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Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology.

ABSTRACT: Genetic discovery in psychiatry and clinical psychology is hindered by suboptimal phenotypic definitions. We argue that the hierarchical, dimensional, and data-driven classification system proposed by the Hierarchical Taxonomy of Psychopathology (HiTOP) consortium provides a more effective approach to identifying genes that underlie mental disorders, and to studying psychiatric etiology, than current diagnostic categories. 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), whereas other genes conferring more specific risk for individual spectra (e.g., internalizing), subfactors (e.g., fear disorders), or narrow symptoms (e.g., mood instability). We propose that the HiTOP model aligns well with the current understanding of the higher order genetic structure of psychopathology that has emerged from a large body of family and twin studies. We also discuss the convergence between the HiTOP model and findings from recent molecular studies of psychopathology indicating broad genetic pleiotropy, such as cross-disorder SNP-based shared genetic covariance and polygenic risk scores, and we highlight molecular genetic studies that have successfully redefined phenotypes to enhance precision and statistical power. Finally, we suggest how to integrate a HiTOP approach into future molecular genetic research, including quantitative and hierarchical assessment tools for future data-collection and recommendations concerning phenotypic analyses. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

SUBMITTER: Waszczuk MA

PROVIDER: S-EPMC6980897 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology.

Waszczuk Monika A MA Eaton Nicholas R NR Krueger Robert F RF Shackman Alexander J AJ Waldman Irwin D ID Zald David H DH Lahey Benjamin B BB Patrick Christopher J CJ Conway Christopher C CC Ormel Johan J Hyman Steven E SE Fried Eiko I EI Forbes Miriam K MK Docherty Anna R AR Althoff Robert R RR Bach Bo B Chmielewski Michael M DeYoung Colin G CG Forbush Kelsie T KT Hallquist Michael M Hopwood Christopher J CJ Ivanova Masha Y MY Jonas Katherine G KG Latzman Robert D RD Markon Kristian E KE Mullins-Sweatt Stephanie N SN Pincus Aaron L AL Reininghaus Ulrich U South Susan C SC Tackett Jennifer L JL Watson David D Wright Aidan G C AGC Kotov Roman R

Journal of abnormal psychology 20191205 2

Genetic discovery in psychiatry and clinical psychology is hindered by suboptimal phenotypic definitions. We argue that the hierarchical, dimensional, and data-driven classification system proposed by the Hierarchical Taxonomy of Psychopathology (HiTOP) consortium provides a more effective approach to identifying genes that underlie mental disorders, and to studying psychiatric etiology, than current diagnostic categories. Specifically, genes are expected to operate at different levels of the Hi ...[more]

PMID: 31804095

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Project description:INTRODUCTION:Fibrinolysis was initially defined using rapid thrombelastography (rTEG). The cutoffs for the pathologic extremes of the fibrinolytic system, hyperfibrinolysis and shutdown, were both defined based on association with mortality. We propose to redefine these phenotypes for both TEG and for rotational thrombelastometry, the other commonly used viscoelastic assay. METHODS:Rotational thrombelastometry, rTEG, and clinical data were prospectively collected on trauma patients admitted to an urban Level I trauma center from 2010 to 2016. Hyperfibrinolysis was defined as the Youden index from EXTEM-clot lysis index 60 minutes after clotting time (CLI60) and rTEG-fibrinolysis 30 minutes after achieving MA (LY30) for predicting massive transfusion (>10 red blood cell units, or death per 6 hours after injury) as a surrogate for severe bleeding. Patients identified as having hyperfibrinolysis were then removed from the data set, and the cutoff for fibrinolysis shutdown was derived as the optimal cutoff for predicting mortality in the remaining patients. RESULTS:Overall, 216 patients (median age, 36 years (interquartile range, 27-49 years), 82% men, 58% blunt injury) were included. Of these, 16% required massive transfusion, and 12.5% died. Rapid thrombelastography phenotypes were redefined as hyperfibrinolysis: rTEG-LY30 greater than7.7%, physiologic rTEG-LY30 0.6% to7.6%, and shutdown rTEG-LY30 less than 0.6%. EXTEM-CLI60 fibrinolysis phenotypes were hyperfibrinolysis CLI60 less than 82%, physiologic (CLI60, 82-97.9%), and shutdown (CLI60 > 98%). Weighted kappa statistics revealed moderate agreement between rotational thrombelastometry- and rTEG-defined fibrinolysis (k = 0.51; 95% confidence interval, 0.39-0.63), with disagreement mostly in the shutdown and physiologic categories. CONCLUSION:We confirmed the U-shaped distribution of death related to fibrinolysis system abnormalities. Both rTEG LY30 and EXTEM CLI60 can identify the spectrum of fibrinolytic phenotypes, have moderate agreement, and can be used to guide hemostatic resuscitation. LEVEL OF EVIDENCE:Diagnostic study, level III.

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Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology.

Publications

Redefining phenotypes to advance psychiatric genetics: Implications from hierarchical taxonomy of psychopathology.

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