Jan. 23 2023

How Long-Term Studies Are Shaping Our Understanding of Autism

In the 80 years since autism was first described by scientists, our understanding of autism and autism spectrum disorders (ASDs) has advanced in leaps and bounds. A new perspective article in the journal Nature Reviews Neurology examines the key role played by longitudinal cohort studies in achieving this progress and providing important insights into the genetic and environmental triggers of ASDs.

The article is written by W. Ian Lipkin, Michaeline Bresnahan, and Ezra Susser—a team of autism researchers at Columbia University Mailman School of Public Health.

Although initially characterized as psychosis and subsequently blamed on socially distant caregivers (the “refrigerator parent”), from the 1970s onwards autism was understood as a developmental disorder with a heritable component. Various environmental exposures were subsequently identified as contributing to the risk of autism spectrum disorder, the understanding of which continues to evolve. Other factors like the MMR vaccine were ruled out.

The authors write that rigorous scientific testing of genetic and environmental factors—especially environmental exposures during pregnancy—necessitated the recruitment of population-based birth cohorts in which biological samples and environmental exposure data are collected at multiple time points during gestation, as well as follow-up of the children with ASDs at various timepoints as they grow older. These efforts were made possible through advocacy and philanthropy of the ASDs community.

The Autism Birth Cohort (ABC) in Norway is arguably the largest population-based birth cohort for the study of ASDs. Analyses based on ABC data—led in part by the authors of the current perspective article—contributed important insights. An ABC study was the first to show that maternal folic acid supplementation is associated with ASDs in offspring, as well as robust evidence for immune dysregulation during pregnancy in mothers of children with ASDs. Subsequently, predictive models based on specific maternal immune molecules have distinguished children with ASDs from control children without ASD—research that might lead to the development of early biomarker(s) for ASDs.

Other birth cohort studies have also generated intriguing investigations of ASD. For example, a study called Generation R aims to identify early environmental and genetic causes of normal and abnormal growth, development, and health in participants monitored from fetal life until young adulthood.

Other research methods, including brain imaging studies and animal model studies, have added their own valuable insights. In the future, cohort research will likely make use of machine learning methods to integrating genetic, epigenetic, and multiomics datasets.

Whatever the technologies employed, the authors write, the value of a specific cohort as a resource is determined by the size and composition of its population, the onset and frequency of collection of data and samples, the types of data and samples collected, the duration of follow-up and the commitment of cohort members to continued engagement with the project.

Beyond Nature vs. Nurture

Genetic and environmental factors are not mutually exclusive when it comes to understanding the factors that trigger ASDs. In the majority of patients with ASDs, no links to a specific genetic or environmental factor can be identified. However, genetic vulnerability and environmental triggers almost certainly act together to cause ASD in some individuals.

The authors write: “For millennia, philosophers and theologians have debated the relative importance of nature and nurture as determinants of biology and behavior. With the advent of prospective birth cohorts, we have an opportunity to move from abstract discussions to rigorous dissection of the interactions of genetic and environmental factors in health and disease.”

W. Ian Lipkin, MD, is the John Snow Professor of Epidemiology and director of the Center for Infection and Immunity. Michaeline Bresnahan, PhD, is associate professor of epidemiology (in Psychiatry). Ezra Susser, MD, is a professor of epidemiology and psychiatry and director of the Psychiatric Epidemiology Training Program.

The authors declare no competing interests.