Perinatal Experience and Epigenetic Change in Autism: Discovering Modifiable Pathways for Intervention

自闭症的围产期经历和表观遗传变化：发现可修改的干预途径

• 批准号: 10660207
• 负责人: Lane Strathearn
• 金额: $ 66.07万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660207
• 关键词: 2 year old; Acceleration; Address; Affect; Age; Aging; Algorithms; Anxiety; Behavior; Behavioral; Biological; Birth; Blood; Cellular Phone; Child; Chronology; Clinical assessments; Communication; DNA Methylation; Data; Day Care; Development; Developmental Delay Disorders; Devices; Diagnosis; Diagnostic; Dryness; Early Intervention; Early treatment; Ecological momentary assessment; Environment; Epigenetic Process; Etiology; Family; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Home; Individual; Infant; Intervention; Knowledge; Language; Life; Link; Measures; Mediating; Mental Depression; Modern Medicine; Modification; Neurodevelopmental Disability; Newborn Infant; Outcome; Oxytocin; Oxytocin Receptor; Parents; Pathway interactions; Patient Self-Report; Pattern; Perinatal; Persons; Phenotype; Play; Pregnancy Trimesters; Pregnant Women; Prevalence; Process; Questionnaires; Race; Receptor Gene; Reporting; Research; Risk; Risk Factors; Role; Sampling; Social Development; Social Interaction; Societies; Socioeconomic Status; Spottings; Standardization; Stress; Symptoms; Testing; Third Pregnancy Trimester; Time; Video Recording; anxiety symptoms; autism spectrum disorder; cognitive development; depressive symptoms; digital; disability; epigenetic marker; experience; genetic predictors; genomic locus; innovation; novel; offspring; polygenic risk score; postnatal; predictive marker; prenatal stress; prospective; receptor; recruit; repetitive behavior; sex; skills; smartphone application; social; social communication

ABSTRACT. 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 an innovative smartphone application, 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 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 27 specific ASD-associated loci and 3 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 stored newborn dried blood spots 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.

摘要。自闭症谱系障碍（ASD）是最常见的神经发育障碍之一，