Precise and Cost-Effective Nanopore Sequencing for Post-GWAS Fine-Mapping and Causal Variant Identification

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Genome-wide association studies (GWAS) identify genetic loci associated with traits but require fine-mapping to pinpoint causal variants.
• Current fine-mapping methods, primarily imputation, have limitations in accuracy and comprehensiveness.
• Accurate identification of causal variants is crucial for understanding disease mechanisms and developing targeted therapies.

Purpose of the Study:

• To develop and validate a precise, cost-effective Nanopore sequencing pipeline for post-GWAS fine-mapping.
• To identify potential causal single-nucleotide polymorphisms (SNPs) at candidate loci with high accuracy.
• To demonstrate the utility of Nanopore sequencing for fine-mapping GWAS findings.

Main Methods:

• Development of a Nanopore sequencing-based pipeline for targeted sequencing of candidate loci.
• Application of the pipeline to fine-map a GWAS positive hit associated with doxorubicin-induced cardiotoxicity.
• Comparative analysis of Nanopore sequencing data with traditional imputation methods.

Main Results:

• The Nanopore sequencing pipeline provides comprehensive and accurate genetic information at candidate loci.
• The method successfully fine-mapped a GWAS hit, identifying a potential causal synonymous SNP.
• The pipeline demonstrated a minimal cost of approximately $10/100 kb/sample.

Conclusions:

• Nanopore sequencing offers a precise and cost-effective alternative for post-GWAS fine-mapping.
• This approach enables accurate identification of potential causal SNPs, advancing genetic research.
• The study provides a proof of principle for Nanopore sequencing in fine-mapping complex trait loci.