In a groundbreaking new study that promises to reshape our understanding of bipolar disorder (BD), researchers have employed whole-exome sequencing to uncover novel genetic candidates within a uniquely affected Chinese pedigree. Bipolar disorder, a chronic and debilitating mental illness characterized by severe mood swings, has long baffled scientists due to its complex genetic underpinnings. With heritability estimates hovering around 70%, unraveling the specific genes contributing to BD remains a critical step toward developing targeted therapies and predictive diagnostics.
The study centered on a multi-affected southern Chinese Han family, providing researchers with a rare genetic microcosm in which multiple relatives suffer from BD. By focusing on this highly specific population, the team aimed to pinpoint rare but functionally significant genetic variants that segregate strictly with the disease phenotype. This approach circumvents the ambiguities inherent in broad population studies, where noise from unrelated genetic variations can obscure real signals.
Whole-exome sequencing (WES) was the methodology of choice, allowing the investigators to decode all protein-coding regions of the genome with tremendous specificity. Through WES, researchers sifted through the intricate genetic blueprint of eight family members—five diagnosed with BD and three unaffected controls. The comparative analyses were designed to isolate variants uniquely present in affected individuals yet absent in healthy relatives, narrowing down a shortlist of potential culprit mutations.
Crucially, the team did not consider all genetic variants equal. They focused exclusively on rare, damaging single nucleotide variations (SNVs) that possess the potential to disrupt critical biological processes. Employing rigorous bioinformatics pipelines, the scientists filtered out common polymorphisms and those unlikely to impact protein function. This fine-tuned selection process elevated the confidence that identified variants truly contribute to pathogenesis.
Among the top candidate genes emerged three notable hits: NTN1, MYH10, and RILP. Each of these genes plays distinct roles within cellular and neural pathways, converging on mechanisms that govern cytoskeletal architecture and intracellular dynamics. NTN1 encodes netrin-1, a protein best known for its role in axon guidance and neuronal migration, critical factors in neurodevelopment and neural circuit formation. Disruptions in NTN1-mediated signaling could plausibly underlie neuropsychiatric dysfunctions observed in BD.
MYH10 encodes a non-muscle myosin heavy chain involved in actin cytoskeleton regulation, which influences cell shape, motility, and intracellular trafficking. Alterations in MYH10 might impair neuronal architecture or synaptic plasticity, contributing to mood regulation defects. Meanwhile, RILP, the Rab-interacting lysosomal protein, partakes in vesicle transport and lysosomal positioning within cells—a process fundamental for maintaining cellular homeostasis and supporting neural function.
Pathway enrichment analyses further underscored the biological relevance of these findings by highlighting associated functional annotations. The candidate genes are implicated in actin binding, substrate-dependent cell migration, the actin cytoskeleton, and nucleotide excision repair pathways. This constellation of cellular functions suggests that BD’s genetic roots may extend beyond neurotransmitter imbalances, encompassing broader disturbances in neuronal cell structure and DNA repair mechanisms.
The implications of these discoveries are vast. By revealing previously unrecognized genetic contributors to BD, the study offers fresh molecular targets for both diagnostic biomarkers and therapeutic intervention. Understanding how aberrations in genes like NTN1, MYH10, and RILP disrupt neuronal function could pave the way for strategies aimed at restoring cellular architecture or enhancing DNA repair capabilities, potentially ameliorating BD symptoms.
However, the researchers emphasize the preliminary nature of their findings. The study’s sample size—restricted to an eight-member pedigree—necessitates further validation in larger, diverse cohorts to confirm the generalizability and robustness of these candidate genes as universal BD risk factors. Replication efforts will be essential to determine whether these variants contribute similarly across different ethnicities and populations.
Beyond clinical applications, this study showcases the power of combining detailed family-based genetic analyses with cutting-edge sequencing and computational tools. By leveraging the unique genetic landscape of a multiplex pedigree, the investigation bypassed some limitations of population-wide association studies, demonstrating a model for future research into other complex psychiatric disorders.
From a broader perspective, the identification of cytoskeleton and nucleotide repair pathways in BD aligns with emerging themes in neuropsychiatric genetics. Increasingly, research is revealing that mental disorders arise not only from neurotransmitter dysregulation but also from subtle disruptions to cellular infrastructure and genomic integrity. This paradigm shift could unify disparate findings and inspire comprehensive models of disease etiology.
In conclusion, this innovative work highlights NTN1, MYH10, and RILP as promising candidate genes for bipolar disorder within a southern Chinese Han family. The strategic use of whole-exome sequencing combined with robust bioinformatic analyses has opened a new frontier in BD genetic research. With further studies poised to validate and expand these insights, the potential to revolutionize diagnosis and treatment of bipolar disorder draws nearer.
Subject of Research: Candidate genes associated with bipolar disorder through whole-exome sequencing in a Chinese multi-affected pedigree
Article Title: Identification of candidate genes associated with bipolar disorder by whole-exome sequencing of a Chinese multi-affected pedigree
Article References:
Wang, Y., Xu, Z., Zhang, Y. et al. Identification of candidate genes associated with bipolar disorder by whole-exome sequencing of a Chinese multi-affected pedigree.
BMC Psychiatry 25, 612 (2025). https://doi.org/10.1186/s12888-025-07002-z
Image Credits: AI Generated
DOI: https://doi.org/10.1186/s12888-025-07002-z
