Genetic Epidemiology and Insights into Interactive Genetic and Environmental Effects in Autism Spectrum Disorders

Abstract

Understanding the pathogenesis of Neurodevelopmental Disorders (NDDs) has proven to be challenging. Using Autism Spectrum Disorder (ASD) as a paradigmatic NDD, this paper reviews the existing literature on the etiologic substrates of ASD and explores how genetic epidemiology approaches including gene-environment interactions (GxE) can play roles in identifying factors associated with ASD etiology. New genetic and bioinformatics strategies have yielded important clues to ASD genetic substrates. Next steps for understanding ASD pathogenesis require significant effort to focus on how genes and environment interact with one another in typical development and its perturbations. Along with larger sample sizes, future study designs should include sample ascertainment that is epidemiologic and population-based to capture the entire ASD spectrum with both categorical and dimensional phenotypic characterization, environmental measurement with accuracy, validity and biomarkers, statistical methods to address population stratification, multiple comparisons and GxE of rare variants, animal models to test hypotheses and, new methods to broaden the capacity to search for GxE, including genome-wide and environment-wide association studies, precise estimation of heritability using dense genetic markers and consideration of GxE both as the disease cause and a disease course modifier. While examination of GxE appears to be a daunting task, tremendous recent progress in gene discovery opens new horizons for advancing our understanding the role of GxE in the pathogenesis of, and ultimately identifying the causes, treatments and even prevention for ASD and other NDDs.

Maternal immune activation alters brain microRNA expression in mouse offspring

“…It has been well established that ASD is a complex disorder caused by both genetic and environmental factors 2. Because no single genetic variation or mutation can account for a majority of ASD cases, the converging actions of ASD‐related genes on common pathways, as well as interaction effects with non‐genetic factors, are considered to be a likely explanation for ASD pathophysiology 2…”

The complex enigma of autism

“…For example, maternal infections during pregnancy seem to increase ASD risk. 8 In the pilot study, salivary levels of lactotransferrin (also called lactoferrin) were 30% higher in ASD patients than controls. Lactotransferrin is involved in gastrointestinal immune responses.…”

“…Concordance rates, for example, are 47-96% in monozygotic twins for ASD and 0-36% in dizygotic twins for autism and wider ASD phenotypes. 8 Genetic studies link 'hundreds of susceptibility loci' to ASD. 9 Broadly, however, 2.6% of ASD cases seem to arise from rare de novo mutations, 3% from rare inherited variants, and 49% from common inherited variants.…”

“…However, twin studies suggest that environment accounts for between 10% and 55% of the risk. 8 Some genetic changes associated with ASD -such as those affecting an area of the short arm of chromosome 16 (16p11.2), which contains 29 genes -are relatively well characterised. Deletions of 16p11.2 occur in 0.1% to 0.7% of ASD patients and 16p11.2 duplications in 0.1% to 0.5% -a rate 10 times higher than in the general population.…”

“…Copy number variations in 16p11.2 seem to be associated with several problems, including intellectual disabilities, delayed development, speech problems, schizophrenia and seizures. 8 However, the largest autism genome study, recently published in Nature Medicine, reveals that the disorder's genetics are even more complex than previously thought. Researchers sequenced 340 whole genomes from members of 85 families, each with two children with ASD.…”