Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms

Abstract

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD.

Microbiome Disturbances and Autism Spectrum Disorders

“…The term epigenetics has become vastly overused to define broadly any transcriptomic change occurring independent of DNA mutation. The field of neuroepigenetics was born under these auspices and is currently invoked as the genesis of many neurologic disorders not explained by genetics alone, including ASD (Wilkinson and Campbell, 2013;Berko et al, 2014;Ladd-Acosta et al, 2014;Lesseur et al, 2014;Tordjman et al, 2014;Wong et al, 2014). Alterations in the gut microbiome might trigger epigenetic changes leading to downstream behavioral manifestations (Mischke and Plösch, 2013;Kumar et al, 2014;Stilling et al, 2014).…”

Risk Factors Associated With Language in Autism Spectrum Disorder: Clues to Underlying Mechanisms

“…It is highly heritable (Colvert et al, 2015), and current research has led to the rapid ongoing discovery of a relatively large number of de novo and transmitted rare and common genomic events that are associated with the diagnosis (Jeste & Geschwind, 2014). The etiology of ASD is complex, involving nongenetic or environmental risk factors, gene-environment interactions, and epigenetic mechanisms, as is true for all neurodevelopmental disorders (Tordjman et al, 2014). The genetic etiology of ASD contributes to alterations in brain development that may be traced back to the prenatal period (Bae, Jayaraman, & Walsh, 2015).…”

Endocannabinoid Signaling in Autism

“…The neurocognitive phenotype in ASD stems from a complex and highly heterogeneous array of genetic and environmental causes, with patients ranging from Bpurely genetic^cases due to known ASD-causing chromosomal aberrations or mutations to Bpurely environmental^cases due to rare prenatal exposure to specific viral agents, drugs, and toxins [60][61][62]. In between these extremes, ASD for most cases fully qualifies for the definition of a Bcomplex^disorder, whereby a host of rare and common genetic variants, often but not necessarily in conjunction with epigenetic factors [63], yield the neurodevelopmental abnormalities summarized above, resulting in autistic behaviors. Finally, neuroinflammation is also a frequent finding in postmortem brains of autistic individuals [64,65].…”