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

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.

doi:10.64898/2026.09.10.750683

bioRxiv · 10.64898/2026.09.10.750683

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

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.

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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.

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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.. 2026-09-16. Point mutations and complex variants impact gene expression and addiction-related behaviors in Heterogeneous Stock rats. https://doi.org/10.64898/2026.09.10.750683

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