Fine-mapping genomic loci refines bipolar disorder risk genes

Area of Science:

• Genetics and Genomics
• Neuroscience
• Psychiatry

Background:

• Bipolar disorder (BD) is a heritable mental illness with a complex genetic basis.
• Previous genome-wide association studies identified 64 BD risk loci, but causal single nucleotide polymorphisms (SNPs) and genes remain unknown.

Purpose of the Study:

• To identify causal SNPs and genes associated with bipolar disorder within known risk loci.
• To investigate the functional consequences of these genetic variants in the brain.
• To improve polygenic risk score performance for bipolar disorder.

Main Methods:

• Applied statistical and functional fine-mapping methods to 64 BD risk loci.
• Integrated variant annotations, brain cell-type epigenomic data, and quantitative trait loci (eQTLs).
• Utilized rare variant exome sequencing data and a high-throughput fine-mapping pipeline.

Main Results:

• Prioritized 17 likely causal SNPs for bipolar disorder.
• Mapped SNPs to genes involved in neurotransmission and neurodevelopment (e.g., SCN2A, TRANK1, SYNE1).
• Demonstrated that fine-mapping improves polygenic risk score performance across diverse populations.

Conclusions:

• Identified novel candidate genes and SNPs implicated in bipolar disorder pathogenesis.
• These findings provide targets for functional studies to elucidate biological mechanisms.
• The developed fine-mapping pipeline can accelerate genetic discovery in complex diseases.