Epigenetic Element-Based Transcriptome-Wide Association Study Identifies Novel Genes for Bipolar Disorder.

Area of Science:

• Genetics
• Psychiatry
• Bioinformatics

Background:

• Genome-wide association studies (GWAS) for bipolar disorder (BD) often identify signals in non-coding regions, complicating biological interpretation.
• Transcriptome-wide association studies (TWAS) identify disease risk genes but do not account for epigenetic regulation of gene expression.

Purpose of the Study:

• To develop and apply a novel epigenetic element-based transcriptome-wide association study (ETWAS) method to identify novel genes associated with bipolar disorder.
• To integrate epigenetic features as prior information to test the effects of genetic variants on gene expression and its association with BD.

Main Methods:

• Developed and implemented an epigenetic element-based transcriptome-wide association study (ETWAS).
• Conducted ETWAS analysis on a large cohort (20,352 cases, 31,358 controls) for bipolar disorder.
• Utilized epigenetic features as prior information to link genetic variants, predicted gene expression, and BD association.

Main Results:

• Identified 44 transcriptome-wide significant hits for bipolar disorder.
• Discovered 14 conditionally independent genes, including 10 novel candidate genes like ASB16.
• Demonstrated that ETWAS identified genes explain significant heritability beyond GWAS-associated SNPs and revealed links to phenotypes like schizophrenia and depression.

Conclusions:

• ETWAS is a powerful method for identifying novel disease-associated genes by integrating genetic and epigenetic information.
• The study identified several novel candidate genes for bipolar disorder, advancing our understanding of its genetic architecture.
• ETWAS provides a robust framework for dissecting the genetic and epigenetic underpinnings of complex diseases.