Possible Maternally Acting Gene Alleles (MAGAs) in Autism

Background:  Maternally Acting Gene Alleles (MAGAs) may act in maternal tissues prenatally to alter fetal environment or in the developing embryo prior to the maternal – zygote transition altering development and affecting offspring phenotype, independently of whether or not they are inherited by the fetus. At least 169 MAGAs have been reported, mostly in neurodevelopmental disorders.

Objectives:  Here, we carried out an analysis of possible MAGAs in SSC trios.

Methods:  We used families of the Simons Simplex Collection (SSC) Version 14 that were largely genotyped on the Illumina Human 1M duo array for imputation of un-genotyped SNPs and subsequent analysis using the Weinberg log-linear method through a convenient implementation in EMIM.

Results: One SNP, while not reaching genome wide significance, was of particular interest. SNP rs6482968, Chr10:129525038, 5’ of FOXI2 gave a corrected p-value of 1.02E−6 with a large number of SNPs in strong LD (r2 > 0.80) and below p-value 1.00E-4, a threshold used for suggestive results.

Conclusions: FOXI2, which belongs to the forkhead-box (FOX) superfamily of transcription factors makes an interesting candidate for a maternally acting allele. It has been reported in a model system that Foxi2 derived from maternal mRNA is an activator of zygotic Foxi1e, an important factor in the early expression of ectoderm specific genes and so may be important in the maternal-zygotic transition. FOXI2 and the gene region have been previously implicated in autism. It has been implicated in Expression quantitative trait loci mapping (eQTLs) in autism. Additionally, CNV’s that span this region have been described in individuals with developmental disorders including autism spectrum disorder. This large group of SNPs may represent a haplotype but since the Weinberg method looks at asymmetries in paternal vs. maternal transmissions, it can not be excluded that our results may be due to maternally derived CNV’s. A different SNP 5’ to FOXI2 and our index SNP gave a p-value of 7.66E-05 in a case GWAS analysis. Others have reported increased FOXI2 mRNA levels in post mortem autism brains. This may suggest that it acts both maternally and in her child. Other forkhead genes have also been implicated in autism such as FOXP2. Last, it has been reported that FOXI2 is a target for 3 miRNA’s previously implicated in autism. Follow up studies are needed to confirm these results.