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

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.