Systems genetics analysis reveals the common genetic basis for pain sensitivity and cognitive function

Abstract

BackgroundThere is growing evidence of a strong correlation between pain sensitivity and cognitive function under both physiological and pathological conditions. However, the detailed mechanisms remain largely unknown. In the current study, we sought to explore candidate genes and common molecular mechanisms underlying pain sensitivity and cognitive function with a transcriptome‐wide association study using recombinant inbred mice from the BXD family.MethodsThe pain sensitivity determined by Hargreaves' paw withdrawal test and cognition‐related phenotypes were systematically analyzed in 60 strains of BXD mice and correlated with hippocampus transcriptomes, followed by quantitative trait locus (QTL) mapping and systems genetics analysis.ResultsThe pain sensitivity showed significant variability across the BXD strains and co‐varies with cognitive traits. Pain sensitivity correlated hippocampual genes showed a significant involvement in cognition‐related pathways, including glutamatergic synapse, and PI3K‐Akt signaling pathway. Moreover, QTL mapping identified a genomic region on chromosome 4, potentially regulating the variation of pain sensitivity. Integrative analysis of expression QTL mapping, correlation analysis, and Bayesian network modeling identified Ring finger protein 20 (Rnf20) as the best candidate. Further pathway analysis indicated that Rnf20 may regulate the expression of pain sensitivity and cognitive function through the PI3K‐Akt signaling pathway, particularly through interactions with genes Ppp2r2b, Ppp2r5c, Col9a3, Met, Rps6, Tnc, and Kras.ConclusionsOur study demonstrated that pain sensitivity is associated with genetic background and Rnf20‐mediated PI3K‐Akt signaling may involve in the regulation of pain sensitivity and cognitive functions.

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease

“…In this study, we integrated phenotypic resources from the BXD panel, including more than 300 neural phenotypes from over 150 mouse strains. The recombinant inbred population of the BXD family, as one of the largest and well-characterized genetic reference populations, is the basis for studying various diseases, such as cancer, cognitive disorders, and heart diseases (Zhu et al, 2020 ; Bajpai et al, 2023 ; Zhou et al, 2023 ; Xu et al, 2024 ). The correlation of the BXD RI family has been extended to genetic analysis of behavioral phenotypes, including drug addiction, neurodegenerative processes, etc.…”

“…Thousands of transcriptomic/phenomic datasets have been published using these BXD strains over the past decades, consisting of ~250 phenotypes associated with cognitive function (Philip et al, 2010 ). In addition, since each BXD strain is a stable inbred, it can be replicated in large numbers, to facilitate the precise localization of complex traits with low to moderate heritability (Xu et al, 2024 ). The BXD panel showed a strong variation in methionine concentrations in the midbrain across different strains, suggesting that it is a suitable population for exploring potential mechanisms underlying the association between methionine and AD.…”