Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2024 May 10:2024.05.09.24307111.
doi: 10.1101/2024.05.09.24307111.

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

Yousef Khan  1 , Christal N Davis  1   2 , Zeal Jinwala  1 , Kyra L Feuer  1 , Sylvanus Toikumo  1   2 , Emily E Hartwell  1   2 , Sandra Sanchez-Roige  3   4   5 , Roseann E Peterson  6 , Alexander S Hatoum  7 , Henry R Kranzler  1   2 , Rachel L Kember  1   2
Affiliations

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

Yousef Khan et al. medRxiv. .

Abstract

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 on FOXP1, NECTIN3, and BTLA genes. 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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. Study schema.
FUMA = Functional Mapping and Annotation of GWAS, CTG-VL = Complex Trait Genetics Virtual Lab, LDSC = linkage disequilibrium score regression, PheWAS = phenome-wide association study.
Figure 2.
Figure 2.. Genomic structural equation models.
AUD = alcohol use disorder, CanUD = cannabis use disorder, TUD = tobacco use disorder, OUD = opioid use disorder, BD = bipolar disorder, SCZ = schizophrenia, MDD = major depressive disorder, ANX = anxiety, GAD-2 = 2-item GAD questionnaire.
Figure 3.
Figure 3.. Manhattan plots for common factors.
The substance use disorders factor GWAS identified 143 lead SNPs, the psychotic disorders factor identified 162 lead SNPs, and the mood/anxiety disorders factor identified 112 lead SNPs. The lead SNPs for loci that were not significant in the input GWAS are annotated with yellow diamonds, and lead SNPs for loci not previously significantly associated with phenotypes related to the common factor (i.e., novel) are annotated with green diamonds.
Figure 4.
Figure 4.. Hudson plots and genetic correlations of GWAS-by-subtraction models.
The left panel presents Hudson plots of the GWAS-by-subtraction model results with the mapped gene for lead SNPs annotated. The right panel presents the genetic correlation results. Independent GWAS refers to the influences on a disorder that do not operate through the common factor, while the Common GWAS refers to influences on the disorder that do operate through the common factor.
Figure 5.
Figure 5.. Genetic correlations for second-order common factors using Complex Trait Genetics Virtual Lab.
The dashed line represents the log-transformed Bonferroni-corrected p-value across the 1,437 traits included in the analysis.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Hunt G.E., Malhi G.S., Lai H.M.X. & Cleary M. Prevalence of comorbid substance use in major depressive disorder in community and clinical settings, 1990–2019: Systematic review and meta-analysis. Journal of Affective Disorders 266, 288–304 (2020). - PubMed
    1. Lai H.M.X., Cleary M., Sitharthan T. & Hunt G.E. Prevalence of comorbid substance use, anxiety and mood disorders in epidemiological surveys, 1990–2014: A systematic review and meta-analysis. Drug and Alcohol Dependence 154, 1–13 (2015). - PubMed
    1. Hunt G.E., Malhi G.S., Cleary M., Lai H.M.X. & Sitharthan T. Comorbidity of bipolar and substance use disorders in national surveys of general populations, 1990–2015: Systematic review and meta-analysis. Journal of Affective Disorders 206, 321–330 (2016). - PubMed
    1. European Monitoring Centre for Drugs and Drug Addiction, Domingo-Salvany A., Torrens M. & Mestre-Pintó J. Comorbidity of substance use and mental disorders in Europe, (Publications Office, 2015).
    1. Hunt G.E., Large M.M., Cleary M., Lai H.M.X. & Saunders J.B. Prevalence of comorbid substance use in schizophrenia spectrum disorders in community and clinical settings, 1990–2017: Systematic review and meta-analysis. Drug and Alcohol Dependence 191, 234–258 (2018). - PubMed

Publication types