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Accomplishments and Challenges that Remain

NIMH neuropsychiatric genomics: crucial foundational accomplishments and the extensive challenges that remain

Molecular Psychiatry volume 22, pages 1656–1658 (2017)Cite this article

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The article, 'Genomic Resources for the Study of Neuropsychiatric Disorders' by Senthil, Dutka, Bingaman and Lehner is an impressive archive of the accomplishments of the NIMH Genomics Research Branch over the past 27 years.1 Their review of the accomplishments of the Genomics Research Branch work is parsed into two major areas: first, the authors describe the extensive, labor intensive construction and coordination of large genomics biorepositories and related resources, which have transformed the field in terms of the publically available data. This repository provides a large foundational base for genomic studies to follow. It has already provided information about the genetic architecture of the nine major serious mental illnesses (SMI) that are archived: schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, anorexia nervosa, attention deficit hyperactivity disorder, obsessive-compulsive disorder, PTSD and substance use disorder. These disorders account for a profound disability burden in a range greater than any other family of medical disorders.2 For these SMIs, we still have a challenging 'Knowledge to Wisdom Gap', whereby our knowledge (for example, genome-wide association study (GWAS) of large samples) currently outpaces our wisdom: our ability to definitively advance these facts for treatment, development or finding 'cures' for SMI.3 Second, the authors have outlined the cultural changes that they have helped to promote in the world of neuropsychiatric genetics: 'data sharing' in a space occupied by large 'team science'. Clearly, in the field of 'disease gene finding' some investigators are understandably possessive of their data and their insights before and sometimes even after publication of the findings. This is to be expected in a scientific field that is relatively early in its development and is also highly competitive and rapidly expanding. The NIMH leaders have begun to transform the neuropsychiatric genomics culture in the direction of affiliative, interacting and open dialogue, and data sharing infused with 'Gemeinschatzgefeul': community spiritedness. With these ideas in mind I will cover my further perceptions of the article and related issues.

One can easily estimate that neuropsychiatric genomics faces challenges that may be a substantially greater challenge than for most common heritable medical diseases. While our colleagues studying type 2 diabetes, familial hyperlipidemia and breast cancer have been quite productive, they have also been faced with many challenges similar to, but in many ways simpler, than challenges faced in neuropsychiatric genetics, as is explained below. These challenges include identifying risk genes and fully understanding complex gene × gene (G × G) and gene by environment (G × E) interactions, and then developing new precision-based treatments. Those challenges are similar to ones long faced in neuropsychiatric genomics.4 Thus there is still an imposing gulf between the early but rapidly expanding knowledge of the genetic basis of common heritable illnesses and the clinical application of this knowledge. While the G × G and G × E challenges are true for even organs such as the liver or breast with simple and relatively homogenous cellular architecture, it is even more true for the complex human brain. Unlike accessible organs such as liver or breast, which are subject to diagnostic probes such as in vivo biopsy, neuropsychiatric genomics faces an order of magnitude greater challenge. The brain is encased in a difficult to breach cranial vault making direct observations and biopsy of in vivo brain tissue practically impossible. Advances in neuroimaging may ameliorate some of these problems, but not all.5 As we know, the brain consists of roughly 75 billion neurons in a complex array of circuits from the cortical mantle to underlying subcortical regions. In addition, over one-third of the human genome is expressed in the brain, which creates many analytic problems. While we have some understanding of neural circuits spanning 'long lines' such as the cortico-striatal-pallido-thalamic circuitry underlying key disease-related function,6, 7 our understanding of the genomic underpinnings and the cellular and circuit architecture of SMI remain largely unresolved.

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  1. Department of Psychiatry, University of California,

    D L Braff

  2. La Jolla, San Diego, CA, USA

    D L Braff

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Braff, D. NIMH neuropsychiatric genomics: crucial foundational accomplishments and the extensive challenges that remain. Mol Psychiatry 22, 1656–1658 (2017). https://doi.org/10.1038/mp.2017.182

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