Point mutations and complex variants impact gene expression and addiction-related behaviors in Heterogeneous Stock rats

Authors

Chen, D., Cohen, K. A., Nguyen, K.-M. H., Ziaei Jam, H., Eveloff, R. J., Wang, Y., Guevara, J., Missfeldt Sanches, T., Mortazavi, M., Munro, D., Polesskaya, O., Sebat, J. L., Gymrek, M., Palmer, A. A.

Abstract

While various variants, including single nucleotide polymorphisms (SNPs), small insertions/deletions, short tandem repeats and structural variants, drive individual genetic differences, their influence on gene expression and complex traits remains unclear. We used short- and long-read sequencing to generate a comprehensive variant catalog in Heterogeneous Stock (HS) rats and performed joint cis-expression quantitative trait loci (cis-eQTL) mapping across five brain regions. We found that non-SNP variants accounted for over 50% of lead regulatory associations, many of which were poorly tagged by nearby SNPs using linkage disequilibrium (LD). Comparison between joint and SNP-only analyses showed that over 46% of shared eQTL genes had a non-SNP lead cis-eQTL, and fewer than half were in strong LD with the corresponding lead eSNP. Linking joint cis-eQTLs to complex trait associations identified mechanisms missed by SNP-only approaches, highlighting the importance of incorporating diverse variant types into genetic studies and providing a foundational resource for the HS rat community.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 17 Sep 2026.

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