A new consortium study, “Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain – ScienceDirect” by Garrett et al. (2024), explores the potential insights that mouse models can offer in understanding neuropsychiatric diseases. The study specifically examines a large set of genes that, when knocked out in mice, alter a Schizophrenia (SZ)-related endophenotype known as prepulse inhibition (PPI). With heritability estimates as high as 81%, SZ is strongly influenced by both common and rare genetic variants. However, identifying causal variants within these has proven difficult. By providing a vast dataset of protein-coding gene knockouts (KO) and standardized phenotypic data—including prepulse inhibition (PPI) of acoustic startle, a key SZ-associated endophenotype—IMPC offers a powerful platform for cross-species genetic analysis. PPI serves as a conserved measure of sensorimotor gating, linking genetic variation to SZ pathology. The authors conducted a cross-species network-based comparison of expression of these genes in the brain, utilising region-specific transcriptomic information from the mouse and human Allen Brain atlas.
Given the complexity of Schizophrenia, which involves significant genetic and phenotypic heterogeneity, the goal of the study was to identify overlapping phenotypes and gene expression patterns in relevant brain regions across both species. By using IMPC PPI data, the authors applied Omnigenic model to map SZ genetic risk. This approach aimed to uncover genes with conserved functions that merit further investigation. By employing hierarchical clustering and weighted gene co-expression network analysis (WGCNA), they identified a convergence of Schizophrenia risk and mouse PPI-related genes in two telencephalic modules, strongly associated with synaptic function and glutamatergic neurotransmission.
IMPC data bridges the gap between human genetic findings and molecular mechanisms, offering a foundation for functionally annotating SZ genetic variants as well as a framework for precision medicine approaches in SZ by identifying the novel targets, especially for under-treated negative symptoms.
Importantly, due to the prevalence of pleiotropy in both mice and humans, and the ongoing need to reform psychiatric disease classifications to reflect better the underlying biology, it is likely that the genes affecting PPI in mice may play roles not only in Schizophrenia, but also in other neurodevelopmental disorders. The results displayed that while all genes in brain tissue contribute to SZ, core genes directly affect disease-relevant traits like PPI. This study therefore provides an important first step for leveraging mouse preclinical genetics to investigate the mechanisms underlying brain-related disorders.
Reference:
Garrett L, Trümbach D, Lee D, et al. (2024) Co-expression of prepulse inhibition and schizophrenia genes in the mouse and human brain. Neuroscience Applied, 3:104075. https://doi.org/10.1016/j.nsa.2024.104075