Study Links Key Imprinted Genes to Autism

Since the turn of the century, circumstantial evidence has accumulated for the role of imprinted genes (those only expressed from one parent) in mental illnesses such as Autism Spectrum Disorder (ASD) and schizophrenia, much of it noted in these posts. Indeed, a small number of key imprinted genes have been identified. But now, a new study by Chinese researchers has drawn up a list of 13. The researchers report that:

"We found a positive correlation between the autism-related genes’ and imprinted genes’ distribution on chromosomes. Through the analysis of the normal brain microarray data, we constructed a spatio-temporal coordinate system of gene expression during human brain development, and obtained 13 genes that are differentially expressed in the process of brain development, which are both autism-related genes and imprinted genes.

"Furthermore, enrichment analysis illustrated that these genes are mainly involved in the biological processes, such as gamma-aminobutyric acid signaling pathway, neuron recognition, learning or memory, and regulation of synaptic transmission. Bioinformatic analysis implied that imprinted genes regulate the development and behavior of the brain."

They add that “mutation or changes in the epigenetic modification state of the imprinted control region could lead to some diseases, indicating that imprinted genes and brain development play an important role in diagnosis and prognosis of autism.” The 13 imprinted genes are shown in red in the diagram below:

Analysis of brain differentially expressed genes, imprinted genes, and autism-related genes.

Source: Li et al. BMC Medical Genomics (2020) 13:54

The authors note that previous studies have shown that most imprinted genes are expressed in the brain and placenta and that an increasing number of researches have suggested that imprinted genes also play important roles after birth, notably in neonatal feeding, regulating metabolism, sleep, and behavior:

"The unanimous conclusion from studies of brain development in ASD is that the head size is normal at birth, but significantly enlarged at age 2–3 […]. Brain imaging studies of at-risk infants with ASD also show that excessive expansion of the cerebral cortex surface area during 6-12 months leads to overgrowth in brain volume in the second year… The overgrowth of the brain volume is related to the occurrence and severity of autism social defects. It indicates that autism had a close relationship with neuron function during brain development.

Expression profiles analysis of normal human brain genes.

Source: Li et al. BMC Medical Genomics (2020) 13:54

As illustrated left, the authors re-analyzed the microarray data of normal human brain development:

"Through comparison of the 15 brain developmental stages, we revealed that the four stages with the largest number of differentially expressed genes compared with the previous stage during brain development were: early embryonic development to early fetal development, mid-late fetal development to prenatal stage, early childhood to childhood and middle age to old age. Furthermore, the distribution count of differentially expressed genes was discrete in early fetal development. It indicated that there was significant difference in different brain regions at this stage. … This result confirmed that different brain structures follow different developmental and maturation trajectories in childhood and adulthood development…"

The researchers conclude that “this study systematically correlates brain development and genomic imprinting with autism, which provides a new perspective for the study of genetic mechanisms of autism”—just as the imprinted brain theory proposes.

Finally, I might add that such studies as this will be the proof or refutation of the imprinted brain theory, according to which, the balance of gene expression should favor paternally-active genes in ASD. Interestingly, seven of the 13 genes identified in this study, GABRA5, GABRG3, SNRPN, FOXG1, TSHZ3, CDH18, and GABRB3, are indeed listed as paternally-active by the authority the authors cite, and four are listed as maternally active (NTM, OTX1, HTR2A, and NLRP2), while GATM’s exact parental expression status is unknown and DHCR7’s varies with time and place.

On the face of it, this is in accordance with the predictions of the theory, but we cannot be sure until more studies are done of the exact patterns of gene expression in each case. At the very least, this study confirms that, whatever the details, imprinted genes play a key role in ASD.