Genetic heterogeneity can be one explanation for the absence of replication of association studies in autism.
However, these results could also be interpreted within the framework of a GxE interaction model.
If, for example, an association has been found in a sample with subjects frequently exposed to a particular environmental risk but not in those infrequently exposed, and exposure was not ascertained, the source of nonreplication will remain elusive.
The existence of interactions between genetic background and environmental factors in autism was first suggested for perinatal complications.
Indeed, in an epidemiological study on autism that included a comparison group of siblings, unaffected siblings had fewer prenatal and perinatal complications than their affected siblings, but more than control subjects.
This suggested that individuals with autism may react differently to the same environmental stimuli and may have less tolerance to the prenatal experience compared with their siblings.
Moreover, studies of animal models have suggested that genetic defects in synaptic function may alter sensitivity to the environment.
Indeed a study has shown that neuroligin-deficient mutants of C. elegans nematodes are hypersensitive to oxidative stress.
Another study reported that the hippocampal slices from MecP2- deficient mice are more susceptible to hypoxia.
Conversely, it was shown in an animal models that the most significant pathology of the extremely premature brain is the disruption of synaptic development.
It was thus hypothesized that synaptic gene defects could interact with environmental factor to increase autism risk.
Another hypothesis is the interaction between genetic variations melatonin pathway genes and oxidative stress. Indeed, low plasma melatonin concentration is a frequent trait in ASD patients, caused by a primary deficit in acetylserotonin-melhyl-transferase (ASMT) activity. It was suggested that genetic variations contribute to the enzymatic deficit.
Several studies have suggested an antioxidant effect of melatonin in vitro, and it was shown that the administration of melatonin reduces oxidative stress in newborn infants exposed to infection or fetal distress, and promotes oligodendroglial maturation in the newborn rat with abnormal white matter related to fetal hypoxia.
Thus it could have a neuroprotective effect in the newborn exposed to fetal distress. Interestingly Gardener et noted that several of the perinatal and neonatal risk factors they identified may be associated with an increased risk of hypoxia.
We can thus hypothesize that a deficit of melatonin could be taken into account in the consequences of perinatal distress.
Beyond these observations, available evidence for the contribution of GxE to autism risk comes from animal models. In a first study, mice haploinsufficient for the TSC2 gene demonstrated a lack of normal social approach behavior only when exposed to maternal immune activation.
The authors propose that disinhibited TSC/mTOR signaling downstream of mediators of gestational immune activation effects amplifies their impact on the mutant mice fetal brain; or that the immune activation may be more pronounced in mutants because of the role of TSC/mTOR signaling in the regulation of the adaptive immune response.
Moreover, exploring further the possible interaction between tuberous sclerosis and maternal immune activation in a cohort of individuals with tuberous sclerosis, the authors found an association of late gestation with peak seasonal flu activity specifically in individuals affected by ASD.
These results suggest that late gestation is the main period of vulnerability of neurodevelopment to flu infection, which is in contradiction with results, discussed earlier, suggesting that summer birth and maternal infection during the first trimester are risk factors for ASD.
However, we can reasonably hypothesize that the period of main vulnerability to infection during gestation may vary according to genetic factors, and that there is a specific period of vulnerability of neurodevelopment during late gestation in tuberous sclerosis.
In another animal model, prenatal maternal immune activation and expression of a mutant DISC1 protein interacted to produce an altered pattern of sociability.
This neurobehavioral profile was absent in untreated mice expressing the mutant.
Although these results are very encouraging, family and population-based association studies in autism have not been extended for GxE interaction yet.
One of the main problems with this kind of study is that power to detect GxE interactions is even lower than power to detect genetic or environmental main effects, and the enthusiasm for GxE research in other psychiatric disorders has recently been tempered by the absence of replication of many positive results.
Nevertheless, these studies are needed since they might help us to understand the inconsistency in results found in classical association studies and provide useful hints with regard to prevendon.
Two large-scale prospective epidemiological studies aiming at exploring environmental factors and GxE interaction were recently launched. The National Children’s study will follow 100 000 children in the US from conception to age 21.
Biological samples are collected from each mother and child. The Autism Birth Cohort will follow 100 000 children from conception to age 7.
Biological samples are collected from children and their parents. Interestingly, an encouraging result came from an association study in attention deficit with hyperactivity disorder (ADHD), which found GxE effects on ASD symptoms in children with ADHD. Multiple regression analyses for GxE effects showed that 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction, and also interacted with low birth weight, increasing rigid behavior.
Last, given the new understanding of the genetic architecture of autism, further study of the interaction of rare variants associated with ASD and environmental factors in populations carrying identical mutations would be useful but are difficult to perform due to the small number of carriers.
Contrary to the frequent assertion that we know only little of the risk of autism, major advances have been made in the past decade in this domain.
In particular, recent advances in genetics have allowed a new conceptualization of molecular and cellular mechanisms of the pathology.
At the same time new questions are raised, including the role of common variants and the relationship between genotype and phenotype.
The contribution of environmental factors through additive or multiplicative effect needs to be further explored.
New funding will need to be dedicated to this domain of research, which has been sparsely funded until very recently.
sourse: https://www.ncbi.nlm.nih.gov
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