What Makes Children of Older Fathers at Increased Risk of Autism?

In this new study, researchers investigated the relationship between paternal age, the BEGAIN gene and autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication and social interaction, as well as repetitive behaviors. It has been observed that children born to older fathers have an increased risk of developing ASD and other neurodevelopmental disorders. This phenomenon suggests that paternal age may have an impact on the risk of ASD in offspring.

Recent research has focused on understanding the potential mechanisms underlying the association between paternal age and ASD. One area of interest is the epigenome, specifically DNA methylation, which refers to the addition or removal of methyl groups to DNA molecules. DNA methylation can affect gene expression and play a role in various biological processes.

In a new study, researchers Ramya Potabattula, Andreas Prell, Marcus Dittrich, Caroline Nava, Christel Depienne, Yosra Bejaoui, Nady El Hajj, Thomas Hahn, Martin Schorsch, and Thomas Haaf from Julius Maximilians University, Groupe Hospitalier Pitié-Salpêtrière, University Hospital Essen, Hamad Bin Khalifa University, and Fertility Center in Wiesbaden, Germany, explored the relationship between paternal age, DNA methylation of the BEGAIN gene, and the risk of ASD. The BEGAIN gene encodes a protein involved in protein-protein interactions at synapses, which are crucial for proper brain function. On November 28, 2023, their research paper was published in Aging’s Volume 15, Issue 22, entitled, “Effects of paternal and chronological age on BEGAIN methylation and its possible role in autism.”

“So far, only 40 genes with sperm ageDMRs [age-associated differentially methylated regions] have been replicated in at least three independent genome-wide methylation screens [19], which makes them primary candidates for mediating paternal age effects on the next generation. Here, we focused on one of these top candidates, the BEGAIN promoter region.”

The Study

The study focused on examining the impact of paternal age on BEGAIN methylation. Various techniques were employed to investigate this relationship. Sperm samples from normozoospermic individuals attending a fertility center were analyzed. The researchers aimed to understand how paternal age influences BEGAIN methylation, specifically observing its trends in sperm.

To extend their exploration of transgenerational effects, fetal cord blood samples were also examined. The team aimed to discern whether paternal age influenced BEGAIN methylation differently in male and female offspring. The research team employed meticulous analyses to understand the sex-specific patterns associated with paternal age and BEGAIN methylation.

They also delved into the effects of chronological age on BEGAIN methylation. Peripheral blood samples from individuals of different ages were analyzed to investigate the relationship between chronological age and BEGAIN methylation. The study aimed to discern whether BEGAIN methylation undergoes changes with age in a sex-specific manner.

“It is tempting to speculate that transmission of paternal age-associated sperm methylation changes into the next generation modulates BEGAIN regulation and susceptibility to neurodevelopmental disorders.”

The Results

The research yielded significant findings. A negative correlation between paternal age and BEGAIN methylation was identified, suggesting a decrease in BEGAIN methylation in sperm as paternal age increases. The sex-specific impact of paternal age on BEGAIN methylation was observed, with a significant negative correlation in male offspring but not in female offspring.

Regarding chronological age, a significant negative correlation with BEGAIN methylation was found in males but not in females, indicating a potential sex-specific age-related change in BEGAIN methylation.

The study also explored the association between BEGAIN methylation and autism (ASD). Individuals with ASD were found to have significantly lower levels of BEGAIN methylation compared to age- and sex-matched controls, suggesting a potential involvement of BEGAIN methylation in the development of ASD.

Furthermore, the researchers identified a genetic variant, SNP rs7141087, associated with BEGAIN methylation. The CC genotype of this SNP was linked to lower levels of BEGAIN methylation compared to the TT genotype, potentially contributing to observed differences in BEGAIN methylation between individuals with ASD and controls.

“Individuals with CC genotype of SNP rs7141087 which show a 6% lower methylation than the TT genotype are significantly more frequent in our ASD group than in controls. This could be due to an association of the C allele with autism.”

Conclusions & Future Research

In conclusion, this research provides valuable insights into the effects of paternal and chronological age on BEGAIN methylation and its potential role in ASD. The findings suggest that paternal age and chronological age can influence BEGAIN methylation, and these changes may be associated with an increased risk of ASD. Further research is needed to fully understand the mechanisms underlying these associations and their implications for the development of ASD.

“The male-specific hypomethylation of the BEGAIN promoter in blood, and by extrapolation other somatic tissues is exaggerated in males suffering from autism. Moreover, our results also show a paternal age effect on BEGAIN methylation in sperm and the male offspring (FCB). […] However, the functional implications of small age-associated methylation changes in BEGAIN in a multifactorial disease model remain to be elucidated.”

Click here to read the full study published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

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