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Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings. | LitMetric

Phenotypes, mechanisms and therapeutics: insights from bipolar disorder GWAS findings.

Mol Psychiatry

Clinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Published: July 2022

AI Article Synopsis

  • Genome-wide association studies (GWAS) have identified key genetic loci linked to bipolar disorder (BD), but understanding the biological mechanisms remains challenging.
  • Some identified risk genes, such as ANK3 and CACNA1C, have been studied in animal models, showing that manipulating these genes can mimic BD symptoms and can be influenced by mood stabilizers.
  • Overall, BD GWAS risk genes are important for understanding the disorder's neurobiology and could serve as potential therapeutic targets, while also emphasizing the need for careful integration of genetic and neuroscience research.

Article Abstract

Genome-wide association studies (GWAS) have reported substantial genomic loci significantly associated with clinical risk of bipolar disorder (BD), and studies combining techniques of genetics, neuroscience, neuroimaging, and pharmacology are believed to help tackle clinical problems (e.g., identifying novel therapeutic targets). However, translating findings of psychiatric genetics into biological mechanisms underlying BD pathogenesis remains less successful. Biological impacts of majority of BD GWAS risk loci are obscure, and the involvement of many GWAS risk genes in this illness is yet to be investigated. It is thus necessary to review the progress of applying BD GWAS risk genes in the research and intervention of the disorder. A comprehensive literature search found that a number of such risk genes had been investigated in cellular or animal models, even before they were highlighted in BD GWAS. Intriguingly, manipulation of many BD risk genes (e.g., ANK3, CACNA1C, CACNA1B, HOMER1, KCNB1, MCHR1, NCAN, SHANK2 etc.) resulted in altered murine behaviors largely restoring BD clinical manifestations, including mania-like symptoms such as hyperactivity, anxiolytic-like behavior, as well as antidepressant-like behavior, and these abnormalities could be attenuated by mood stabilizers. In addition to recapitulating phenotypic characteristics of BD, some GWAS risk genes further provided clues for the neurobiology of this illness, such as aberrant activation and functional connectivity of brain areas in the limbic system, and modulated dendritic spine morphogenesis as well as synaptic plasticity and transmission. Therefore, BD GWAS risk genes are undoubtedly pivotal resources for modeling this illness, and might be translational therapeutic targets in the future clinical management of BD. We discuss both promising prospects and cautions in utilizing the bulk of useful resources generated by GWAS studies. Systematic integrations of findings from genetic and neuroscience studies are called for to promote our understanding and intervention of BD.

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Source
http://dx.doi.org/10.1038/s41380-022-01523-9DOI Listing

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