Placenta has clues for an early diagnosis of ASD

The researchers of the‘UC Davis MIND during their research they used the genomic sequencing to find a DNA methylation signature in the placenta of infants diagnosed with autism. This hallmark has been linked to early fetal neurodevelopment. Thanks to this study, a new human gene linked to fetal brain development and al autism spectrum disorder (ASD). The finding also links the gene to the mother’s early use of prenatal vitamins and to placental oxygen levels.

Placenta
ASD-associated DMRs are enriched in fetal brain enhancers and a co-methylated block in 22q13.33 replicates across studies and platforms. A schematic of the experimental design for the discovery of DMR ASD, replication of the co-methylated 22q13.33 locus, genetic associations and functional follow-up of a new gene (NHIP). B Manhattan circular chart of epigenomic association of DNA methylation in placenta diagnosed with ASD at 36 months. The results are represented as DMR association test results (- log 10 (P)). Significant thresholds are blue for permutation p-value

The results of the Research have been published in the scientific journal Genome Biology.

Placenta and clues to autism spectrum disorder: here’s what the research says

Taking an unbiased approach to studying placental DNA methylation differences, we discovered a new gene in a poorly mapped region of the genome associated with autism.“, he has declared Janine LaSallelead author of the study and professor of microbiology and immunology at theUC Davis Health.

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ASD is a complex neurological condition linked to genetic and environmental factors. The US Centers for Disease Control and Prevention (CDC) estimates that one in 44 children are diagnosed with ASD, much more prevalent in boys than girls.

The placenta supports fetal development in the uterus. It regulates oxygen supply and metabolism and provides hormones and neurotransmitters that are essential for the development of the fetus’ brain.

The placenta is an often misunderstood and overlooked tissue, despite its importance in regulating and thus reflecting events critical to brain development in the uterus. It’s like a time capsule to find things that happened in the womb. For decades, hospital births have thrown placentas away despite this tissue being a gold mine for finding molecular clues to children’s outcomes.“, LaSalle explained.

During pregnancy, the fetus could experience oxidative stress, an imbalance of free radicals and antioxidants in the body. This is common in normal brain development. However, in some cases, exposure to environmental factors such as air pollution and pesticides can lead to excessive oxidative stress. This state can lead to cell and tissue damage or delayed neurodevelopment.

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Oxidative stress is normal. But excessive oxidative stress can result from ASD-related environmental exposures such as air pollution, pesticides, maternal obesity, and inflammation.LaSalle said.

The epigenome is a collection of chemical compounds and proteins that tell DNA what to do. These compounds attach themselves to DNA and change its function. One such compound is CH3 (known as the methyl group) which leads to DNA methylation. The neonatal epigenome can reflect past interactions between genetic and environmental factors during early development. It can also affect future health outcomes.

The placenta is a promising tissue for identifying DNA methylation changes in genes that also function in the fetal brain. This study examined the association of ASD with placental DNA methylation.

The researchers studied the development of 204 babies born to mothers enrolled in the studies MARBLES e EARLI. These mothers had at least one older child with autism and were considered to be more likely to have another child with ASD. When these babies were born, the mothers’ placentas were kept for future analysis.

At 36 months, the babies received diagnostic and developmental evaluations. Based on these tests, the researchers grouped children in “typical development” (TD), “with ASD” and “non-typical development” (Non-TD).

The researchers also extracted and quantified DNA from placental tissues. They divided the placenta samples into specificity discovery, replication, and replication groups.

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For the discovery group, they split and sequenced 92 samples (46 ASD, 46 TD) from the MARBLES study using whole genome bisulfite sequencing (WGBS) and whole genome sequencing (WGS). To determine whether differential methylation was reproducible in a different population, the replication group included WGBS data from 16 ASD and 31 TD samples from the EARLI study.

The replication specificity group had 21 ASD, 13 Non-TD, and 31 TD placenta samples from the MARBLES study. The researchers used these samples to determine if the methylation changes were ASD-specific.

Finally, they performed whole genome sequencing on 41 ASD children and 37 TD MARBLES.

The researchers identified a differential methylation block in the ASD at 22q13.33, a region on chromosome 22 not previously linked to the ASD. They identified and characterized a new gene known as LOC105373085 within that region and renamed it NHIP (inducible, placenta-associated neuronal hypoxia).

To understand the function of this gene, they detected NHIP expression levels in human cell lines and brain tissue. The researchers tested NHIP’s reactivity to hypoxia, a state of low oxygen levels in tissues. The researchers found that NHIP is a gene that activates in neurons following hypoxia and regulates other gene pathways with functions in neuronal development and oxidative stress response. Higher levels of NHIP increased cell division in an embryonic cell line.

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This is important because in the placenta, hypoxia triggers placental cell division to make further contact with the maternal blood vessels to provide enough oxygen for the developing brain.

The researchers also found that NHIP was less activated in the placenta and brain ASD than the TD samples, supporting a protective role for NHIP in the prevention of ASD.

We found that the NHIP gene is active in the brain, responds to oxidative stress, and affects the expression of other known genes associated with autism.“, LaSalle specified. “In most pregnancies, the placenta experiences some inevitable levels of stress. We think NHIP is there to buffer the effects of excessive oxidative stress“.

Another notable result of the study was the role played by prenatal vitamins in regulating the work of MINIMUM. Prenatal vitamins are rich in folic acid and can reduce oxidative stress.

Prenatal use of vitamins during the first month of pregnancy showed a significant protective effect among individuals with genetic differences in the NHIP 22q13.33 region. The intake of prenatal vitamins in the first month of pregnancy seems to provide essential metabolic elements to counter the genetic inheritance of the reduced reactivity of NHIP to oxidative stress.

In line with previous studies, we have found that taking a prenatal vitamin is essential when planning a pregnancyLaSalle said. “The results of our study provide key insights that can help identify infants most likely to develop autism and get them to intervene sooner or just knowing to look at them first.“.

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The researchers pointed out that these findings will require further replication before being used diagnostically.

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