The placenta is key to early diagnosis and intervention

In a study published Feb.

"Through an unbiased investigation of placental DNA methylation differences, we have uncovered an autism-associated genome in an autism-associated genome," said study lead author Janine LaSalle, a professor of microbiology and immunology at UC Davis.

ASD is a complex neurological disorder associated with genetic and environmental factors

Why studying the placenta is important

The placenta supports the development of the fetus in the womb

"The placenta is an often misunderstood and overlooked tissue, despite its importance in regulating and reflecting events critical to brain development in the womb

During pregnancy, the fetus may experience oxidative stress, an imbalance of free radicals and antioxidants in the body

"Oxidative stress is normal

The epigenome is a set of chemical compounds and proteins that tell DNA what to do

The placenta is a promising tissue for identifying DNA methylation changes in genes that also function in the fetal brain

Placenta may contain factors that predict autism

The researchers studied the development of 204 children born to mothers who participated in the MARBLES and EARLI studies

At 36 months old, the children underwent diagnostic and developmental assessments

The researchers also extracted and quantified DNA from placental tissue

For this discovery team, they isolated and sequenced 92 samples (46 ASD, 46 TD) from the MARBLES study using whole genome bisulfite sequencing (WGBS) and whole genome sequencing (WGS)

The replication-specific group had 21 ASD, 13 Non-TD and 31 TD placental samples

Finally, they performed whole-genome sequencing of 41 children with ASD and 37 with TD MARBLES

Placenta reveals genes linked to ASD

The researchers identified a differentially methylated region on chromosome 22 at 22q13.

To understand the function of this gene, they examined the expression levels of NHIP in human cell lines and brain tissue
.
They tested the responsiveness of NHIP to hypoxia, the state of low oxygen levels in tissues
.
The researchers found that NHIP is a gene that is activated in neurons after hypoxia and regulates other gene pathways that play a role in neuronal development and response to oxidative stress
.
Higher NHIP levels increased cell division in embryonic cell lines
.

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

The researchers also found lower levels of NHIP activation in the ASD placenta and brain compared to the TD samples, supporting a protective role for NHIP in preventing ASD
.

"We found that the NHIP gene is active in the brain, responds to oxidative stress, and affects the expression of other genes known to be associated with autism," LaSalle said
.
"During most pregnancies, the placenta experiences some unavoidable stress
.
We think the role of NHIP is to buffer the effects of excessive oxidative stress
.
"

Prenatal Vitamins and Autism

Another striking finding of this study is the role of prenatal vitamins in regulating the work of NHIP
.
Prenatal vitamins are rich in folic acid, which reduces oxidative stress
.

Among individuals with genetic differences in the 22q13.
33 NHIP region, gestational vitamin use in the first month of pregnancy showed a significant protective effect
.
Taking prenatal vitamins during the first month of pregnancy appears to provide the necessary metabolic elements to counteract the genetic inheritance of NHIP's reduced responsiveness to oxidative stress
.

"Consistent with previous research, we found that taking prenatal vitamins is necessary when planning a pregnancy," LaSalle said.
"
Our findings provide key insights that may help identify newborns who are more likely to develop autism.
, and get them to intervene earlier, or just know to watch them earlier
.
"

These results need further replication before they can be used for diagnosis, the researchers noted
.

Yihui Zhu, J.
Antonio Gomez, Benjamin I.
Laufer, Charles E.
Mordaunt, Julia S.
Mouat, Daniela C.
Soto, Megan Y.
Dennis, Kelly S.
Benke, Kelly M.
Bakulski, John Dou, Ria Marathe, Julia M.
Jianu, Logan A.
Williams, Orangel J.
Gutierrez Fugón, Cheryl K.
Walker, Sally Ozonoff, Jason Daniels, Luke P.
Grosvenor, Heather E.
Volk, Jason I.
Feinberg, M.
Daniele Fallin, Irva Hertz -Picciotto, Rebecca J.
Schmidt, Dag H.
Yasui, Janine M.
LaSalle.
Placental methylome reveals a 22q13.
33 brain regulatory gene locus associated with autism .
Genome Biology , 2022; 23 (1)