Genomic SEM reveals shared genetic architecture and expands locus discovery for locomotor activity in heterogeneous stock rats
Abstract
Locomotor response to a novel environment is a heritable, addiction-relevant behavioral phenotype in rodents. We characterized its genetic basis in 9,341 male and female heterogeneous stock (HS) rats from eight studies. Locomotor activity was heritable across studies, while pairwise genetic correlations were positive but variable, indicating shared yet nonidentical genetic influences. Given nonuniform genetic architecture, we compared three complementary approaches to locus discovery that analyzed SNP effects 1) on a pooled locomotor phenotype (MEGA), 2) across studies under a fixed-effect model (METAL), or 3) on a shared genetic factor (Genomic SEM). To ensure comparability, all three locus-discovery approaches were applied to a common subset of seven studies. Together, these approaches identified 38 loci, with both convergence and method-specific discovery across analyses. Genomic SEM identified 31 loci, compared to 8 for MEGA and 13 for METAL. To interpret the loci, we integrated brain molecular QTLs, predicted coding and splice consequences, and open-field locomotor phenotypes from knockouts of orthologous mouse genes. Our results highlighted established neurobehavioral candidates spanning locomotor and reward-related biology (Negr1 and Lmo4), serotonergic signaling (Htr1b), and GABAergic signaling (Gabrg2), as well as relatively novel genes including Tcerg1l, Pcdh10, and Tmem132e. Our results illustrate how Genomic SEM can integrate genetically correlated yet heterogeneous behavioral measures and enable discovery of loci underlying their shared genetic architecture, highlighting its utility for complex-trait studies in rodents.
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BibTeX
@misc{chitre2026genomic,
title = {{Genomic SEM reveals shared genetic architecture and expands locus discovery for locomotor activity in heterogeneous stock rats}},
author = {A. S. Chitre and T. M. Sanches and G. Ang and N. K. Amissah and R. Avila and H. Bimschleger and P. Campo and N. Cannella and D. Chen and R. Cheng and K. A. Cohen and A. D. Crow and E. Dereschewitz and M. R. Doyle and M. Eid and A. M. George and A. P. Horvath and K. Ishiwari and B. B. Johnson and E. Keung and C. King and C. D. Martin and A. Garcia Martinez and D. Munro and A. H. Netzley and K.-M. Nguyen and B. Peng and D. Pullmann and S. R. M. U. Rahman and A. T. Roberts and M. Sadegi and D. Sevigny-Resetco and L. Soverchia and C. L. St. Pierre and N. Suzuki and B. M. Thompson and S. Tyagi and M. Ubaldi and R. M. Vogel and T. Wang and Y. Wang and H. Chen and R. Ciccocioppo and d},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.756043},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.756043v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Genomic SEM reveals shared genetic architecture and expands locus discovery for locomotor activity in heterogeneous stock rats
AU - A. S. Chitre
AU - T. M. Sanches
AU - G. Ang
AU - N. K. Amissah
AU - R. Avila
AU - H. Bimschleger
AU - P. Campo
AU - N. Cannella
AU - D. Chen
AU - R. Cheng
AU - K. A. Cohen
AU - A. D. Crow
AU - E. Dereschewitz
AU - M. R. Doyle
AU - M. Eid
AU - A. M. George
AU - A. P. Horvath
AU - K. Ishiwari
AU - B. B. Johnson
AU - E. Keung
AU - C. King
AU - C. D. Martin
AU - A. Garcia Martinez
AU - D. Munro
AU - A. H. Netzley
AU - K.-M. Nguyen
AU - B. Peng
AU - D. Pullmann
AU - S. R. M. U. Rahman
AU - A. T. Roberts
AU - M. Sadegi
AU - D. Sevigny-Resetco
AU - L. Soverchia
AU - C. L. St. Pierre
AU - N. Suzuki
AU - B. M. Thompson
AU - S. Tyagi
AU - M. Ubaldi
AU - R. M. Vogel
AU - T. Wang
AU - Y. Wang
AU - H. Chen
AU - R. Ciccocioppo
AU - d
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.756043
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.756043v1
AB - Locomotor response to a novel environment is a heritable, addiction-relevant behavioral phenotype in rodents. We characterized its genetic basis in 9,341 male and female heterogeneous stock (HS) rats from eight studies. Locomotor activity was heritable across studies, while pairwise genetic correlations were positive but variable, indicating shared yet nonidentical genetic influences. Given nonuniform genetic architecture, we compared three complementary approaches to locus discovery that analyzed SNP effects 1) on a pooled locomotor phenotype (MEGA), 2) across studies under a fixed-effect model (METAL), or 3) on a shared genetic factor (Genomic SEM). To ensure comparability, all three locus-discovery approaches were applied to a common subset of seven studies. Together, these approaches identified 38 loci, with both convergence and method-specific discovery across analyses. Genomic SEM identified 31 loci, compared to 8 for MEGA and 13 for METAL. To interpret the loci, we integrated brain molecular QTLs, predicted coding and splice consequences, and open-field locomotor phenotypes from knockouts of orthologous mouse genes. Our results highlighted established neurobehavioral candidates spanning locomotor and reward-related biology (Negr1 and Lmo4), serotonergic signaling (Htr1b), and GABAergic signaling (Gabrg2), as well as relatively novel genes including Tcerg1l, Pcdh10, and Tmem132e. Our results illustrate how Genomic SEM can integrate genetically correlated yet heterogeneous behavioral measures and enable discovery of loci underlying their shared genetic architecture, highlighting its utility for complex-trait studies in rodents.
ER -