A postmortem brain study attempts to determine whether genetic differences associated with autism have a significant impact on gene expression in the brain

By Azra Jaferi, Ph. D.

Introduction

Several types of differences (or variants) in genes can influence the likelihood of developing autism spectrum disorder (ASD). The most common type of genetic difference that is inherited from parents is known as a single nucleotide polymorphism (SNP – pronounced “snip”),1 occurring when there is a change at a single position in a person’s DNA sequence. One key challenge in figuring out the role of SNPs in human health is that not all SNPs have a meaningful functional significance. A recent brain study3 led by Ziarih Hawi and Mark Bellgrove at Monash University in Australia set out to get a clearer picture of the functional relevance of genetic markers linked to ASD. Their study selected a set of SNPs that they predicted to befunctionally important and then investigated whether they did indeed affect gene expression in postmortem brain tissue (coming from people with ASD whose brains were donated to Autism BrainNet for research).

Methodology

The researchers selected a set of SNPs already associated with ASD and then screened them for their regulatory effects on genes.4 They did this using computer-based tools to collect and analyze the genetic data. Next, they sought to confirm whether the selected SNPs are relevant for influencing gene expression in postmortem brain tissue from people with or without ASD. The researchers focused on the inferior frontal gyrus, a region involved in language and other cognitive abilities, and a key region of interest in studying the brain mechanisms that might contribute to ASD.5,6

Findings and implications for autism

The study identified 82 SNPs predicted to have regulatory effects on genes that may contribute to ASD. The researchers measured the impact of 11 of the SNPs on gene expression in postmortem brain samples. Surprisingly, the researchers found that none of the variants were associated with significant changes in how genes functioned. The results suggest that a closer look may be needed at the way that researchers have regularly predicted and measured the biological function of genetic mutations in neurodevelopmental conditions. The data uncover the possibility that these approaches may not be as effective as previously thought in capturing the subtle influence that individual SNPs may have on ASD-related biology.

Overall, this study bridges a gap between the identification of SNPs associated with ASD and the actual validation of the biological mechanisms through which these SNPs might increase the likelihood of an ASD diagnosis. The results provide the basis for a possible re-thinking of the contribution of non-coding genetic variants to ASD and for future studies to innovate different approaches for studying the role of SNPs in neurodevelopmental conditions.

References

  1. Gaugler T, Klei L, Sanders SJ, et al. Nat Genet. 46, 881-885 (2014) PubMed
  2. ENCODE Project Consortium. Nature 489, 57-74 (2012) PubMed
  3. Pugsley K, Namipashaki A, Bellgrove MA, Hawi Z. Autism Res. Published online February 7, 2024. PubMed
  4. Tong JHS, Hawi Z, Dark C, et al. Mol Psychiatry 21, 1589-1598 (2016) PubMed
  5. Peng Z, Chen J, Jin L, et al. Psychiatry Res Neuroimaging 298, 111063 (2020) PubMed
  6. Li Y, Zhu Y, Nguchu BA, et al. Autism Res. 13, 230-243 (2020). PubMed
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