Genome-wide Methylation Analysis of Post-Mortem Cerebellum Samples Supports the Role of Peroxisomes in Autism Spectrum Disorder

Abstract

Aim: We tested the hypothesis that a subset of patients with autism spectrum disorder (ASD) contains candidate genes with high DNA methylation differences (effective values) that potentially affect one of the two alleles. Materials & methods: Genome-wide DNA methylation comparisons were made on cerebellum samples from 30 patients and 45 controls. Results: 12 genes with high effective values, including GSDMD, MMACHC, SLC6A5 and NKX6-2, implicated in ASD and other neuropsychiatric disorders were identified. Monoallelic promoter methylation and downregulation were observed for SERHL (serine hydrolase-like) and CAT (catalase) genes associated with peroxisome function. Conclusion: These data are consistent with the hypothesis implicating impaired peroxisome function/biogenesis for ASD. A similar approach holds promise for identifying rare epimutations in ASD and other complex disorders.

Plain language summary

Genetic susceptibility of autism spectrum disorder (ASD) is well recognized but found only in one among 30–50% of identical twins. Epigenetic modifications such as DNA methylation underlie differences in gene function without alteration in the sequence. In this study, we identified large DNA methylation changes in nine gene promoters in cerebellum tissues of patients with ASD. Several were already implicated in ASD and other neuropsychiatric disorders. Promoters of two genes (SERHL and CAT) involved in peroxisome function showed increased methylation and low-level expression. The two abnormalities identified support the hypothesis associating ASD with defects in peroxisomes that are involved in detoxification of reactive oxygen species.

Graphical abstract

Keywords::

• autism spectrum disorder
• DNA methylation
• epimutations
• haploinsufficiency
• peroxisome biogenesis/function
• triplosensitivity

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0184

Author contributions

The study was conceived by KN Mohan. Experiments and analysis described in this manuscript were conducted by A Anne and S Saxena. KN Mohan and A Anne carried out the bioinformatic analysis and wrote the draft and subsequent versions of the manuscript.

Acknowledgments

The authors thank the Maryland and the Harvard Brain Banks for sharing the post mortem samples and BITS Pilani Hyderabad Campus for providing infrastructural facilities.

Financial & competing interests disclosure

This work in KN Mohan’s laboratory was supported by Research Initiation, Centre for Human Disease Research (CHDR), Seed and OPERA grants from BITS Pilani. A Anne was supported by a fellowship from CHDR of BITS Pilani Hyderabad Campus. S Saxena was supported by a fellowship from a project sponsored by Deprtment of Biotechnology to NM Kommu. The funding agencies played no role in design or outcome of these experiments. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work in KN Mohan’s laboratory was supported by Research Initiation, Centre for Human Disease Research (CHDR), Seed and OPERA grants from BITS Pilani. A Anne was supported by a fellowship from Centre for Human Disease Research (CHDR) of Birla Institute of Technology & Science (BITS) Pilani Hyderabad Campus. S Saxena was supported by a fellowship from a project sponsored by Deprtment of Biotechnology to NM Kommu. The funding agencies played no role in design or outcome of these experiments. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.