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

Area of Science:

• Genetics
• Psychiatry
• Genomic Epidemiology

Background:

• Substance use disorders (SUDs) and psychiatric disorders share complex genetic etiologies.
• Understanding both common (transdiagnostic) and independent genetic risk factors is crucial for dissecting these relationships.

Purpose of the Study:

• To investigate transdiagnostic and disorder-specific genetic factors for SUDs, psychotic, mood, and anxiety disorders.
• To identify novel genetic variants and their associations with psychiatric and medical phenotypes across different ancestries.

Main Methods:

• Applied genomic structural equation modeling and genome-wide association studies (GWAS) in European (EUR) and African (AFR) ancestry individuals.
• Utilized second-order GWAS and phenome-wide association studies (PheWAS) to identify shared and independent genetic effects.

Main Results:

• Identified significant transdiagnostic genetic factors for SUDs, psychotic, and mood/anxiety disorders in EUR individuals, including novel SNPs linked to mood/anxiety disorders.
• Discovered a novel lead SNP for SUDs in AFR individuals and identified 12 additional SNPs associated with the overlap between SUDs and psychiatric disorders in EUR individuals.
• Demonstrated distinct associations of independent genetic components with behavioral and medical phenotypes, highlighting disorder-specific genetic influences.

Conclusions:

• Combining transdiagnostic and disorder-level genetic analyses enhances the understanding of etiological overlap in psychiatric disorders.
• This approach improves the specificity of genetic discovery, crucial for conditions with significant symptom and etiological overlap.