Knockoff-Based Fine Mapping of MS-Associated SNPs in Sardinian Trios

Area of Science:

• Genetics
• Immunology
• Neuroscience

Background:

• Genetic predisposition is crucial in complex diseases like multiple sclerosis (MS).
• Identifying specific genetic variants for MS susceptibility is challenging.
• The Sardinian population offers unique genetic characteristics for studying MS.

Purpose of the Study:

• To identify genetic variants associated with multiple sclerosis susceptibility using a family-based fine mapping approach.
• To leverage the unique genetic landscape of the Sardinian population for enhanced detection of genetic signals.
• To investigate the functional implications of identified variants through expression and trait analyses.

Main Methods:

• A family-based fine mapping approach was applied to 142 Sardinian trios.
• Genotype imputation identified 2537 variants within a targeted genomic region including ASIC2.
• The knockoff Trio method was used to analyze variants for association with MS susceptibility.

Main Results:

• The variant rs756787 (MYO1D 3'UTR) was associated with increased MS risk (OR 1.57, p=0.02).
• The variant rs56175840 (ASIC2 intronic) showed a protective effect against MS (OR 0.17, p=0.02).
• Expression and trait analyses linked rs756787 to genes involved in neurodegeneration and Epstein-Barr virus response.

Conclusions:

• Knockoff-based fine mapping in family datasets is effective for identifying MS genetic risk factors.
• The identified variants in MYO1D and ASIC2 contribute to understanding MS pathogenesis.
• Integrating genetic data with expression and trait information provides insights into disease mechanisms.