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Maternally Acting Gene Alleles Contribute to Autism
Environmental, genetic and epigenetic factors contribute to fetal development. Genetic factors acting prenatally include maternal genes acting in maternal tissues, i.e., maternally acting gene alleles (MAGAs). MAGAs act independently of whether or not they are inherited by the fetus. From the mother’s perspective, MAGAs are genetic factors, producing gene products that influence intrauterine environment. From the fetus’s perspective, MAGAs are environmental factors since they act independently of any inheritance from mother to fetus and since their effects result from gene action in the mother not in the fetus.
Maternally acting gene alleles, MAGAs, act in the mother during pregnancy to change the intrauterine environment. MAGAs produce gene products that may influence intrauterine environment. Maternal genes may have greatest effect when ratio of maternal to fetal mass is greatest, especially early in gestation. Certain anatomic effects in autism reflect changes in very early development. The role of MAGAs is less well understood than that of fetal genes.
Objectives: To assess the current data on maternal alleles in autism.
Methods: We identified reports of prenatal maternal effects and excluded those resulting from: Parent of origin effect, mitochondrial DNA variations and acute maternal environmental exposures. Methods and results for all publications were evaluated and compared.
Results: Among reports of candidate genes we found 11 reports of maternal alleles implicating 7 genes that altered the risk of autism. Five reports were of immune related alleles including C4B and HLA-DRB1. Three of these reported increased risk when mothers had the allele HLA-DRB1*04. A non-inherited maternal allele, NIMA, HLA-DRB1*1302 is also a risk factor for autism. Four reports were of alleles of folate / 1-carbon metabolism, (MTHFR, SLC19A1 and CBS). Three of these showed altered risk based on maternal pre-natal vitamin intake. One report was of a maternal haplotype in GSTP1, ahaplotype made up of 2 missense polymorphisms not in high Linkage Disequilibrium with each other. Last, a maternal association of MAOA is contingent on male offspring having the same allele.
Conclusions: Maternal alleles in autism reported so far act in immune pathways, folate / 1-carbon metabolism, oxidative stress / detoxification pathways and monoamine metabolism, all of which are important in maintaining a proper environment for fetal development. Since MAGA’s play an important role in autism but one less well studied then fetal genetic factors in autism, additional study is needed. A large study considering environmental influence, fetal alleles and interactions between mother and fetus and possibly epistasis is needed to better understand maternal allelic contributions to autism.