Fine-mapping genomic loci refines bipolar disorder risk genes

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

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

Purpose of the Study:

• To fine-map bipolar disorder risk loci to identify causal SNPs and associated genes.
• To investigate the functional consequences of these genetic variants in the brain.
• To improve polygenic risk score performance using fine-mapped effect sizes.

Main Methods:

• Applied statistical and functional fine-mapping methods to 64 bipolar disorder risk loci.
• Integrated variant annotations, brain cell-type epigenomic data, and quantitative trait loci (QTLs).
• Utilized rare variant exome sequencing data for further investigation.

Main Results:

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

Conclusions:

• Identified specific genes and SNPs as promising candidates for understanding bipolar disorder's biological mechanisms.
• These findings offer potential targets for future functional studies and therapeutic development.
• Developed a high-throughput fine-mapping pipeline for genetic studies.