Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies

Waszczuk, Monika A.; Jonas, Katherine; Bornovalova, Marina A.; Breen, Gerome; Bulik, Cynthia M.; Docherty, Anna R.; Eley, Thalia C.; Hettema, John M.; Kotov, Roman; Krueger, Robert F.; Lencz, Todd; Li, James J.; Vassos, Evangelos; Waldman, Irwin D.

doi:10.1038/s41380-023-02142-8

Cited by 15 publications

(4 citation statements)

References 148 publications

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“…Aus einer Forschungsperspektive ergeben sich insbesondere durch die hierarchische Struktur von HiTOP neue Fragestellungen und Impulse für die Erforschung der spezifischen genetischen Grundlagen, Umweltbedingungen, neurobiologischen Mechanismen, Behandlung und Prävention von psychischen Problemen (Conway et al, 2019;Conway et al, 2023;DeYoung et al, 2023;Hopwood et al, 2020;Mullins-Sweatt et al, 2020;Perkins et al, 2020;Tiego et al, 2023;Waszczuk et al, 2020;Waszczuk et al, 2023).…”

Section: Implikationen Für Forschung Und Praxisunclassified

Hierarchische Taxonomie der Psychopathologie (HiTOP): Ein neues Modell zur Beschreibung psychischer Probleme

Zimmermann,

Witthöft,

Cicero

et al. 2024

Preprint

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Aktuelle Klassifikationssysteme für psychische Störungen wie das DSM-5 und ICD-11 stehen zunehmend in der Kritik, die Komplexität psychischer Probleme nicht adäquat abzubilden. Ungünstig sind insbesondere die implizite Orientierung am medizinischen Krankheitsmodell, die mangelnde strukturelle Validität sowie die kategoriale Abgrenzung zu psychischer Gesundheit. Als Antwort auf diese Herausforderungen wird aktuell im Rahmen eines Konsortiums eine Hierarchische Taxonomie der Psychopathologie (HiTOP) entwickelt – ein empirisch fundiertes, hierarchisch organisiertes, und dimensionales Modell zur Beschreibung psychischer Probleme. In diesem Artikel wird das HiTOP-Modell erstmals in umfassender Weise für den deutschsprachigen Raum zugänglich gemacht. Nach einer Kritik an aktuellen Klassifikationssystemen erläutern wir zunächst die methodischen Grundprinzien von HiTOP und stellen das aktuell gültige Modell vor. Anschließend berichten wird von neuen Studien und Überlegungen zur Validierung und Weiterentwicklung des Modells, geben einen Einblick in die Entwicklung eines umfassenden Selbsteinschätzungsfragebogens zur Erfassung der HiTOP-Dimensionen und veranschaulichen den Einsatz von HiTOP in der diagnostischen Praxis. In der Diskussion klären wir Bezüge zu alternativen Ansätzen zur Konzeptualisierung psychischer Störungen, arbeiten die Implikationen von HiTOP für zukünftige Forschung und Praxis heraus und thematisieren Forschungslücken und Limitationen.

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Section: Implikationen Für Forschung Und Praxisunclassified

Hierarchische Taxonomie der Psychopathologie (HiTOP): Ein neues Modell zur Beschreibung psychischer Probleme

Zimmermann,

Witthöft,

Cicero

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…A related potential future direction includes incorporating other “addiction-like” behaviors, such as pathological gambling, into this shared genetic framework. Second, and relatedly, as GWAS sample sizes and available sources of phenotypic data grow, deep phenotyping, alternative phenotype definitions, and use of secondary or intermediate phenotypes could be leveraged to ask intriguing and nuanced questions regarding the nature of SUD- g ( 128 – 130 ). One potential approach may involve using increasingly rigorous case-control designs (e.g., specific diagnostic thresholds to define cases and use of substance-exposed versus substance-naive controls) ( 103 , 131 ) to provide stronger contrasts between genetic influences on normative versus problematic substance use.…”

Section: Future Scientific Advancements In Studying Sud- Gmentioning

confidence: 99%

Generalized genetic liability to substance use disorders

Miller,

Bogdan,

Agrawal

et al. 2024

Journal of Clinical Investigation

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Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

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“…Combining transdiagnostic and disorder-level approaches enhances statistical power to detect pleiotropic effects, while identifying patterns of genetic heterogeneity and increasing the specificity of SNP discovery. 23…”

Section: Introductionmentioning

confidence: 99%

Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

Khan,

Davis,

Jinwala

et al. 2024

Preprint

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The etiology of substance use disorders (SUDs) and psychiatric disorders reflects a combination of both transdiagnostic (i.e., common) and disorder-level (i.e., independent) genetic risk factors. We applied genomic structural equation modeling to examine these genetic factors across SUDs, psychotic, mood, and anxiety disorders using genome-wide association studies (GWAS) of European-(EUR) and African-ancestry (AFR) individuals. In EUR individuals, transdiagnostic genetic factors represented SUDs (143 lead single nucleotide polymorphisms [SNPs]), psychotic (162 lead SNPs), and mood/anxiety disorders (112 lead SNPs). We identified two novel SNPs for mood/anxiety disorders that have probable regulatory roles onFOXP1,NECTIN3, andBTLAgenes. In AFR individuals, genetic factors represented SUDs (1 lead SNP) and psychiatric disorders (no significant SNPs). The SUD factor lead SNP, although previously significant in EUR- and cross-ancestry GWAS, is a novel finding in AFR individuals. Shared genetic variance accounted for overlap between SUDs and their psychiatric comorbidities, with second-order GWAS identifying up to 12 SNPs not significantly associated with either first-order factor in EUR individuals. Finally, common and independent genetic effects showed different associations with psychiatric, sociodemographic, and medical phenotypes. For example, the independent components of schizophrenia and bipolar disorder had distinct associations with affective and risk-taking behaviors, and phenome-wide association studies identified medical conditions associated with tobacco use disorder independent of the broader SUDs factor. Thus, combining transdiagnostic and disorder-level genetic approaches can improve our understanding of co-occurring conditions and increase the specificity of genetic discovery, which is critical for psychiatric disorders that demonstrate considerable symptom and etiological overlap.

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Dimensional and transdiagnostic phenotypes in psychiatric genome-wide association studies

Cited by 15 publications

References 148 publications

Hierarchische Taxonomie der Psychopathologie (HiTOP): Ein neues Modell zur Beschreibung psychischer Probleme

Hierarchische Taxonomie der Psychopathologie (HiTOP): Ein neues Modell zur Beschreibung psychischer Probleme

Generalized genetic liability to substance use disorders

Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample

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