Autism spectrum disorder (ASD) is a complex developmental syndrome that affects one in 44 children born in the United States as of 2021 according to the Centers for Disease Control and Prevention (CDC)1, and Utah’s most recent published rate, one in 44 children in 2018 (https://www.cdc.gov/ncbddd/autism/addm-community-report/executive-summary.html)2. The disorder is characterized by neurodevelopmental characteristics and behaviors that vary in severity, impacting learning, communication, and social interactions.3,4,5
The etiology of ASD is complex and includes both environmental and genetic factors.6,7,8 As biotechnology has improved, the capability of studying genetics and heritability has improved with the ability of genetic testing for ASD as more investigators have shown that ASD is highly heritable (heritability rates 0.61–0.73).9–13 Both maternal and paternal genetic variants have been associated with an increased risk for ASD.14,15 However, environmental exposures still play a role. Ambient air pollution exposure from polyaromatic hydrocarbons of roadway air pollutants, nitrogen dioxide, and particulate matter during vulnerable developmental windows of growth has been associated with increased risk of ASD and its severity.16–21 Endocrine-disrupting chemicals, gestational infections, early life infections, and stress have been found to contribute to the risk of ASD. 22
One intersection between the two etiologies of environment and genes can be epigenetics. Epigenes are small marks or switches on DNA that can silence or activate portions of DNA, essentially changing gene expression.23,24 Epigenetic mechanisms have been proposed as potential means by which environmental exposures in previous generations (2 + generations) might exert increased risks in future generations and induce increased levels of heritability.25,26 DNA methylation, histone modification, and RNA silencing are epigenetic mechanisms by which the environment acts on gene expression.27,28 Rett syndrome and Fragile X syndrome (FXS) are common comorbidities with ASD and show firsthand evidence of epigenetic methylation and non-binding RNA effects as mechanisms for ASD outcomes.29 Exposures to nickel, cadmium, mercury, arsenic, pesticides, and other gases and particulates30, all of which are considered environmental pollutants, have been found to impact epigenetics that contribute to disease outcomes across generations.29 Epigenetic changes may originate during the ancestor’s (parents, grandparents, or previous ancestor) vulnerable developmental stages of growth, such as the prenatal and birth stage when developmental programming of organs is underway, and exposures occur.31 Direct-contact exposure studies for the exposed generation have shown neurological impairment from certain exposures.32 Perera et al found that higher concentration exposures to incomplete fossil fuel combustion between gestation and 5 years of age resulted in statistically significantly lower IQ, and verbal scores.32
Animal studies have confirmed transgenerational effects from environmental exposures.26 Controlled laboratory settings simulating environmental pollution exposures from pesticides, fungicides, heavy metals, and petrochemicals have shown transgenerational effects in mice models.26,33 For the study of human subjects, challenges remain in testing the hypothesis that environmental exposures of ancestors’ affect ASD outcomes in progeny.
Space-time cluster analysis is one method used for exploratory research of environmental effects for hypothesis development. Among other things, it is used to align complex data and examine patterns of individuals with a disease suspected to be associated with an environmental exposure spatially and temporally.34,35 It can be extended as an approach for examining potential transgenerational effects of an environmental risk factor by identifying spatial-temporal patterns of grandparents and parents of individuals that have a health outcome associated with an environmental factor. The approach can be used to identify whether ancestors of ASD cases shared the same space and time, implying that there could be common factors (i.e., environment) elevating the risk of ASD among their descendants.36,37 Some diseases have been shown to originate during periods when growth and development are most susceptible to environmental stimuli (e.g., gestation when programming of specific organs is underway, or during childhood, adolescence, or preconception when rapid growth and development occur.27,31,32,38 The approach can be further refined by focusing on these same developmental ages during ancestors’ lives in space-time cluster analyses. Using geographic residential data to investigate and identify the shared environmental space and time of parents and grandparents related to a child diagnosed with ASD could shed light on increased risks, vulnerable developmental windows that may be more susceptible to exposures and disease outcomes and provide evidence regarding whether there is a greater risk for disease of descendants associated with ancestral environmental exposures.
The aims of this study are to (1) Identify space-time clusters of parents and grandparents of children with a clinical ASD diagnosis and their matched controls. (2) Identify developmental windows of parents and grandparents with the highest relative risk for ASD in their children/grandchildren. (3) Identify how the relative risk may vary through the maternal or paternal line.