Redefining Phenotypes to Advance Psychiatric Genetics: Implications from Hierarchical Taxonomy of Psychopathology

Authors: Monika A Waszczuk, Nicholas R. Eaton, Robert F. Krueger, Alexander J. Shackman, Irwin D. Waldman, David H. Zald, Benjamin B. Lahey, the HiTOP Consortium, and Roman KotovAbstractGenetic discovery in psychiatry is... [ view full abstract ]

Authors: Monika A Waszczuk, Nicholas R. Eaton, Robert F. Krueger, Alexander J. Shackman, Irwin D. Waldman, David H. Zald, Benjamin B. Lahey, the HiTOP Consortium, and Roman Kotov

Abstract

Genetic discovery in psychiatry is hindered by suboptimal phenotypic definitions, including diagnostic unreliability, comorbidity among disorders, and heterogeneity within them. The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium proposed a data-driven, dimensional classification system for a wide range of psychiatric disorders—based on a comprehensive review of existing nosologic and psychometric research—that addresses many shortcomings of traditional diagnoses^1,2. The system promises to be a useful guide for psychiatric geneticists, who require valid and reliable phenotypes to maximize precision and statistical power in the search for genetic vulnerabilities to mental illness. Conversely, genetic findings are a crucial external validator of psychiatric nosology. The current presentation addresses both issues.

First, I will present a review of how the HiTOP model dovetails with our existing understanding of the genetic architecture of psychopathology that emerged from a large body of family and twin studies. I will also discuss the convergence between the HiTOP model and findings from recent molecular genetic studies of psychopathology, such as cross-disorder SNP-based genetic correlations and polygenic risk scores, which inform genetic architecture and indicate broad genetic pleiotropy³.

Second, I will discuss how the HiTOP model can inform future psychiatric genetic research by providing quantitative, hierarchically organized and easily implementable phenotypes. Specifically, genes are expected to operate at different levels of the HiTOP hierarchy, with some highly pleiotropic genes influencing higher-order psychopathology (e.g. the general factor^4,5), whereas other genes confer specific risk for individual spectra (e.g. internalizing), subfactors (e.g. fear disorders), or narrow symptoms (e.g. mood instability). I will highlight molecular genetic studies that have successfully redefined phenotypes to enhance precision and statistical power. Finally, I will suggest how to integrate the HiTOP approach into future molecular genetic research, including quantitative and hierarchical assessment tools for future data-collection, and tips for phenotypic analyses.

Keywords: behavior genetics, comorbidity, general factor, molecular genetics, pleiotropy, taxonomy

Selected references

1.            Kotov R, Krueger RF, Watson D, et al. The Hierarchical Taxonomy Of Psychopathology (HiTOP): A dimensional alternative to traditional nosologies. J Abnorm Psychol. 2017;126(4):454.

2.            Kotov R, Krueger RF, Watson D. A paradigm shift in psychiatric classification: the Hierarchical Taxonomy Of Psychopathology (HiTOP). World Psychiatry. 2018;17(1):24-25.

3.            Smoller JW, Andreassen OA, Edenberg HJ, Faraone SV, Glatt SJ, Kendler KS. Psychiatric genetics and the structure of psychopathology. Molecular psychiatry. 2018:1.

4.            Lahey BB, Krueger RF, Rathouz PJ, Waldman ID, Zald DH. A Hierarchical Causal Taxonomy of Psychopathology Across the Life Span. Psychological Bulletin. 2016.

5.            Caspi A, Houts RM, Belsky DW, et al. The p factor one general psychopathology factor in the structure of psychiatric disorders? Clinical Psychological Science. 2014;2(2):119-137.