Written by Charlotte Harrison, Science Writer.
Alternative splicing of RNA controls the flow of genetic information from DNA to protein, and is associated with many complex neurological disorders. A new study by researchers at Indiana University School of Medicine shows that alternative gene splicing impacts a person’s risk of alcohol use disorder (AUD).
As well as providing further understanding of the genetic causes of AUD risk, the findings might one day lead to better treatments for the disorder in which excessive alcohol consumption leads to health and social problems.
Exon skipping
First, the authors aimed to identify skipped exons — the main splicing event in the brain — that contribute to AUD risk. To do this, they developed a computational model using RNA-seq and genotype data from the CommonMind Consortium.
The result and models were then applied to data from the Collaborative Studies on Genetics of Alcoholism to examine the link between the splicing event outcome and traits related to AUD.
This strategy identified 27 exon-skipping events that were predicted to affect AUD risk. To boost reproducibility, the researchers repeated the same analysis using the Australian Twin-family Study of Alcohol Use Disorder dataset.
Six genes were common to both datasets: DRC1, ELOVL7, LINC00665, NSUN4, SRRM2 and TBC1D5, which are linked to neuroimmune pathways.
A focus on ELOVL7
The researchers then focused on an alternatively spliced non-coding exon in ELOVL7 (fatty acid elongase 7). The impact of this gene on AUD susceptibility was corroborated by additional analyses in four AUD-related GWAS datasets. This finding indicates that the splicing regulation of ELOVL7 likely plays an important role in the genetic basis of AUD.
To assess the impact of the ELOVL7 skipped exon, the researchers conducted association analysis with magnetic resonance imaging data from the UK Biobank. Here they found that the spliced ELOVL7 exon was implicated in immunological and neurological functions.
In particular, this exon contributed to changes in brain grey matter volumes in brain regions known to be involved in AUD.
Future research
“This is the first time that we’ve seen how the exon inclusion on specific genes can potentially lead to addiction,” said senior author Yunlong Liu in a press release.
Liu also added that future research could target the novel genes, or regions of special interest of the genes, to further understand molecular mechanisms in complex diseases, including AUD and other substance use disorders, and potentially develop new therapeutics.
