Unraveling the enigma of mental disorders: a genetics-first approach and the role of mouse models based on rare disease-susceptible genome variants.

Mental disorders are a major global cause of disability that involve significant disturbances in thinking, emotional regulation, or behavior. The pathogenesis of these illnesses is complicated by their obscure nature and lack of biological markers. A genetics-first approach has been proposed to address this complexity. This approach associates clinical phenotypes with disease-susceptible genomic variants, such as copy number variations and single nucleotide variants. These rare variants significantly affect disease development and are thus crucial for assessing the effects of specific variants on disease and in determining the underlying biological mechanisms. In particular, mouse models that reflect these variants are instrumental in defining the causal relationships between genetic variants and disease-relevant phenotypes. Recent studies have highlighted the importance of sensory information processing in humans and mice. Advanced technologies that are valuable in unraveling the neural circuit mechanisms of these phenotypes include optogenetics and in vivo 2-photon imaging. Furthermore, mouse models can guide the integration of findings from patients and induced pluripotent stem cells, supporting a multidimensional approach to understanding the pathophysiology of mental disorders. In this review, we briefly discuss the utility of mouse models in a genetics-first approach to elucidate the pathophysiology of mental disorders. We also present examples of our mouse models based on rare disease-susceptible variants.