ecological momentary assessments (EMAs) of prenatal stress and parental anxiety and depression, collected using BabySteps; 2) app-recorded free play between parent and child analyzed for dyadic synchrony and interactive behavior; 3) standardized assessments of child social communication skills; and 4) a Language ENvironment Analysis (LENA), using a LENA audio-recording device worn by the child at home and in daycare. We expect to identify epigenetic biomarkers that link prenatal stress and early social experience with social communication outcomes in ASD. A better understanding of how polygenic risk and perinatal experience-via epigenetic mechanisms-contribute to the ASD phenotype will help overcome a critical barrier to progress in the field, by identifying modifiable pathways for intervention.

Inclusion criteria

A. Criteria for Pregnant Women:

• Pregnant women in their 1st or 2nd trimester of a singleton pregnancy.
• Age 18 to 50 years
• Currently use a smart phone

B. ASD Group at age 18 to 27 months

• M-CHAT score >= 4 or POSI score >= 3
• Child has subsequently clinically confirmed diagnosis of ASD, based on ADOS/TAP testing and/or other clinical evaluation

C. Developmental Delay (DD) Group at age 18 to 27-months

• Developmental screening score on SWYC in the "at risk" range.
• Child has subsequently clinically confirmed developmental delay on clinical evaluation and/or self-report measure

D. Typically Developing (TD) Group at age 18 to 27 months - None

Exclusion criteria

A. Criteria for Pregnant Women:

• Non-English speaking mother
• History of severe mental illness in the past year, resulting in inpatient admission

B. All children

• <35 weeks gestational age at birth
• History of serious neonatal complications requiring NICU admission for one week or more
• Known genetic or syndromic condition (e.g. Down Syndrome, etc.) that impacts learning and brain development
• Hearing impairment

C. ASD Group at age 18 to 27 months

• None

D. Developmental Delay (DD) Group at age 18 to 27 months

• Screen positive for ASD (M-CHAT >= 4 AND POSI >= 3)
• First-degree relative who has been diagnosed with ASD

E. Typically Developing (TD) Group at age 18 to 27 months

• Screen positive for ASD (M-CHAT >= 4 AND POSI >= 3)
• Developmental screening/assessment score in the "at risk" range.
• First-degree relative who has been diagnosed with ASD