Integrative analysis of transcriptome-wide association study and mRNA expression profiles identifies candidate genes associated with autism spectrum disorders.
Genes linked to mitochondrial energy pathways keep showing up in autism genomics, but the data are not ready for clinical use.
01Research in Context
What this study did
Huang et al. (2019) merged two big data sets. One set came from a genome-wide association scan. The other set held brain mRNA levels from people with autism.
The team ran a transcriptome-wide association study, or TWAS. This method links DNA variants to gene expression changes. They also checked which genes were turned up or down in actual autism brain tissue.
The goal was to find genes that both carry risk DNA and show wonky expression in autism.
What they found
The scan flagged 85 genes. Five of these genes were also mis-expressed in autism brains. Two examples are MUTYH and ARHGAP27.
Many of the hits sit in mitochondrial pathways. That fits the idea that energy factories in cells may act differently in autism.
How this fits with other research
Ch'ng et al. (2015) got the same mitochondrial signal earlier. Their meta-analysis of over 1,000 brain samples also pointed to energy-pathway genes. Huimei adds fresh TWAS evidence that DNA variants drive those expression changes.
Rojas et al. (2025) moved from computer data to real kids. They measured mitochondrial DNA copy number in cheek cells of children with autism. Copy number was high, but the replisome genes Huimei flagged were not over-active. The two studies agree that mitochondria matter, yet they spotlight different parts of the machinery.
Pu et al. (2013) tied the MTHFR gene to autism risk. Ezedinma et al. (2025) later showed an EEG rhythm can hint at MTHFR status. Huimei did not focus on MTHFR, so the gene sits in a separate lane of the autism gene map.
Why it matters
You will not use this paper to pick an intervention tomorrow. Still, it gives you talking points when families ask about biological research. You can say that mitochondrial pathways keep popping up in autism genetics, and that scientists are tracing how DNA differences may push those pathways off track. Keep the findings in your back pocket for interdisciplinary meetings, but keep your focus on behavior.
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02At a glance
03Original abstract
Autism spectrum disorders (ASD) are a group of highly heritable psychiatric syndromes with high prevalence. The genetic mechanism of ASD remains elusive now. Here we conducted a transcriptome-wide association study (TWAS) of ASD. The GWAS summary data of ASD was driven from the Psychiatric Genomics Consortium (PGC) portal, totally involving 5,305 ASD cases and 5,305 controls. FUSION software was applied to the GWAS summary data for tissue-related TWAS of ASD considering brain and blood. The ASD associated genes identified by TWAS were further validated by mRNA expression profiling of ASD and the Simons Foundation for Autism Research (SFARI) Gene tool. DAVID 6.8 was used to perform gene ontology (GO) enrichment analysis of ASD associated genes identified by TWAS. TWAS identified 85 genes with TWAS P value <0.05 for ASD. Further comparing the 85 genes with the differentially expressed genes identified by mRNA expression profiling of ASD patients found 5 overlapped genes, including MUTYH (PTWAS = 0.0460, PmRNA = 0.0040), ARHGAP27 (PTWAS = 0.0100, PmRNA = 0.0016), GCA (PTWAS = 0.0480, PmRNA = 0.0063), CCDC14 (PTWAS = 0.0067, PmRNA = 0.0035), and MED15 (PTWAS = 0.0324, PmRNA = 0.0092). Gene Ontology (GO) enrichment analysis of the genes identified by TWAS detected 10 significant GO terms, such as mitochondrion (P = 0.0051), NAD or NADH binding (P = 0.0169), mitochondrial part (P = 0.0386) and 2-oxoglutarate metabolic process (P = 0.0399). In conclusion, this study identified multiple ASD associated genes and gene sets, providing novel clues for revealing the pathogenesis of ASD. Autism Research 2019, 12: 33-38. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Recent genetic studies of autism spectrum disorders (ASD) have found multiple ASD related genes. However, the results of these studies were hardly replicated with each other, providing limited clues for exploring the genetic mechanism of ASD. This study detected a group of candidate genes showing transcriptome-wide associations with ASD. These results may provide novel clues for revealing the pathogenesis of ASD.
Autism research : official journal of the International Society for Autism Research, 2019 · doi:10.1002/aur.2048