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Are novel treatments for brain disorders hiding in plain sight?

Neuropsychopharmacology volume 49, pages 276–281 (2024)Cite this article

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Abstract

Psychiatric diseases are strongly influenced by genetics, but genetically guided treatments have been slow to develop, and precise molecular mechanisms remain mysterious. Although individual locations in the genome tend to not contribute powerfully to psychiatric disease incidence, genome-wide association studies (GWAS) have now successfully linked hundreds of specific genetic loci to psychiatric disorders [1,2,3]. Here, building upon results from well-powered GWAS of four phenotypes relevant to psychiatry, we motivate an exploratory workflow leading from GWAS screening, through causal testing in animal models using methods such as optogenetics, to new therapies in human beings. We focus on schizophrenia and the dopamine D2 receptor (DRD2), hot flashes and the neurokinin B receptor (TACR3), cigarette smoking and receptors bound by nicotine (CHRNA5, CHRNA3, CHRNB4), and alcohol use and enzymes that help to break down alcohol (ADH1B, ADH1C, ADH7). A single genomic locus may not powerfully determine disease at the level of the population, but the same locus may nevertheless represent a potent treatment target suitable for population-wide therapeutic approaches.

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Fig. 1: Selected schizophrenia and hot flash GWAS results have mechanistic and pharmacological relevance.
Fig. 2: Cigarettes per day and alcohol per week GWAS reveal mechanistically relevant genes in top loci.

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Notes

  1. Throughout this manuscript we refer to genome-wide studies, singular and plural, as GWAS. GWAS have historically been conducted using array-based (“chip”) technology but sequencing-based genome-wide studies are increasingly common as sequencing costs decrease.

  2. Note that the presence of significant variants in the DRD2 gene does not necessarily imply that variation in DRD2 genotypes influences schizophrenia risk; functional studies would be needed to conclusively establish this link.

  3. The linking of loci to genes constitutes an entire field of research. There is no field-wide consensus regarding the best approach, since much remains unknown about the function of individual genes and their regulation by genetic elements within and outside of genes. Leading approaches include nearest gene, MAGMA gene-level p value, and numerous fine-mapping approaches.

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Acknowledgements

We would like to thank the Psychiatric Genomics Consortium (PGC) for the vision, perseverance, and international collaboration necessary to create a well-powered psychiatric GWAS. We thank Katy Werwath, Kevina Wang, Ciera Stafford, and Hanyang Shen for help with this manuscript.

Funding

This work was supported by NIMH grants to LD (R01 MH123486, R21 MH125358) and the Jaswa Innovator Award. KD is supported by NIDA, NIMH, and the BRAIN Initiative. Funding bodies had no role in the design of the study, in the collection and analysis of data, or in decisions regarding publication.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Laramie Duncan & Karl Deisseroth

  2. Department of Bioengineering and Howard Hughes Medial Institute, Stanford University, Stanford, CA, USA

    Karl Deisseroth

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  1. Laramie Duncan
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LD and KD were responsible for the conception, drafting, and revision of the work.

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Correspondence to Laramie Duncan or Karl Deisseroth.

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LD has no competing interests. KD is a cofounder and consultant for Maplight Therapeutics.

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Duncan, L., Deisseroth, K. Are novel treatments for brain disorders hiding in plain sight?. Neuropsychopharmacol. 49, 276–281 (2024). https://doi.org/10.1038/s41386-023-01636-x

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