Integrating Long-Read Structural Variant Analysis with single-nucleus RNA-seq to Elucidate Gene Expression Effects in Disease

Long-read whole-genome sequencing of 100 post-mortem Parkinson’s disease brain samples enabled a high-confidence catalog of 74,552 structural variants linked to gene expression in specific cell types.

• Why it matters: Short-read limits have left how structural variants affect cell types in complex brain diseases largely unclear, especially for Parkinson’s disease.
• What they did: The team generated long-read WGS for 100 samples, built a catalog of 74,552 SVs, and integrated single-nucleus RNA-seq from two brain regions to test SVs near cis-regulated genes nominated as PD GWAS targets.
• The result: Expression quantitative trait locus and allele-specific expression analyses identified SVs significantly associated with expression in particular cell types and also effects shared across cell types, supporting cell type-resolved discovery of disease-relevant SVs.

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