Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats
- 1University of California San Diego, La Jolla, CA
Abstract
Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).
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BibTeX
@misc{munro2026deep,
title = {{Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats}},
author = {D. B. Munro and K.-M. H. Nguyen and C. L. St. Pierre and H. Bimschleger and K. A. Cohen and Y. Wang and R. Ward and K. Holl and D. Chen and B. B. Johnson and G. Ang and M. Mortazavi and E. Keung and C. King and J. A. Tripi and B. N. Kuhn and B. M. Thompson and A. Lionikas and D. Daniels and C. Vulpe and P. W. Kalivas and O. George and D. J. Adams and D. M. Dietz and S. Flagel and R. Hitzemann and A. Gusev and L. M. Saba and M. M. Jablonski and T. C. Jhou and F. Telese and P. J. Meyer and S. H. Mitchell and L. C. Solberg Woods and H. Chen and O. Polesskaya and P. Mohammadi and A. A. Palmer},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.764420},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.764420v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats
AU - D. B. Munro
AU - K.-M. H. Nguyen
AU - C. L. St. Pierre
AU - H. Bimschleger
AU - K. A. Cohen
AU - Y. Wang
AU - R. Ward
AU - K. Holl
AU - D. Chen
AU - B. B. Johnson
AU - G. Ang
AU - M. Mortazavi
AU - E. Keung
AU - C. King
AU - J. A. Tripi
AU - B. N. Kuhn
AU - B. M. Thompson
AU - A. Lionikas
AU - D. Daniels
AU - C. Vulpe
AU - P. W. Kalivas
AU - O. George
AU - D. J. Adams
AU - D. M. Dietz
AU - S. Flagel
AU - R. Hitzemann
AU - A. Gusev
AU - L. M. Saba
AU - M. M. Jablonski
AU - T. C. Jhou
AU - F. Telese
AU - P. J. Meyer
AU - S. H. Mitchell
AU - L. C. Solberg Woods
AU - H. Chen
AU - O. Polesskaya
AU - P. Mohammadi
AU - A. A. Palmer
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.764420
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.764420v1
AB - Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).
ER -