Allele-specific splicing modulates protein isoforms and Alzheimer's risk

Area of Science:

• Neurogenetics
• Molecular Biology
• Genomics

Background:

• Genetic variation's functional impact is largely unknown, especially concerning alternative splicing in the human brain.
• Alternative splicing is a key post-transcriptional regulation mechanism influencing gene expression and protein diversity.

Purpose of the Study:

• To systematically map allele-specific alternative splicing (ASAS) events in human postmortem brain tissues.
• To identify functional single nucleotide polymorphisms (SNPs) associated with ASAS and explore their links to complex traits and diseases.

Main Methods:

• Systematic mapping of ASAS events in four brain regions using postmortem brain tissues.
• Concordance-based nomination of functional SNPs associated with ASAS, integrating data from splicing QTLs, RNA-binding protein sites, and GWAS loci.
• Analysis of ASAS event enrichment in specific gene sets (e.g., mitochondrial function) and genomic regions (e.g., 5' UTRs).

Main Results:

• Hundreds of genetically regulated ASAS events identified across four brain regions.
• Over 500 putative functional SNPs nominated, many overlapping with sQTLs, RNA-binding protein sites, and GWAS loci for Alzheimer's disease (AD), brain traits, and immune phenotypes.
• ASAS events enriched in mitochondrial genes and 5' UTRs, linked to translation and proteome complexity; disease-specific splicing patterns observed in AD brains.

Conclusions:

• ASAS analysis provides a brain-specific map of regulatory variation, crucial for interpreting noncoding variants.
• Identified novel mechanisms linking genetic variation to transcript and protein changes, particularly relevant for Alzheimer's disease.
• Highlights the importance of ASAS for understanding genetic contributions to complex human disorders.